Clinical trial NCT03729245
Conditions: Renal Cell Carcinoma Metastatic Renal Cell Carcinoma
Keywords: Kidney Cancer Kidney Neoplasms Renal Cancer Renal Neoplasms CD122 CD122-Biased Agonist CD122-Biased Cytokine IL-2 receptor agonist Immuno-oncology therapy NKTR-214 Nivolumab Opdivo® PD-L1 PD-1 Bempegaldesleukin IL-2 BEMPEG CD122-Preferential IL-2 pathway agonist Checkpoint inhibition Immune checkpoint inhibitor
Sponsor: Nektar Therapeutics
Start date: 2018-12-18; Completion date: 2022-10-19
Enrollment: 623 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The main purpose of this study is to compare the objective response rate (ORR) and overall survival (OS) of bempegaldesleukin (NKTR-214: BEMPEG) combined with nivolumab to that of tyrosine kinase inhibitor (TKI) monotherapy (sunitinib or cabozantinib) in IMDC intermediate- or poor-risk patients and IMDC all-risk patients with previously untreated advanced renal cell carcinoma (RCC).

Detailed description:

Arms: arm 1: Patients in Arm A will receive bempegaldesleukin in combination with nivolumab. arm 2: Patients in Arm B will receive the Investigator's choice of either one of two treatment options.
Interventions: intervention 1: bempegaldesleukin intervention 2: sunitinib intervention 3: nivolumab intervention 4: cabozantinib
Intervention descriptions: intervention 1: Specified dose on specified days intervention 2: Specified dose on specified days intervention 3: Specified dose on specified days intervention 4: Specified dose on specified days

Protocol documents:
Prot_000.pdf: 
Protocol No. 17-214-09/CA045002 Amendment 3.0 
 
bempegaldesleukin (NKTR-214) and nivolumab 
Nektar Therapeutics 
 
Page 1 of 165 
Confidential and Proprietary 
 
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Nektar Therapeutics 
CLINICAL PROTOCOL 
 
Protocol No. 
17-214-09 / CA045002 
Title: 
A Phase 3 Randomized Open Label Study to Compare NKTR-214 
Combined with Nivolumab to the Investigator's Choice of Sunitinib or 
Cabozantinib in Patients with Previously Untreated Advanced Renal 
Cell Carcinoma 
Version: 
Amendment 3.0 
Date: 
19 October 2021 
Supersedes: 
Amendment 2.0, 03 February 2020 
US IND No.: 
140913 
Ex US: 
Non-IND 
Eudra CT No.: 
Not applicable 
Investigational Product: 
Bempegaldesleukin (NKTR-214) in combination with nivolumab 
Indication: 
Treatment of advanced renal cell carcinoma 
Sponsor: 
Nektar Therapeutics 
455 Mission Bay Boulevard South 
San Francisco, CA 94158 USA 
Sponsor’s Medical Contact and Study 
Medical Monitor: 
  
 
 
  
 
  
 
CONFIDENTIALITY STATEMENT 
The confidential information in this document is provided to you as an Investigator or consultant for review by 
you, your staff, and the applicable Institutional Review Board/Independent Ethics Committee and applicable 
Regulatory Authorities. Your acceptance of this document constitutes agreement that you will not disclose the 
information herein to others without written authorization from Nektar Therapeutics except to the extent 
necessary to obtain informed consent from persons who participate as patients in this study. 
 


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PRINCIPAL INVESTIGATOR COMMITMENT 
Protocol No. 
17-214-09 / CA045002 
Title: 
A Phase 3 Randomized Open Label Study to Compare NKTR-214 
Combined with Nivolumab to the Investigator's Choice of Sunitinib or 
Cabozantinib in Patients with Previously Untreated Advanced Renal Cell 
Carcinoma 
Version, Date: 
Amendment 3.0, 19 October 2021 
Sponsor: 
Nektar Therapeutics 
455 Mission Bay Boulevard South 
San Francisco, CA 94158 USA 
 
I, the undersigned Principal Investigator, submit this statement of commitment as evidence that I 
understand my responsibilities pursuant to the Code of Federal Regulations (21 CFR § 312) and 
ICH E6 Good Clinical Practice guidelines, as well as with any and all applicable federal, state 
and/or local laws and regulations, and agree to conduct the study in accordance with the protocol 
referenced herein. 
 
 
 
Principal Investigator 
 
 
Printed Name: 
 
 
Institution: 
 
 
Address: 
 




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LIST OF STUDY CONTACTS 
Study Contact 
Name 
Contact Information 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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TABLE OF CONTENTS 
PRINCIPAL INVESTIGATOR COMMITMENT ....................................................................2 
PROTOCOL APPROVAL PAGE ...............................................................................................3 
LIST OF STUDY CONTACTS ....................................................................................................4 
1.0 
STUDY SYNOPSIS .........................................................................................................17 
1.1 
Study Schematic.....................................................................................................23 
1.2 
Schedule of Events .................................................................................................24 
2.0 
INTRODUCTION............................................................................................................42 
2.1 
Study Rationale ......................................................................................................42 
2.1.1 
Research Hypothesis .............................................................................42 
2.2 
Background ............................................................................................................42 
2.2.1 
Renal Cell Carcinoma - Epidemiology .................................................42 
2.2.2 
Current Treatment .................................................................................43 
2.2.3 
NKTR-214 Mechanism of Action .........................................................44 
2.2.4 
Study 15-214-01 (EXCEL; NKTR-214 Monotherapy) ........................45 
2.2.5 
Nivolumab Mechanism of Action .........................................................47 
2.3 
Benefit/Risk Assessment .......................................................................................48 
2.3.1 
Nivolumab in Renal Cell Carcinoma ....................................................48 
2.3.2 
Observed Events of Cerebrovascular Accident ....................................50 
2.3.2.1 
Initial Analysis of Cerebrovascular Accident Events in Study 
16-214-02 (PIVOT-02) ..................................................................50 
2.3.2.2 
Updated Analysis of CVA Events Observed with NKTR-214 ......51 
2.3.3 
Mitigation Measures..............................................................................51 
2.3.4 
Nivolumab and NKTR-214 in Renal Cell Carcinoma ..........................52 
2.3.5 
NKTR-214 Safety Profile .....................................................................52 
2.3.6 
Nivolumab Safety Profile ......................................................................52 
2.3.7 
NKTR-214 and Nivolumab Benefit and Risk Assessment ...................53 
2.4 
Scientific Rationale for Study Design ....................................................................54 
2.4.1 
Sunitinib in Renal Cell Carcinoma .......................................................54 
2.4.2 
Cabozantinib in Renal Cell Carcinoma .................................................54 
2.4.3 
Rationale for the Combination of NKTR-214 and Immune 
Checkpoint Inhibitors ............................................................................55 
2.4.4 
Rationale for the Comparator ................................................................56 
2.4.5 
Rationale for Endpoints ........................................................................56 
2.4.6 
Rationale for Open-Label Design .........................................................57 
2.4.7 
Rationale for Stratification by IMDC Prognostic Score and TKI 
Choice ...................................................................................................57 


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2.4.8 
Duration of Treatment for NKTR-214 Combined with Nivolumab .....57 
2.5 
Justification for Dose .............................................................................................59 
2.5.1 
Justification for Dose of NKTR-214 .....................................................59 
2.5.2 
Justification for Dose of Nivolumab .....................................................59 
3.0 
STUDY OBJECTIVES ....................................................................................................61 
3.1 
Primary Objectives .................................................................................................61 
3.2 
Secondary Objectives .............................................................................................61 
 
 
4.0 
SELECTION OF STUDY POPULATION ...................................................................63 
4.1 
Inclusion Criteria ...................................................................................................63 
4.2 
Exclusion Criteria ..................................................................................................66 
5.0 
INVESTIGATIONAL PLAN .........................................................................................69 
5.1 
Study Design ..........................................................................................................69 
5.2 
Screening Period ....................................................................................................70 
5.3 
Screening Failure ...................................................................................................70 
5.4 
Treatment Period ....................................................................................................70 
5.4.1 
Administration of Study Drug ...............................................................71 
5.4.1.1 
NKTR-214 Dosing .........................................................................71 
5.4.1.2 
Nivolumab Dosing .........................................................................72 
5.4.1.3 
Sunitinib and Cabozantinib Dosing ...............................................73 
5.4.2 
Monitoring Vital Signs and Hydration Guidelines ...............................73 
5.4.2.1 
Frequent Vital Signs ......................................................................73 
5.4.2.2 
Hydration Guidelines for Arm A ...................................................73 
5.4.3 
Duration of Treatment ...........................................................................74 
5.4.4 
Treatment Beyond Progression .............................................................75 
5.5 
Discontinuation from Study Treatment .................................................................76 
5.6 
Long-Term Follow-Up...........................................................................................76 
5.6.1 
Safety Follow Up ..................................................................................76 
5.6.2 
Survival Follow Up ...............................................................................77 
5.7 
End of Study ..........................................................................................................77 
5.8 
Tumor and Radiographic Assessments ..................................................................77 
5.9 
Pharmacokinetic, Biomarker, 
 Measurements ......................78 
5.9.1 
Pharmacokinetics ..................................................................................80 
 
 
5.10 
Biomarkers .............................................................................................................81 
5.10.1 
Tumor Tissue Biopsy Collection ..........................................................81 


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5.10.4 
Sample Collection and Storage .............................................................83 
5.11 
Medical Resource Utilization and Health Economics ...........................................83 
5.12 
Health-Related Quality of Life (HRQoL) ..............................................................84 
5.13 
Dosage Modification ..............................................................................................84 
5.13.1 
NKTR-214 Dose-Delay and Reduction Criteria ...................................85 
5.13.2 
Nivolumab Dose-Delay and Reduction Criteria ...................................85 
5.13.3 
Dose-Modification Criteria for NKTR-214 and Nivolumab for 
Cycle 1 ALT/AST Elevations ...............................................................86 
5.13.4 
Monitoring and Management of Elevated Hepatic Transaminases ......87 
5.13.5 
Monitoring and Management of Adrenal Insufficiency and 
Hypophysitis .........................................................................................88 
5.13.6 
Monitoring and Management of Eosinophilia ......................................88 
5.13.6.1 
NKTR-214-induced Eosinophilia ..................................................88 
5.13.6.2 
Eosinophilic Disorders ...................................................................88 
5.13.7 
Criteria to Resume NKTR-214 and/or Nivolumab ...............................88 
5.13.8 
Management Algorithms for Immune-Mediated AEs and Cytokine 
Release Syndrome .................................................................................89 
5.13.8.1 
Management Algorithms for Immune-Mediated AEs 
Associated with Immuno-Oncology Agents ..................................89 
5.13.8.2 
Cytokine Release Syndrome ..........................................................90 
5.13.9 
Treatment of NKTR-214 or Nivolumab-Related Infusion Reactions ...90 
5.13.10 
Sunitinib or Cabozantinib Dosing-Delay Criteria .................................92 
5.13.11 
Criteria to Resume Sunitinib or Cabozantinib ......................................93 
5.13.12 
Sunitinib or Cabozantinib Dose Reduction and Escalation ..................94 
5.13.12.1 
Sunitinib .........................................................................................94 
5.13.12.2 
Cabozantinib ..................................................................................95 
5.13.12.3 
For Patients Who Start Taking a Concomitant Strong CYP3A4 
Inhibitor .........................................................................................96 
5.14 
Discontinuation Criteria .........................................................................................96 
5.14.1 
Discontinuation from Study Treatment .................................................96 
5.14.1.1 
NKTR-214 Combined with Nivolumab Discontinuation 
Criteria ...........................................................................................97 
5.14.1.2 
Sunitinib Discontinuation Criteria ...............................................100 
5.14.1.3 
Cabozantinib Discontinuation Criteria ........................................101 
5.15 
Prior and Concomitant Medications ....................................................................102 


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5.15.1 
Premedication ......................................................................................102 
5.15.2 
Permitted Concomitant Treatment ......................................................102 
5.15.2.1 
Steroids ........................................................................................102 
5.15.2.2 
Prophylaxis ..................................................................................103 
5.15.2.3 
Palliative and Supportive Care .....................................................103 
5.15.3 
Prohibited and/or Restricted Concomitant Medications .....................103 
5.15.3.1 
Prohibited Medications ................................................................103 
5.15.3.2 
Blood Pressure Medications ........................................................104 
5.15.3.3 
Anticoagulation ............................................................................104 
5.15.3.4 
Cytochrome P450 Potential Drug Interactions ............................105 
5.15.3.5 
Effect of NKTR-214 on PK of Concomitant Medications ..........105 
5.15.3.5.1 
Potential Interaction of NKTR-214 and Warfarin .......................105 
5.16 
Adverse Events ....................................................................................................105 
5.17 
Treatment Assignment and Patient Number Assignment ....................................106 
6.0 
INVESTIGATIONAL PRODUCT(S)/STUDY DRUGS ............................................107 
6.1 
NKTR-214 ...........................................................................................................107 
6.1.1 
Drug Description and Formulation .....................................................107 
6.1.2 
Drug Packaging and Labeling .............................................................107 
6.1.3 
Drug Reconstitution and Handling......................................................108 
6.1.4 
Drug Storage .......................................................................................108 
6.1.5 
Drug Shipment ....................................................................................108 
6.2 
Nivolumab, Sunitinib, and Cabozantinib Formulation, Preparation, Storage, 
and Packaging ......................................................................................................108 
6.3 
Study Drug Accountability and Reconciliation ...................................................108 
7.0 
ASSESSMENT OF EFFICACY ...................................................................................110 
7.1 
Imaging Assessments for the Study .....................................................................110 
7.2 
Methods of Measurement ....................................................................................110 
7.3 
Imaging and Clinical Assessment ........................................................................112 
7.4 
Central Imaging ...................................................................................................112 
7.5 
Additional Imaging Assessments for the Study ...................................................112 
7.6 
Patient-Reported Outcomes .................................................................................113 
7.6.1 
FKSI-19 ...............................................................................................113 
7.6.2 
EQ-5D-3L ...........................................................................................113 
7.6.3 
PRO-CTCAE ......................................................................................114 
8.0 
ASSESSMENT OF SAFETY ........................................................................................115 
8.1 
AE Definition and Assessment ............................................................................115 


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8.2 
Monitoring AEs ...................................................................................................115 
8.3 
Grading of AEs ....................................................................................................116 
8.4 
Causality Relationship of AEs .............................................................................116 
8.5 
AE Reporting and Follow-up ...............................................................................117 
8.6 
Serious AE Definition ..........................................................................................117 
8.7 
Serious AE Reporting ..........................................................................................118 
8.8 
Serious AE Follow-up..........................................................................................119 
8.9 
Disease Progression and Death Due to Disease Progression – Not Reportable 
as an AE/SAE ......................................................................................................119 
8.10 
Immune-mediated Adverse Events and Other Monitored Events .......................120 
8.11 
Adverse Events of Special Interest ......................................................................120 
8.12 
Pregnancy Tests/Pregnancy .................................................................................120 
8.12.1 
Pregnancy Tests ..................................................................................120 
8.12.2 
Pregnancy ............................................................................................120 
8.12.2.1 
Pregnancies in Female Patients ....................................................120 
8.12.2.2 
Pregnancies in Female Partners of Male Patients ........................121 
8.13 
Potential Drug-Induced Liver Injury ...................................................................121 
8.14 
Emergency Medical Support and Patient Card ....................................................122 
8.15 
Clinical Laboratory Tests .....................................................................................122 
8.16 
Physical Examinations .........................................................................................123 
8.17 
Vital Signs ............................................................................................................123 
8.18 
Electrocardiograms ..............................................................................................123 
8.19 
Echocardiograms..................................................................................................123 
9.0 
STATISTICAL PLAN ...................................................................................................125 
9.1 
General Considerations ........................................................................................125 
9.2 
Determination of Sample Size .............................................................................125 
9.2.1 
Sample Size Justification for ORR .....................................................126 
9.2.2 
Sample Size Justification for OS ........................................................126 
9.3 
Analysis Sets ........................................................................................................129 
9.4 
Demographics and Baseline Characteristics ........................................................129 
9.5 
Efficacy Analyses ................................................................................................130 
9.6 
Safety Analyses ....................................................................................................132 
9.7 
Interim and Final Analyses ..................................................................................132 
 
 
 
 
 
 




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LIST OF APPENDICES 
Appendix 1: 
INTERNATIONAL METASTATIC RCC DATABASE 
CONSORTIUM (IMDC) PROGNOSTIC CRITERIA ...........................147 
Appendix 2: 
PERFORMANCE STATUS CRITERIA ................................................148 
Appendix 3: 
CLINICAL LABORATORY TESTS ......................................................149 
Appendix 4: 
WOMEN OF CHILDBEARING POTENTIAL, DEFINITIONS AND 
METHODS OF CONTRACEPTION ......................................................150 
Appendix 5: 
CORTICOSTEROID DOSE EQUIVALENTS .......................................153 
Appendix 6: 
CEREBROVASCULAR ACCIDENT ADVERSE EVENT 
MANAGEMENT ALGORITHM (ARM A AND ARM B)....................154 
Appendix 7: 
CYTOKINE RELEASE SYNDROME MANAGEMENT 
ALGORITHM..........................................................................................155 
Appendix 8: 
INDUCERS AND STRONG INHIBITORS OF CYP3A4 .....................156 
Appendix 9: 
RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
GUIDELINES (VERSION 1.1) WITH BRISTOL-MEYERS SQUIBB 
MODIFICATIONS ..................................................................................157 
 


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ABBREVIATIONS 
Abbreviation or Term 
Definition 
ACE 
angiotensin-converting-enzyme 
ADA 
anti-drug antibodies 
AE 
adverse event 
AEC 
absolute eosinophil count 
AESI 
adverse event of special interest 
AJCC 
American Joint Committee on Cancer 
ALT (SGPT) 
alanine aminotransferase (serum glutamic pyruvic transaminase) 
ANC 
absolute neutrophil count 
AST (SGOT) 
aspartate aminotransferase (serum glutamic oxaloacetic transaminase) 
bempegaldesleukin 
International Nonproprietary Name (INN) for NKTR-214 
BICR 
blinded independent central review 
BTLA 
B- and T-lymphocyte attenuator 
Cavgss 
simulated steady state average concentration 
CBR 
clinical benefit rate 
CFR 
Code of Federal Regulations 
CHF 
congestive heart failure 
CI    
confidence interval 
CMH 
Cochran-Mantel Haenszel 
CMV 
cytomegalovirus 
CNS 
central nervous system 
CR 
complete response 
CRF 
case report form 
CRS 
cytokine release syndrome 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTLA-4 
cytotoxic T lymphocyte-associated protein 4 
CVA 
cerebrovascular accident 
CYP3A4 
cytochrome P450 3A4 
D5W 
dextrose 5% in water for injection  
DCI 
data collection instrument(s) 
DILI 
drug-induced liver injury 


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Abbreviation or Term 
Definition 
DMC 
Data Monitoring Committee 
DOAC 
direct oral anticoagulation 
DOR 
duration of response 
DRS 
disease-related symptoms 
DVT 
deep vein thrombosis 
DWI 
diffusion-weighted imaging 
ECG 
electrocardiogram 
ECLA 
electrochemiluminescence assays 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EQ-5D-3L 
3-level version of the EuroQol Group’s EQ-5D 
EU 
European Union 
FACT 
Functional Assessment of Cancer Therapy 
FDA 
Food and Drug Administration 
FDG-PET 
fluorodeoxyglucose-positron emission tomography 
FFPE 
formalin-fixed paraffin-embedded 
FKSI-19 
Functional Assessment of Cancer Therapy (FACT) Symptom Index for Kidney Cancer  
FSH 
follicle-stimulating hormone 
g 
gram 
GCP 
Good Clinical Practice 
GI 
gastrointestinal 
HBsAg 
hepatitis B surface antigen 
hCG 
human chorionic gonadotropin 
HCRU 
health care resource utilization 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
HR 
hazard ratio 
HRQoL 
health-related quality of life 
ICF 
informed consent form 
ICH 
International Council for Harmonisation (of Technical Requirements for 
Pharmaceuticals for Human Use) 
ICOS 
inducible T-cell co-stimulator  


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Abbreviation or Term 
Definition 
IEC 
independent ethics committee 
IFN-α 
interferon-alpha 
IFN- γ 
interferon gamma 
IHC 
immunohistochemistry 
IL-2 
interleukin-2. For bempegaldesleukin (NKTR-214), IL-2 and rhIL-2 refer to the same 
molecule. 
IL-2Rβγ 
IL-2 receptor beta gamma  
imAE 
immune-mediated adverse event 
IMDC 
International Metastatic Renal Cell Carcinoma Database Consortium 
IND 
Investigational New Drug (application) 
INR 
international normalized ratio 
IRB 
institutional review board 
IRT 
Interactive Response Technology  
ITT 
intent-to-treat 
IV 
intravenous(ly) 
kg 
kilogram 
LDH 
lactate dehydrogenase 
LFT 
liver function test 
LMWH 
low molecular weight heparin  
LVEF 
left ventricular ejection fraction 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
milligram 
min 
minute(s) 
mL 
milliliter 
mm Hg 
millimeters of mercury 
mRECIST 
modified Response Evaluation Criteria in Solid Tumors 
MRI 
magnetic resonance imaging 
MSKCC 
Memorial Sloan-Kettering Cancer Center 
MTD 
maximum tolerated dose 
mTOR 
mammalian target of rapamycin 
MUGA 
multigated acquisition  
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 


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Abbreviation or Term 
Definition 
NE 
not evaluable 
NK 
natural killer 
NSCLC 
non-small cell lung cancer 
NYHA 
New York Heart Association 
ORR 
objective response rate  
OS 
overall survival 
OTC 
over-the-counter 
PD 
progressive disease 
PD-1 
programmed cell death protein 1 
PD-L1 
programmed cell death ligand 1 
PE 
pulmonary embolism 
PEG 
polyethylene glycol 
PET 
positron emission tomography 
PFS 
progression-free survival 
PFS2 
PFS after the next line of treatment 
PK 
pharmacokinetic(s) 
po  
orally 
PPK 
population pharmacokinetic 
PR 
partial response  
PRO-CTCAE 
Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse 
Events 
q2w 
every 2 weeks 
q3w 
every 3 weeks 
QTcF 
Fridericia’s corrected QT interval 
R&D 
Research and Development 
RCC 
renal cell carcinoma 
RECIST 
Response Evaluation Criteria in Solid Tumors 
rhIL-2 
recombinant human interleukin 2. For bempegaldesleukin (NKTR-214), IL-2 and rhIL-
2 refer to the same molecule. 
RP2D 
recommended Phase 2 dose 
SAE 
serious adverse event 
SAP 
statistical analysis plan  
sCD25 
soluble CD25 


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Abbreviation or Term 
Definition 
SD 
stable disease 
SmPC 
Summary of Product Characteristics 
SOP 
standard operating procedure 
SUSAR 
suspected unexpected serious adverse reaction 
TIA 
transient ischemic attack 
TKI 
tyrosine kinase inhibitor 
TME 
tumor microenvironment 
Treg 
regulatory T cell 
TSE 
treatment side effects 
TTR 
time to response 
UK 
United Kingdom 
ULN 
upper limit of normal 
UPCR 
urine protein creatinine ratio 
US, USA 
United States of America 
VEGF 
vascular endothelial growth factor 
VEGFR 
vascular endothelial growth factor receptor 
WBC 
white blood cell 
WOCBP 
women of childbearing potential 
 


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1.0 
STUDY SYNOPSIS 
Title of Study: 
A Phase 3 Randomized Open Label Study to Compare NKTR-214 Combined 
with Nivolumab to the Investigator's Choice of Sunitinib or Cabozantinib in 
Patients with Previously Untreated Advanced Renal Cell Carcinoma 
Sponsor: 
Nektar Therapeutics 
Name of Finished Product(s): 
NKTR-214 drug product 
Opdivo® 
Sutent® 
Cabometyx®  
Name of Active Ingredient(s): 
bempegaldesleukin (NKTR-214) drug substance 
Nivolumab (anti-PD-1) 
Sunitinib malate 
Cabozantinib (S)-malate 
Phase of Development: 
Phase 3 
Objectives: 
The primary objectives are: 
• 
To compare the objective response rate (ORR) by blinded independent 
central review (BICR) assessment using modified Response Evaluation 
Criteria in Solid Tumors (mRECIST; Appendix 9) 1.1 of NKTR-214 
combined with nivolumab to that of tyrosine kinase inhibitor (TKI) 
monotherapy (sunitinib or cabozantinib) in International Metastatic Renal 
Cell Carcinoma Database Consortium (IMDC) intermediate- or poor-risk 
patients with previously untreated advanced renal cell carcinoma (RCC) 
• 
To compare the ORR by BICR using mRECIST 1.1 of NKTR-214 
combined with nivolumab to that of TKI monotherapy (sunitinib or 
cabozantinib) in IMDC all-risk patients with previously untreated 
advanced RCC 
• 
To compare the overall survival (OS) of NKTR-214 combined with 
nivolumab to that of TKI monotherapy (sunitinib or cabozantinib) in 
IMDC intermediate- or poor-risk patients with previously untreated 
advanced RCC 
• 
To compare the OS of NKTR-214 combined with nivolumab to that of 
TKI monotherapy (sunitinib or cabozantinib) in IMDC all-risk patients 
with previously untreated advanced RCC  
The key secondary objectives are:  
• 
To compare the progression-free survival (PFS) by BICR using 
mRECIST 1.1 of NKTR-214 combined with nivolumab to TKI 
monotherapy (sunitinib or cabozantinib) in IMDC intermediate- or 
poor-risk patients with previously untreated advanced RCC 
• 
To compare the PFS by BICR using mRECIST 1.1 of NKTR-214 
combined with nivolumab to TKI monotherapy (sunitinib or cabozantinib) 
in IMDC all-risk patients with previously untreated advanced RCC 
The other secondary objectives are:  
• 
To estimate the incidence of adverse events (AEs) of NKTR-214 
combined with nivolumab versus TKI monotherapy (sunitinib or 
cabozantinib) in patients with previously untreated advanced RCC 




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Study Design: 
This is a multicenter, randomized, open label, Phase 3 study that will evaluate 
the efficacy and safety of NKTR-214 combined with nivolumab compared 
with the Investigator’s choice of a TKI, either sunitinib or cabozantinib, in 
patients with previously untreated advanced RCC. Patients will be randomized 
in a 1:1 ratio to one of the two treatment arms:  
• 
Arm A: NKTR-214 0.006 mg/kg intravenous (IV) every 3 weeks (q3w) 
combined with nivolumab 360 mg IV q3w 
• 
Arm B: The Investigator’s choice of either one of the following treatments 
o 
Sunitinib 50 mg orally (po) once daily for 4 weeks followed by 
2 weeks off  
OR 
o 
Cabozantinib 60 mg po once daily  
The treatment period of the study is divided into multiple treatment cycles with 
associated evaluations and procedures. One cycle of treatment is defined as 
6 weeks. This study is divided into a Screening period, a Treatment period, and 
a Long-Term Follow-Up period, which will continue until withdrawal of 
consent, death, loss to follow-up, or study termination by the Sponsor, 
whichever occurs first. 
Randomization will be stratified by: 
• 
The IMDC prognostic score (0 [favorable risk] vs 1-2 [intermediate risk] 
vs 3-6 [poor risk])  
• 
TKI choice (sunitinib or cabozantinib) 
The overall alpha for this study is 0.05, which is split with 0.001 to evaluate 
ORR in IMDC intermediate- or poor-risk and IMDC all-risk populations and 
0.049 to evaluate OS in IMDC intermediate- or poor-risk and IMDC all-risk 
populations. All alpha levels are two-sided. The test in IMDC all-risk 
population is gated by the one in IMDC intermediate- or poor-risk population 
for both ORR and OS. That is, ORR in IMDC all-risk population will not be 
tested unless ORR in IMDC intermediate- or poor-risk population is 
statistically significant; and similarly, OS in IMDC all-risk population will not 
be tested unless OS in IMDC intermediate- or poor-risk population is 
statistically significant. 
In addition, a fallback approach will be used to reallocate alpha from ORR to 
OS. If ORR is significant in IMDC intermediate- or poor-risk and IMDC 
all-risk populations, the alpha of 0.001 will be passed to OS. OS in IMDC 
intermediate- or poor-risk population can then be tested at 0.05 (instead of 
0.049) level. If it is significant, the alpha of 0.05 will be passed to OS in IMDC 
all-risk population.  
Key Eligibility Criteria:   
All eligibility criteria are listed in Section 4.0. 
Test Product, Dose and Mode of 
Administration:   
• 
NKTR-214 administered IV over 30 (± 5) minutes at a starting dose of 
0.006 mg/kg q3w 
• 
Nivolumab administered IV over 30 (± 5) minutes at a 360 mg flat dose 
q3w (Nivolumab administration should start at least 30 minutes after the 
end of the NKTR-214 administration). 
Comparator Product, Dose and 
Mode of Administration:   
Sunitinib 50 mg po once daily for 4 weeks followed by 2 weeks off 
OR 
Cabozantinib 60 mg po once daily 


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Biomarkers: 
For all patients: Tumor tissue will be collected during the Screening period for 
characterization of PD-L1 expression, immune system-related genes, and 
proteins and mutations in cancer-related genes. Optional tumor biopsies may 
occur on study in Cycle 1 and at disease progression. 
For Arm A only: Biomarkers will be assessed from PK blood samples 
collected on study.   
 
 
 
 
 
CVA biomarker samples 
will be obtained from patients from whom a Cycle 1 Day 1 biomarker sample 
has been collected (see Table 6, Section 5.10.3, and Appendix 6). 
Pharmacokinetic Evaluation: 
Blood samples for PK analyses will be collected from patients randomized to 
Arm A. Serial blood samples will be collected at multiple scheduled sampling 
times to measure plasma concentrations of NKTR-214 and its metabolites 
using validated method(s). Blood samples will also be collected for the 
measurement of nivolumab concentrations. Population PK will be used to 
estimate the exposure parameters. 
Efficacy Evaluation: 
The primary efficacy measurements are ORR by BICR in the IMDC 
intermediate- or poor-risk population and IMDC all-risk population, and OS in 
the IMDC intermediate- or poor-risk population and IMDC all-risk population. 
The key secondary efficacy measurements are PFS by BICR in the IMDC 
intermediate- or poor-risk population and IMDC all-risk population.  
Tumor measurements should be performed every 9 weeks (± 7 days) from 
randomization through (and inclusive of) Week 54 and then every 12 weeks 
(± 7 days). Tumor assessment schedule will be maintained regardless of dose 
delays. Tumor assessments will continue until both BICR and Investigator’s 
assessments of tumor images have determined progression.  Patients who are 
receiving study treatment beyond progression should continue scans until the 
criteria for treatment discontinuation are met and BICR-assessed progression 
has occurred. Tumor assessments are no longer required if subsequent 
anticancer therapy is started, even if the patient has not yet progressed.    
Safety Evaluation: 
Assessment of safety will be determined by an ongoing review of the 
following: 
• 
incidence of AEs, including serious AEs (SAEs) 
• 
clinical laboratory tests (blood and urine sampling) 
• 
vital signs 
• 
physical examinations 


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Statistical Methods 
General Considerations: In general, continuous data will be summarized by 
descriptive statistics, including number of patients, mean, standard deviation, 
median, minimum, and maximum. Categorical data will be summarized by the 
number and percentage of patients. 
Efficacy:  ORR is defined as the percentage of patients with a confirmed best 
overall response of complete response (CR) or partial response (PR) by 
mRECIST 1.1 (Appendix 9) per BICR. As a primary efficacy endpoint, the 
ORR in IMDC intermediate- or poor-risk and IMDC all-risk populations will 
be compared using a stratified Cochran-Mantel Haenszel (CMH) test at an 
alpha level of 0.001. The ORR difference between the two treatment arms with 
its 95% and 99.9% confidence intervals (CI) will be reported.  
Overall survival (OS) is defined as the time between the date of randomization 
and the date of death due to any cause. Patients who do not have a date of 
death will be censored on the last date for which a patient was known to be 
alive. 
As a primary efficacy endpoint, OS in IMDC intermediate- or poor-risk and 
all-risk population will be evaluated at an alpha level of 0.049. The CHW 
version of the stratified log-rank test statistic with pre-specified weights will be 
used to compare OS between the 2 treatment arms. A stratified Cox 
proportional hazards model with treatment as the single covariate will be used 
to estimate the hazard ratio and corresponding 95% CI. The Kaplan-Meier 
method will be used to further summarize OS, including Kaplan-Meier curves, 
medians with corresponding 95% CIs. The OS rates at 12 and 24 months will 
also be estimated. 
Progression-free survival is defined as the time between the date of 
randomization and the first date of documented tumor progression using 
mRECIST 1.1 per BICR or death due to any cause, whichever comes first. As 
the secondary efficacy endpoint, PFS in IMDC intermediate- or poor-risk and 
IMDC all-risk populations will be analyzed in a similar manner as OS; a 
Fleming-Harrington test will be used due to the delayed effect observed in 
another nivolumab study of patients with RCC (Motzer 2018b). 
The total planned sample size is 600 patients and it is estimated that at least 
500 IMDC intermediate- or poor-risk and approximately 100 IMDC favorable-
risk patients with previously untreated advanced RCC will be randomized into 
the two treatment arms (NKTR-214 combined with nivolumab vs TKIs) in a 
1:1 ratio. 
At an interim analysis when at least 156 OS events in IMDC intermediate- or 
poor-risk population are observed, all primary endpoints will be tested. Two 
parallel sequential tests will be conducted: (1) ORR in IMDC intermediate- or 
poor-risk and IMDC all-risk populations at α = 0.001 and (2) OS in IMDC 
intermediate- or poor-risk and IMDC all-risk populations at α = 0.01. Within 
(1), ORR in IMDC all-risk population will only be tested at 0.001 if ORR in 
IMDC intermediate- or poor-risk is statistically significant at 0.001. Within (2), 
OS in IMDC all-risk population will only be tested at 0.01 if OS in IMDC 
intermediate- or poor-risk is statistically significant at 0.01.  If OS in the IMDC 
intermediate-or poor-risk population is not statistically significant, conditional 
power will be calculated based on this population. The adaptive method in  
Liu and Hu (2016) and Mehta and Pocock (2011) will be used to determine the 
number of OS events in IMDC intermediate- or poor-risk population needed to 
target approximately 85% to 90% conditional power for the final analysis. If 
OS in IMDC intermediate- or poor-risk is statistically significant, but not in the 
IMDC all-risk population, then the conditional power will be calculated for the 
IMDC all-risk population. The adaptive method in Liu and Hu (2016), and 
Mehta and Pocock (2011) will be used to determine the number of OS events 


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in IMDC all-risk population needed to target approximately 85% to 90% 
conditional power for the final analysis. The minimum and maximum number 
of OS events in IMDC intermediate- or poor-risk population for the final 
analysis are 200 and 308, respectively.  The minimum event size is calculated 
to achieve 90% power with alpha = 0.049 (two-sided) assuming an exponential 
distribution in each treatment arm and a hazard ratio = 0.63 with median OS 
for the TKI arm of 26 months in IMDC intermediate- or poor-risk population. 
The maximum event size is determined based on the minimum clinically 
meaningful effect.  
Safety: Safety assessments will include AEs, clinical laboratory tests, vital 
signs, and physical examinations. All safety data will be summarized for the 
Safety Population using descriptive statistics by treatment arm. 
 
 


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1.1 
Study Schematic  
Figure 1: 
Study Schematic 
 
IMDC = International Metastatic Renal Cell Carcinoma Database Consortium; IV = intravenous(ly); mRECIST 1.1 = Modified Response Evaluation Criteria in Solid Tumors 
version 1.1; PD = progressive disease; PD-L1 = programmed cell death ligand 1; po = oral(ly); q12w = every 12 weeks; q3w = every 3 weeks; R = randomized; RCC = renal cell 
carcinoma; TKI = tyrosine kinase inhibitor 
a. 
Maximum treatment duration of 2 years from Cycle 1 Day 1 (Arm A only); see Section 5.4.3 for other protocol-defined reasons for treatment discontinuation. 
b. Tumor assessments will continue until both BICR and Investigator’s assessments of tumor images have determined progression. 
 


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1.2 
Schedule of Events 
Table 1: 
Screening Schedule of Events 
Procedure a 
Screening Visit 
Notes 
Eligibility Assessments  
Informed Consent 
X 
Register in Interactive Response System to obtain patient number. Must occur prior to any protocol-specific 
study assessments. 
Inclusion/Exclusion Criteria 
X 
Must be confirmed prior to randomization.  
Medical History 
X 
Assessment of signs and symptoms and all medical history, including smoking history and alcohol use  
International Metastatic RCC Database 
Consortium (IMDC) Prognostic Score 
X 
See Appendix 1. 
Tumor Sample  
X 
All patients must have tumor tissue available, preferably most recent archival sample, from a site not previously 
irradiated and with no intervening treatment between time of acquisition and randomization 
or 
A fresh pre-treatment biopsy obtained during the Screening period. 
Tissue may be from a core biopsy, punch biopsy, excisional biopsy, or surgical specimen; fine needle aspiration 
and other cytology samples are not acceptable. A formalin-fixed paraffin-embedded block or unstained slides 
sectioned from a block within 3 months prior to randomization (minimum of 8 slides, preferably 20 slides). 
 
Please refer to Section 5.10.1 for further details. 
Safety Assessments 
Full Physical Examination and Vital Signs 
X 
Height and weight 
Vital Signs: blood pressure, heart rate, temperature, and pulse oximetry 
Within 14 days from randomization. See Sections 8.16 and 8.17. 
Karnofsky Performance Status 
X 
Within 14 days from randomization. See Appendix 2. 
Concomitant Medication Use 
X 
Document all medication (including vaccine) use within 30 days prior to randomization. 
Assess within 14 days prior to randomization. 
Abbreviations used in this table appear on the final page of Table 4. 


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Table 1: 
Screening Schedule of Events (Contd)  
Procedure a 
Screening Visit 
Notes 
SAE Assessment 
X 
Collected from time of consent. See Section 8.7 for further details. 
ECG 
X 
12-lead within 14 days from randomization. See Section 8.18 for further details. 
Echocardiogram or MUGA 
X 
Left Ventricular Ejection Fraction > 45% scan test within 60 days prior to randomization required for eligibility. 
The Investigator should also evaluate patients with any significant abnormalities on echocardiogram or MUGA 
and use best clinical judgment for decisions regarding treatment on study. 
Laboratory Tests 
Clinical Laboratory Testing  
(central lab) 
X 
All laboratory assessments to be performed within 14 days prior to randomization.  
Refer to Appendix 3 for a list of required laboratory assessments and Section 8.15 for further details. 
Urinalysis 
(central lab) 
X 
All laboratory assessments to be performed within 14 days prior to randomization. If proteinuria is observed 
(UPCR ≥ 1.0 [≥ 113 mg/mmol]), measurement of 24-hour urine protein is required  
Pregnancy Test  
X 
Serum or urine test (minimum sensitivity 25 IU/L or equivalent units of hCG) in WOCBP to be performed 
within 28 days prior to randomization. 
Tumor Assessment 
Body Imaging 
X 
Contrast-enhanced CT of the chest, contrast-enhanced CT or MRI of the abdomen, pelvis, and all other known 
and suspected sites of disease within 28 days prior to randomization. See Section 7.2 if patient has 
contraindications to contrast CT or MRI. Bone scans may be collected per local standards, if clinically 
indicated. Digital photography should be performed and submitted, if clinically indicated.  
See Section 7.0 for further details. 
Brain Imaging 
X 
MRI of the brain without and with contrast is required for all patients at baseline within 28 days prior to 
randomization. See Section 7.2 if patient has contraindications to contrast MRI. See Section 7.0 for further 
details.  
Outcomes Research Assessments 
FKSI-19 
X 
Within 28 days from randomization. See Section 7.6 for further details. 
EQ-5D-3L 
X 
Within 28 days from randomization. See Section 7.6 for further details. 
a. 
Assessments that occur outside of protocol-specified windows (e.g., for holidays, travel issues, insurance issues) may be acceptable on a case-by-case basis after review by the 
Medical Monitor. 
Abbreviations used in this table appear on the final page of Table 4. 


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Table 2: 
On-Treatment Schedule of Events for Arm A 
Procedurea 
Arm A 
NKTR-214 0.006 mg/kg IV q3w and Nivolumab 360 mg IV q3w 
Cycle = 6 Weeks 
Notes 
Cycle 1 
Cycle 2 and all 
subsequent cycles 
Day 1 
Day 3 
(−1 day) 
Day 5 
(± 1 day) 
Day 8 
(−1 day) 
Day 22 
(± 3 days) 
Day 1 
(± 3 days) 
Day 22 
(± 3 days) 
Study Drug 
 
 
Randomize 
X 
 
 
 
 
 
 
 
Administer Study Drug 
X 
 
 
 
X 
X 
X 
The first dose should be administered within 5 calendar 
days following randomization. 
 
NKTR-214 0.006 mg/kg IV q3w + Nivolumab 360 mg 
IV q3w 
 
Refer to Section 5.4.1 for sequential dosing 
instructions. 
If the IV study drug administration is delayed, the 
procedures scheduled for that visit should be performed 
with the delayed visit for drug administration (does not 
apply to tumor assessments; see Body Imaging below).  
Administer IV fluids 
X 
 
 
 
X 
X 
X 
May be withheld if deemed in the best interest of the 
patient by the Investigator 
Refer to Section 5.4.2.2 for further details. 
Review hydration 
guidelines with patient  
X 
 
 
 
X 
X 
X 
Applicable only while NKTR-214 is administered 
Abbreviations used in this table appear on the final page of Table 4. 


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Table 2: 
On-Treatment Schedule of Events for Arm A (Contd) 
Procedurea 
Arm A 
NKTR-214 0.006 mg/kg IV q3w and Nivolumab 360 mg IV q3w 
Cycle = 6 Weeks 
Notes 
Cycle 1 
Cycle 2 and all 
subsequent cycles 
Day 1 
Day 3 
(−1 day) 
Day 5 
(± 1 day) 
Day 8 
(−1 day) 
Day 22 
(± 3 days) 
Day 1 
(± 3 days) 
Day 22 
(± 3 days) 
Oral Hydration 
Follow-up 
X1 
 
 
 
X1 
X2 
X2 
X1 = Between 2 and 4 days following the first 
2 administrations of NKTR-214 in Cycle 1, site personnel 
must contact the patient (by telephone or clinic visit) to 
remind the patient of the oral hydration guidelines, to 
assess for any symptomatology and compliance with the 
guidelines, and document compliance and symptoms from 
the discussion.  
X2 = For subsequent NKTR-214 administrations in Cycle 2 
and beyond, oral hydration follow-up should be conducted 
as clinically indicated between 2 and 4 days following 
NKTR-214 administration (see Section 5.4.2.2).  
Safety Assessment 
Targeted Physical 
Examination, Weight, 
Vital Signs  
X 
VW 
VW 
VW 
VW 
X 
VW 
Vital Signs: blood pressure, heart rate, temperature  
Vital signs should be monitored at the following timepoints 
relative to study drug dose administrations: 
• 
Pre-dose (NKTR-214) 
• 
Within 30 minutes after administration of nivolumab 
VW = Vital Signs and Weight only 
Karnofsky Performance 
Status 
X 
 
 
 
 
X 
 
See Appendix 2. 
Abbreviations used in this table appear on the final page of Table 4. 


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Table 2: 
On-Treatment Schedule of Events for Arm A (Contd) 
Procedurea 
Arm A 
NKTR-214 0.006 mg/kg IV q3w and Nivolumab 360 mg IV q3w 
Cycle = 6 Weeks 
Notes 
Cycle 1 
Cycle 2 and all 
subsequent cycles 
Day 1 
Day 3 
(−1 day) 
Day 5 
(± 1 day) 
Day 8 
(−1 day) 
Day 22 
(± 3 days) 
Day 1 
(± 3 days) 
Day 22 
(± 3 days) 
AE Assessments  
(including SAEs) 
Continuously 
Record at each visit. 
Refer to Section 8.2 for the timing of AE/SAE collection. 
Concomitant 
Medication Use 
Continuously 
Record at each visit. 
Laboratory Tests 
Pregnancy Test 
(WOCBP Only) 
X 
 
 
 
X 
X 
X 
Serum or urine pregnancy test (minimum sensitivity 
equivalent units 25 IU/L or equivalent units of hCG) is 
required within 24 hours prior to treatment. 
Local laboratory tests 
prior to study drug 
dosing 
X 
 
 
 
X 
X 
X 
Within 24 hours, or as soon as locally feasible, prior to 
study drug administration (See Section 8.15 and 
Appendix 3) 
Clinical Laboratory 
Testing (central lab) 
X 
 
 
X 
X 
X 
X 
Refer to Section 8.15 for further details on clinical safety 
laboratory assessments (Hematology, Chemistry, 
Coagulation, and Additional Labs). 
See Appendix 3 for a list of required laboratory 
assessments. 
Central laboratory samples must be collected within 5 days 
of administering study drug(s). If central lab results will 
not be available in time, treatment may be based on local 
lab results (see Appendix 3 for details).  All lab results 
must be assessed prior to administering study drug(s). 
Abbreviations used in this table appear on the final page of Table 4. 


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Table 2: 
On-Treatment Schedule of Events for Arm A (Contd) 
Procedurea 
Arm A 
NKTR-214 0.006 mg/kg IV q3w and Nivolumab 360 mg IV q3w 
Cycle = 6 Weeks 
Notes 
Cycle 1 
Cycle 2 and all 
subsequent cycles 
Day 1 
Day 3 
(−1 day) 
Day 5 
(± 1 day) 
Day 8 
(−1 day) 
Day 22 
(± 3 days) 
Day 1 
(± 3 days) 
Day 22 
(± 3 days) 
Urinalysis  
(central lab) 
X 
 
 
 
 
Y 
 
See Appendix 3. 
Y = Performed every 3 cycles starting with Cycle 3 
If clinically significant proteinuria (UPCR ≥ 2.0 
[≥ 227 mg/mmol] or dipstick protein ≥ 3+) is observed, 
measurement of 24-hour urine protein is required. 
Tumor Assessment 
Body Imaging 
• 
Contrast-enhanced CT of the chest, contrast-enhanced CT or MRI of the abdomen, 
pelvis, and all known and suspected sites of disease should be performed every 9 weeks 
(± 7 days) from randomization through (and inclusive of) Week 54 and then every 
12 weeks (± 7 days). See Section 7.2 if patient has contraindications to contrast CT or 
MRI. 
• 
Tumor assessment schedule is relative to the date of randomization and will be 
maintained regardless of dose delays. 
• 
Tumor assessments will continue until both BICR and Investigator’s assessments of 
tumor images have determined progression.  
• 
Patients who are receiving study treatment beyond progression should continue scans 
until the criteria for treatment discontinuation are met and BICR-assessed progression 
has occurred. 
• 
Tumor assessments are no longer required if subsequent anticancer therapy is started, 
even if the patient has not yet progressed. 
• 
Use same imaging method as was used at screening.  
• 
Bone scans may be collected per local standards, if clinically indicated. Digital 
photography should be performed and submitted, if clinically indicated. 
All study treatment decisions will be based on the 
Investigator’s assessment of tumor images. 
See Section 7.0 for further details. 
Abbreviations used in this table appear on the final page of Table 4. 


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Table 2: 
On-Treatment Schedule of Events for Arm A (Contd) 
Abbreviations used in this table appear on the final page of Table 4. 
 
Procedurea 
Arm A 
NKTR-214 0.006 mg/kg IV q3w and Nivolumab 360 mg IV q3w 
Cycle = 6 Weeks 
Notes 
Cycle 1 
Cycle 2 and all subsequent 
cycles 
Day 1 
Day 3 
(−1 day) 
Day 5 
(± 1 day) 
Day 8 
(−1 day) 
Day 22 
(± 3 days) 
Day 1 
(± 3 days) 
Day 22 
(± 3 days) 
Brain Imaging 
• 
Patients with a history of brain metastasis or neurological symptoms should have MRI with and 
without contrast. See Section 7.2 if patient has contraindications to contrast MRI.  Performed on 
same schedule as body tumor assessments, and as clinically indicated  
• 
Tumor assessments will continue until both BICR and Investigator’s assessments of tumor 
images have determined progression.  
• 
Patients who are receiving study treatment beyond progression should continue scans until the 
criteria for treatment discontinuation are met and BICR-assessed progression has occurred. 
• 
Tumor assessments are no longer required if subsequent anticancer therapy is started, even if the 
patient has not yet progressed. 
• 
Use same imaging method as was used at screening. 
All study treatment decisions will be based on 
the Investigator’s assessment of tumor images. 
See Section 7.0 for further details. 
Pharmacokinetic and Biomarker Assessments 
 
 
 
 
 
 
  
 
 
 
 
NKTR-214 PK Blood 
Samples 
X  
X  
X  
X 
X  
Z 
 
Z = Cycles 3, 6, 9, 12, and 15 only 
See Table 6 and Section 5.9 for further details. 
Nivolumab PK Blood 
Samples 
X  
 
 
 
X  
Z 
 
Z = Cycles 3, 6, 9, 12, and 15 only 
See Table 6 and Section 5.9 for further details. 
Tumor Tissue Sample 
 
 
 
 
 
 
 
Optional Cycle 1 Day 14-21 and at disease 
progression. 
See Section 5.10.1 for further details. 


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Table 2: 
On-Treatment Schedule of Events for Arm A (Contd) 
a. 
Assessments and visits that occur outside of protocol-specified windows (e.g., for holidays, travel issues, insurance issues) may be acceptable on a case-by-case basis after 
review by the Medical Monitor. 
Abbreviations used in this table appear on the final page of Table 4. 
Procedurea 
Arm A 
NKTR-214 0.006 mg/kg IV q3w and Nivolumab 360 mg IV q3w 
Cycle = 6 Weeks 
Notes 
Cycle 1 
Cycle 2 and all subsequent 
cycles 
Day 1 
Day 3 
(−1 day) 
Day 5 
(± 1 day) 
Day 8 
(−1 day) 
Day 22 
(± 3 days) 
Day 1 
(± 3 days) 
Day 22 
(± 3 days) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Outcomes Research Assessments 
EQ-5D-3L 
X 
 
 
 
X 
X 
X 
Patients should complete the assessment at the 
start of the clinic visit, prior to dosing and 
scheduled activities. 
Completed on Days 1 and 22 of every cycle 
through Cycle 4, and then on Day 1 of all 
subsequent cycles. 
See Section 7.6 for further details. 
FKSI-19 
X 
 
 
 
X 
X 
X 
PRO-CTCAE 
X 
 
 
 
X 
X 
X 
Health Care Resource 
Utilization 
X 
 
 
 
X 
X 
X 
Site staff will collect health care resource 
utilization data using the CRF. 


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Table 3: 
On-Treatment Schedule of Events for Arm B 
Procedurea 
Arm B 
Cabozantinib 60 mg PO once daily (continuously) 
OR 
Sunitinib 50 mg PO once daily (4 weeks on treatment, followed by 2 weeks off 
treatment) 
Cycle = 6 Weeks 
Notes 
Cycle 1 
Cycle 2 and subsequent 
on-treatment visits  
Day 1 
Day 8 
(−1 day) 
Day 22 
(± 3 days) 
Day 1 
(± 3 days) 
Day 22 
 (± 3 days) 
Study Drug 
 
 
 
 
 
 
Randomize 
X 
 
 
 
 
 
Dispense Study Drug 
X 
 
X 
X 
X 
The first dose should be administered within 
5 calendar days following randomization (see 
Section 5.4.1 for details). 
Cabozantinib or sunitinib study treatment and Pill 
Diary provided Day 1 of each cycle. Cabozantinib 
may also be dispensed on Day 22 of each cycle. 
Pill Diary 
X 
 
 
X 
 
 
Safety Assessments 
 
 
 
 
 
 
Targeted Physical Examination, 
Weight, Vital Signs 
X 
VW 
VW 
X 
VW 
Vital Signs: blood pressure, heart rate, temperature 
VW = Vital Signs and Weight only 
Karnofsky Performance Status 
X 
 
 
X 
 
See Appendix 2. 
AE Assessments (including 
SAEs) 
Continuously 
Record at each visit.  
See Section 8.2 for the timing of AE/SAE 
collection. 
Concomitant Medication Use 
Continuously 
Record at each visit. 
Abbreviations used in this table appear on the final page of Table 4. 


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Table 3: 
On-Treatment Schedule of Events for Arm B (Contd) 
Procedurea 
Arm B 
Cabozantinib 60 mg PO once daily (continuously) 
OR 
Sunitinib 50 mg PO once daily (4 weeks on treatment, followed by 2 weeks off 
treatment) 
Cycle = 6 Weeks 
Notes 
Cycle 1 
Cycle 2 and subsequent 
on-treatment visits  
Day 1 
Day 8 
(−1 day) 
Day 22 
(± 3 days) 
Day 1 
(± 3 days) 
Day 22 
 (± 3 days) 
Laboratory Tests 
Local laboratory tests prior to 
study drug dosing 
X 
 
X 
X 
X 
Within 24 hours, or as soon as locally feasible, 
prior to study drug administration (See 
Section 8.15 and Appendix 3) 
Clinical Laboratory Testing 
(central laboratory) 
X 
X 
X 
X 
X 
Refer to Section 8.15 for further details on clinical 
safety laboratory assessments (Hematology, 
Chemistry, Coagulation, and Additional Labs). 
See Appendix 3 for a list of required laboratory 
assessments. 
Central laboratory samples must be collected 
within 5 days before dispensing study drug. If 
central lab results will not be available in time, 
treatment decisions may be based on local lab 
results (see Appendix 3 for details). All lab results 
must be assessed prior to drug dispensation. 
Urinalysis  
(central laboratory) 
X 
 
 
Y 
 
Y = Performed every 3 cycles starting with Cycle 3  
If clinically significant proteinuria is observed 
(UPCR ≥ 2.0 [≥ 227 mg/mmol] or dipstick protein 
≥ 3+), measurement of 24-hour urine protein is 
required. 
Abbreviations used in this table appear on the final page of Table 4. 


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Table 3: 
On-Treatment Schedule of Events for Arm B (Contd) 
Procedurea 
Arm B 
Cabozantinib 60 mg PO once daily (continuously) 
OR 
Sunitinib 50 mg PO once daily (4 weeks on treatment, followed by 2 weeks off 
treatment) 
Cycle = 6 Weeks 
Notes 
Cycle 1 
Cycle 2 and subsequent 
on-treatment visits  
Day 1 
Day 8 
(−1 day) 
Day 22 
(± 3 days) 
Day 1 
(± 3 days) 
Day 22 
 (± 3 days) 
Pregnancy Test  
(WOCBP Only) 
X 
  
X 
X 
X 
Serum or urine pregnancy test (minimum sensitivity 
equivalent units 25 IU/L or equivalent units of hCG) 
is required within 24 hours before the first dose of 
study drug dispensation and before any assessments 
on Day 1 and Day 22 of each cycle. 
Tumor Assessment 
Brain Imaging 
• 
Patients with a history of brain metastasis or neurological symptoms should have 
MRI with and without contrast. See Section 7.2 if patient has contraindications to 
contrast MRI. Performed on same schedule as body tumor assessments, and as 
clinically indicated.  
• 
Tumor assessments will continue until both BICR and Investigator’s assessments of 
tumor images have determined progression.  
• 
Patients who are receiving study treatment beyond progression should continue scans 
until the criteria for treatment discontinuation are met and BICR-assessed progression 
has occurred. 
• 
Tumor assessments are no longer required if subsequent anticancer therapy is started, 
even if the patient has not yet progressed. 
• 
Use same imaging method as was used at screening. 
All study treatment decisions will be based on the 
Investigator’s assessment of tumor images. 
See Section 7.0 for further details. 
Abbreviations used in this table appear on the final page of Table 4. 


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Table 3: 
On-Treatment Schedule of Events for Arm B (Contd) 
Procedurea 
Arm B 
Cabozantinib 60 mg PO once daily (continuously) 
OR 
Sunitinib 50 mg PO once daily (4 weeks on treatment, followed by 2 weeks off 
treatment) 
Cycle = 6 Weeks 
Notes 
Cycle 1 
Cycle 2 and subsequent 
on-treatment visits  
Day 1 
Day 8 
(−1 day) 
Day 22 
(± 3 days) 
Day 1 
(± 3 days) 
Day 22 
 (± 3 days) 
Body Imaging 
• 
Contrast-enhanced CT of the chest, contrast-enhanced CT or MRI of the 
abdomen, pelvis, and all known and suspected sites of disease should be 
performed every 9 weeks (± 7 days) from randomization through (and inclusive 
of) Week 54 and then every 12 weeks (± 7 days). See Section 7.2 if patient has 
contraindications to contrast CT or MRI. 
• 
Tumor assessment schedule is relative to the date of randomization and will be 
maintained regardless of dose delays. 
• 
Tumor assessments will continue until both BICR and Investigator’s 
assessments of tumor images have determined progression. 
• 
Patients who are receiving study treatment beyond progression should continue 
scans until the criteria for treatment discontinuation are met and BICR-assessed 
progression has occurred. 
• 
Tumor assessments are no longer required if subsequent anticancer therapy is 
started, even if the patient has not yet progressed. 
• 
Use same imaging method as was used at screening.  
• 
Bone scans may be collected per local standards, if clinically indicated. Digital 
photography should be performed and submitted, if clinically indicated. 
All study treatment decisions will be based on the 
Investigator’s assessment of tumor images. 
See Section 7.0 for further details. 
Biomarker Assessments 
Tumor Tissue Sample 
 
 
 
 
 
Optional Cycle 1 Days 14-21 and at disease progression. 
See Section 5.10 for further details. 
Abbreviations used in this table appear on the final page of Table 4. 




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Table 3: 
On-Treatment Schedule of Events for Arm B (Contd) 
Procedurea 
Arm B 
Cabozantinib 60 mg PO once daily (continuously) 
OR 
Sunitinib 50 mg PO once daily (4 weeks on treatment, followed by 2 weeks off 
treatment) 
Cycle = 6 Weeks 
Notes 
Cycle 1 
Cycle 2 and subsequent 
on-treatment visits  
Day 1 
Day 8 
(−1 day) 
Day 22 
(± 3 days) 
Day 1 
(± 3 days) 
Day 22 
 (± 3 days) 
Health Care Resource Utilization 
X 
 
X 
X 
X 
Site staff will collect the health care resource 
utilization data at each visit using the CRF.  
a. 
Assessments and visits that occur outside of protocol-specified windows (e.g., for holidays, travel issues, insurance issues) may be acceptable on a case-by-case basis after 
review by the Medical Monitor. 
Abbreviations used in this table appear on the final page of Table 4. 


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Table 4: 
Long-Term Follow-Up Schedule of Events 
Procedurea 
Safety Follow-Up  
Visit 1b 
Safety Follow-Up  
Visit 2b 
Survival Follow-Upc  
Every 12 Weeks 
( 14 days) 
Notesd 
Safety Assessments 
Vital Signs  
X 
X 
 
Blood pressure, heart rate, temperature  
Weight 
AE and SAE Assessments  
X 
X 
X 
All AEs will be documented until 100 days after the last 
dose of all study drug(s). SAEs to be collected after the 
100-day safety visit if the SAE is deemed to be related or 
residual toxicities are persisting.  
Patients will be followed for drug-related toxicities until 
these toxicities resolve, return to baseline, or are deemed 
irreversible.  
Karnofsky Performance Status  
X 
X 
 
See Appendix 2. 
Review of Subsequent Medications and 
Anticancer Therapy   
X 
X 
X 
In Survival Follow-up, subsequent anticancer treatment 
only. Additional subsequent anticancer therapy details 
such as regimen, setting of the regimen, line of therapy, 
start date and end date of each regimen, best response to 
the regimen, and date of progression to subsequent 
anticancer therapies will be collected. 
Laboratory Tests 
Pregnancy Test (WOCBP only) 
X 
X 
 
Patients (WOCBP) will continue to follow instructions for 
methods of contraception through 5 months post 
treatment completion. 
Clinical Lab Testing (central laboratory) 
X 
See Notes 
 
During Safety Follow-up Visit 2 if toxicities are present. 
Refer to Section 8.15 for list of laboratory tests. 
Pharmacokinetic and Biomarker Assessments  
Nivolumab PK Blood Samples (Arm A only) 
X 
X 
 
See Section 5.9 for further details. 
Abbreviations used in this table appear on the final page of the table. 


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Table 4: 
Long-Term Follow-Up Schedule of Events (Contd) 
Procedurea 
Safety Follow-Up  
Visit 1b 
Safety Follow-Up  
Visit 2b 
Survival Follow-Upc 
Every 12 Weeks 
( 14 days) 
Notesd 
 
 
 
 
 
 
Tumor Tissue Sample 
See Section 5.10 
Optional upon disease progression 
Efficacy Assessments 
Body Imaging  
• 
Contrast-enhanced CT of the chest, contrast-enhanced CT or 
MRI of the abdomen, pelvis, and all known and suspected sites 
of disease. See Section 7.2 if patient has contraindications to 
contrast CT or MRI. 
• 
Imaging should continue every 9 weeks (± 7 days) from 
randomization through (and inclusive of) Week 54 and then 
every 12 weeks (± 7 days).  
• 
Tumor assessments will continue until both BICR and 
Investigator’s assessments of tumor images have determined 
progression.  
• 
Patients who are receiving study treatment beyond progression 
should continue scans until the criteria for treatment 
discontinuation are met and BICR-assessed progression has 
occurred. 
• 
Tumor assessments are no longer required if subsequent 
anticancer therapy is started, even if the patient has not yet 
progressed. 
• 
Use same imaging method as was used at screening.  
• 
Bone scans may be collected per local standards, if clinically 
indicated. Digital photography should be performed and 
submitted, if clinically indicated. 
All study treatment decisions will be based on the 
Investigator’s assessment of tumor images. 
See Section 7.0 for further details. 
Abbreviations used in this table appear on the final page of the table. 
 


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Table 4: 
Long-Term Follow-Up Schedule of Events (Contd) 
Procedurea 
Safety Follow-Up  
Visit 1b 
Safety Follow-Up  
Visit 2b 
Survival Follow-Upc 
Every 12 Weeks 
( 14 Days) 
Notesd 
Brain Imaging 
• 
Patients with a history of brain metastasis or neurological 
symptoms should have MRI with and without contrast. See 
Section 7.2 if patient has contraindications to contrast MRI.  
• 
Brain imaging assessments should be performed on same 
schedule as body tumor assessments, or as clinically indicated  
• 
Tumor assessments will continue until both BICR and 
Investigator’s assessments of tumor images have determined 
progression.  
• 
Patients who are receiving study treatment beyond progression 
should continue scans until the criteria for treatment 
discontinuation are met and BICR-assessed progression has 
occurred. 
• 
Tumor assessments are no longer required if subsequent 
anticancer therapy is started, even if the patient has not yet 
progressed. 
• 
Use same imaging method as was used at screening. 
All study treatment decisions will be based on the 
Investigator’s assessment of tumor images. 
See Section 7.0 for further details. 
Survival Status 
 
 
X 
Survival Follow-up can be administered in person or by 
telephone, if needed. 
Health Outcomes Assessments 
EQ-5D-3L 
X 
 
 
See Section 7.6 for further details. 
FKSI-19 
X 
 
 
PRO-CTCAE 
X 
 
 
Health Care Resource Utilization 
X 
 
 
Study site staff should collect health care resource 
utilization data using the CRF. 
AE = adverse event; BICR = blinded independent central review; CT = computed tomography; CRF = case report form; CVA = cerebrovascular accident; ECG = electrocardiogram; 
eCRF = electronic case report form; EQ-5D-3L = 3-level version of the EuroQol Group’s EQ-5D; FKSI-19 = Functional Assessment of Cancer Therapy (FACT) Symptom Index for Kidney 
Cancer; hCG = human chorionic gonadotropin; IMDC = International Metastatic RCC Database Consortium; IV = intravenous(ly); MRI = magnetic resonance imaging; 


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MUGA = multigated acquisition; PK = pharmacokinetic(s); PO = orally; PRO-CTCAE = Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events; 
q3w = every 3 weeks; RCC = renal cell carcinoma; SAE = serious adverse event; TIA = transient ischemic attack; UPCR = urine protein creatinine ratio; VW = vital signs and weight only; 
WOCBP = women of childbearing potential 
a. 
Assessments and visits that occur outside of protocol-specified windows (e.g., for holidays, travel issues, insurance issues) may be acceptable on a case-by-case basis after review by 
the Medical Monitor.  
b. 
Patients must be followed for 100 days after the last dose of study treatment. Safety Follow-Up Visit 1 should occur 30 (± 7) days from the last dose of all study drug(s), or at the time 
of permanent treatment discontinuation if discontinuation is after the Safety Follow-Up Visit 1 window. Safety Follow-Up Visit 2 occurs 100 (± 7) days from the last dose of all study 
drug(s). Safety Follow-up Visits should occur regardless of initiation of subsequent anticancer therapy. Both Safety Follow-up Visits should be conducted in person.  
c. 
Survival Follow-Up to occur every 12 weeks ( 14 days) following the Safety Follow-Up Visit 2. Survival Follow-Up may be conducted in person or by telephone. The Sponsor may 
request that survival data be collected on all treated patients outside of the 3-month specified window. At the time of this request, each patient will be contacted to determine their 
survival status unless the patient has withdrawn consent for all contact. Information about subsequent anticancer therapy will also be collected during these contacts. 
d. 
Some of the assessments referred to in this section may not be captured as data in the eCRF. They are intended to be used for safety monitoring purposes by the treating physician. 
Additional testing or assessments may be performed as clinically necessary or where required by institutional or local regulations.  


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2.0 
INTRODUCTION  
This is a Phase 3, randomized, open-label study of bempegaldesleukin (NKTR-214) combined 
with nivolumab compared with the Investigator’s choice of a tyrosine kinase inhibitor (TKI) 
therapy (either sunitinib or cabozantinib monotherapy) in previously untreated patients with 
advanced or metastatic renal cell carcinoma (advanced RCC). 
The immunogenic properties of NKTR-214 in combination with checkpoint inhibitors that target 
and inhibit the programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) 
pathway make it a potentially promising combination therapy.  The side effect profile of 
NKTR-214 does not overlap with that of checkpoint inhibitors, further supporting the use of 
NKTR-214 as a potentially complementary combination partner with checkpoint inhibitors. 
This Phase 3 study will allow direct comparison of NKTR-214 combined with nivolumab versus 
TKI therapy of Investigator’s choice (sunitinib or cabozantinib) as measured by overall survival 
(OS), objective response rate (ORR), and other clinical endpoints in treatment-naive patients 
with advanced RCC. 
2.1 
Study Rationale 
In the Phase 1/2 setting, NKTR-214 combined with nivolumab has demonstrated encouraging 
clinical activity, as measured by ORR, in multiple tumor types including RCC. Given the 
durability of responses associated with immunotherapies, NKTR-214 combined with nivolumab 
is hypothesized to lead to greater clinical benefit, as measured by ORR, progression-free survival 
(PFS), or OS, compared to tyrosine kinase inhibitors of Investigator’s choice (sunitinib or 
cabozantinib), a widely used standard-of-care agent in this patient population. This study will 
allow for direct comparison of ORR, PFS and OS between arms.  If NKTR-214 combined with 
nivolumab has an acceptable safety profile and is shown to improve ORR or OS, versus the 
tyrosine kinase inhibitors, this study may support the approval of NKTR-214 combined with 
nivolumab in patients with previously untreated advanced RCC. 
2.1.1 Research Hypothesis 
Treatment with NKTR-214 combined with nivolumab will improve ORR and OS when 
compared to sunitinib monotherapy or cabozantinib monotherapy in patients with previously 
untreated advanced RCC. 
2.2 
Background 
2.2.1 Renal Cell Carcinoma - Epidemiology 
Renal cell carcinoma (RCC) is the eighth most common cancer in the world and is increasing in 
incidence (Znaor, 2015).  Globally, RCC occurs in more than 330,000 cases with approximately 
a third of the patients succumbing to their disease.  Despite the earlier detection of smaller 
kidney tumors, the rate of RCC-related mortality has increased, suggesting that recurrence and 
advanced disease are responsible for mortality (Sun, 2011; Hollingsworth, 2006).  With the rise 


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in RCC incidence, as well as mortality and morbidity associated with advanced RCC, the 
medical need for improved treatment options in this population remains. 
Multiple scoring systems are available to characterize prognosis in treatment-naive RCC.  Two 
of the most commonly used are the Memorial Sloan-Kettering Cancer Center (MSKCC) 
prognostic scoring system and the International Metastatic RCC Database Consortium (IMDC) 
prognostic scoring system (see Appendix 1).  Each of these systems categorizes patients as 
favorable-, intermediate-, or poor-risk based on how many adverse prognostic factors are present 
(0: favorable risk, 1-2: intermediate risk, 3 or more: poor risk).  The six parameters of 
importance for IMDC prognostic score classification are Karnofsky Performance Status 
(Appendix 2), time from diagnosis to treatment, hemoglobin value, corrected calcium 
concentration, absolute neutrophil count, and platelet count.  With each system, total number of 
adverse prognostic factors present has been shown to correlate with OS. 
Approximately 25% of patients are in the favorable-risk group, 50% are in the intermediate-risk 
group, and 25% are in the poor-risk group. In an analysis of 1028 patients scored using the 
IMDC system, median OS for favorable-, intermediate-, and poor-risk patients was 43.2 months, 
22.5 months, and 7.8 months, respectively (Heng, 2013). 
2.2.2 Current Treatment 
Until 2006 in the United States (US) and European Union (EU), the cytokines interleukin-2 
(IL-2) and interferon-alpha (IFN-α) were the only active treatments for advanced RCC.  Over the 
last several years, an increased understanding of the biology of RCC has led to development of 
multiple agents that target specific growth pathways.  The vascular endothelial growth factor 
(VEGF) pathway and targeted serine/threonine protein kinase therapies that block the 
mammalian target of rapamycin (mTOR) have been found to be important targets in RCC 
disease. Global health authorities have approved multiple drugs targeting these pathways, 
including anti-VEGF agents, such as the tyrosine kinase inhibitors sunitinib, pazopanib, 
sorafenib, and cabozantinib, the anti-VEGF monoclonal antibody, bevacizumab, and mTOR 
pathway inhibitors, such as temsirolimus and everolimus (Banumathy, 2010).  
In the Phase 2 CABOSUN study, cabozantinib showed superior PFS in the intermediate/poor 
risk population compared to sunitinib, which led to regulatory approval in first-line advanced 
RCC in United States for all risk types in 2017 (Choueiri, 2017).  In 2018, cabozantinib also was 
approved for the treatment of first-line advanced RCC intermediate/poor risk population in the 
EU (Cabometyx, 2018).  CABOSUN study was not powered to show benefit in OS, which 
remains to be demonstrated against sunitinib by another TKI.  The ORR, PFS and OS data 
reported for sunitinib in favorable-risk patients had long been unchallenged and sunitinib 
remains a preferred standard of care in this population (Motzer, 2018a). 
Recent innovation of treating cancer with immunotherapies has also expanded treatment options. 
Nivolumab, an anti-PD-1 antibody, given as monotherapy or in combination with the 
anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibody, ipilimumab, has 


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demonstrated clinical activity in multiple tumor types, including RCC.  Recently in the Phase 3 
CA209214 study, nivolumab in combination with ipilimumab showed superior clinical efficacy, 
ORR and OS along with a positive trend in PFS compared to sunitinib in patients with previously 
untreated intermediate/poor risk advanced RCCs and is the new standard of care in this patient 
population (Motzer, 2018b).  The nivolumab/ipilimumab combination received Food and Drug 
Administration (FDA) approval in the US in April 2018 and European Medicines Agency 
approval in the EU in November 2018; health authority submissions in other countries are 
underway.  Most recently, the combination of pembrolizumab (an anti-PD-1 antibody) and 
another TKI, axitinib, demonstrated statistically significant OS and PFS improvement over 
sunitinib in all risk groups of patients with previously untreated advanced RCC (Rini, 2019), and 
the combination of avelumab (an anti-PD-L1 antibody) with axitinib also demonstrated 
statistically significant PFS improvement over sunitinib (Motzer, 2019).  These data led to FDA 
approval of these combinations in the US in April 2019 and May 2019, respectively. Although 
combinations of more than one checkpoint inhibitor and combinations of checkpoint inhibitors 
with TKIs significantly improved clinical outcome, the potential for long-term disease control 
may be improved with combination immune-oncology agents. If tolerable toxicity, this may 
prove a preferred option in patients with first-line RCC.  
According to the most recent National Comprehensive Cancer Network (NCCN) guidelines there 
are several recommended treatment options for first-line, advanced RCC (NCCN, 2019).  These 
include TKIs (sunitinib, cabozantinib [intermediate- and poor-risk patients], pazopanib, axitinib, 
and temsirolimus [poor prognosis patients only]), nivolumab in combination with ipilimumab 
(intermediate- and poor-risk patients), and axitinib in combination with pembolizumab. 
High-dose IL-2 is also a choice for select patients.  Given the global availability of sunitinib for 
this international clinical trial and the countries included in this trial, sunitinib was selected for 
the control arm of this trial.  At the time of the trial conception, cabozantinib is available in the 
US and EU for intermediate- and poor-risk patients, having shown improved PFS in a 
randomized clinical trial involving 157 patients.  Pazopanib (available in the US, EU, United 
Kingdom [UK], and Australia) did not show improved PFS or OS when compared to sunitinib 
(Motzer, 2013; Motzer, 2014).  Given the complexity of global supply (to supply 3 versus 
2 agents for the control arm) and the limited availability of pazopanib, a decision was made to 
prioritize the selection of sunitinib and cabozantinib, which remain among the preferred 
monotherapy TKI options in the targeted advanced RCC patient population.      
2.2.3 NKTR-214 Mechanism of Action 
NKTR-214 is a prodrug of a conjugated cancer immunotherapy cytokine that exerts its biological 
activity by binding to the IL-2 receptor and subsequent activation of effector T cells.  As a 
PEGylated human recombinant IL-2 molecule of aldesleukin with an average of six releasable 
polyethylene glycol (PEG) chains, NKTR-214 can be administered conveniently in the outpatient 
setting using an antibody-like dosing regimen.  The polymer conjugation renders the cytokine 
initially inactive. Upon intravenous (IV) administration, the PEG chains slowly release to 
generate the active cytokine species (mainly 2-PEG-IL-2 and 1-PEG-IL-2) that have a peak 


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plasma concentration 26 to 48 hours after infusion.  The slow generation of the 2-PEG-IL-2 and 
1-PEG-IL-2 significantly mitigates the rapid-onset, systemic IL-2 mediated adverse events (AEs) 
associated with high dose IL-2.   
The polymer conjugation of NKTR-214 promotes biased signaling through the IL-2 receptor beta 
gamma (IL-2Rβγ).  Specifically, the location of the NKTR-214 PEG chains interferes with 
binding to the IL-2 alpha receptor subunit responsible for the undesirable effect of activating 
regulatory T cells (Tregs) in the tumor while continuing to permit binding to the IL-2Rβγ 
(CD122) receptor.  Upon infusion, NKTR-214 preferentially increases the proliferation, 
activation, and effector function of tumor antigen-specific CD8+ T cells and natural killer (NK) 
cells within the tumor microenvironment (TME) over expansion of unwanted intra-tumoral 
Tregs that are activated through the IL-2 receptor alpha beta gamma (IL-2Rαβγ) 
(Charych, 2016a; Charych, 2016b).   
NKTR-214 also correspondingly promotes expression of PD-1 on the surface of CD8+ T cells 
and induction of a Type II interferon gene signature in the TME, driving cell surface expression 
of PD-L1 on tumor cells (Diab, 2017). 
The immunological properties of NKTR-214 with the induction of tumor infiltrating 
lymphocytes and upregulation of the PD-1/PD-L1 axis makes NKTR-214 a potentially 
promising combination therapy for use with checkpoint inhibitors that target and inhibit the 
PD-1/PD-L1 pathway.  Moreover, the safety profile of NKTR-214 does not overlap with that of 
checkpoint inhibitors, further supporting the use of NKTR-214 as a potentially complementary 
combination partner with checkpoint inhibitors. 
2.2.4 Study 15-214-01 (EXCEL; NKTR-214 Monotherapy) 
The NKTR-214 clinical development program started with the monotherapy study EXCEL 
(Study 15-214-01; A Phase 1/2, Open-label, Multicenter, Dose-Escalation and Dose Expansion 
Study of NKTR-214 in Subjects with Locally Advanced or Metastatic Solid Tumor 
Malignancies).  The first part of the study was a dose escalation phase, designed to evaluate the 
safety and tolerability, and define the maximum tolerated dose (MTD) or recommended Phase 2 
dose (RP2D) of NKTR-214.  The second part of the study was an expansion phase following 
identification of the RP2D, designed to evaluate the safety and tolerability, as well as the 
efficacy of NKTR-214 in specific tumor types.  NKTR-214 at a dose of 0.009 mg/kg 
administered every 3 weeks (q3w) was deemed the MTD by pre-defined dose-limiting toxicity 
criteria.  The RP2D was determined to be 0.006 mg/kg q3w.  Enrollment was closed after 28 
patients were exposed to NKTR-214 in the dose-escalation phase and the dose expansion phase 
was not initiated. 
The safety of single-agent NKTR-214 has been assessed in 28 patients across 5 dose cohorts 
administered NKTR-214 q3w at doses ranging from 0.003 mg/kg to 0.012 mg/kg and a dosing 
frequency of every 2 weeks (q2w) was explored at 0.006 mg/kg.  For the q3w dosing frequency, 
doses up to 0.009 mg/kg were well tolerated. One patient dosed at 0.012 mg/kg experienced 


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cytokine release syndrome (CRS) and the dose-limiting toxicities of hypotension and syncope; 
this patient received 2 additional cycles of NKTR-214 at a lower dose of 0.006 mg/kg. 
As of the data cutoff date of 29 March 2018, 593 treatment-emergent AEs were reported among 
the 28 patients who received single-agent NKTR-214.  Overall, the most common treatment-
emergent AEs were fatigue (23 patients, 82.1%), flu-like symptoms (consisting of influenza-like 
illness, influenza, pyrexia, and chills; 20 patients, 71.4%), pruritus (19 patients, 67.9%), 
hypotension (18 patients, 64.3%), rash (consisting of erythema, rash, rash erythematous, rash 
maculo-papular, rash papular, rash pruritic, rash pustular, rash vesicular, rash generalized, and 
rash macular; 15 patients, 53.6%), decreased appetite (15 patients, 53.6%), and arthralgia or 
cough (12 patients, 42.9% each). 
The most common AEs considered by the Investigator to be related to NKTR-214 were fatigue 
(20 patients, 71.4%), flu-like symptoms (19 patients, 67.9%), pruritus (18 patients, 64.3%), 
hypotension (16 patients, 57.1%), rash (14 patients, 50.0%), decreased appetite (13 patients, 
46.4%), and arthralgia or cough (9 patients, 32.1% each).  Such treatment-related AEs as flu-like 
symptoms, rash and pruritus were generally mild or moderate in severity, predictable, 
manageable, and short-lived.  These IL-2 mediated AEs generally occurred 3 to 4 days after 
dosing and corresponded to the time of peak plasma concentration of the active cytokines.  The 
flu-like symptoms were managed with acetaminophen and non-steroidal anti-inflammatory drugs 
(NSAIDs) and the cases of rash/pruritus were either self-limiting or treated with anti-histamines 
(steroids were administered for occasional patients who had severe rash/pruritus). 
The most frequently reported Grade ≥ 3 events were hypotension (5 of 28 patients, 17.9%), 
syncope (3 patients, 10.7%), metastases to central nervous system (3 patients, 10.7%), and 
abdominal pain, headache (1 of 2 related), and anemia (each: 2 patients, 7.1%). 
Six of 28 patients reported Grade 3 treatment-related AEs, which included hypotension, 
abdominal pain, infusion-related reaction, headache, and syncope.  The cases of Grade 3 
hypotension were rapidly reversed with intravenous fluids, and a hydration management 
guideline was implemented during the study which mitigated the hypotension severity. One 
patient, who had a prior history of an infusion reaction to a previously administered 
immunotherapy, discontinued treatment due to an infusion-related reaction following the first 
dose of NKTR-214.  With the exception of one event of hypothyroidism, no other immune 
mediated AEs consistent with checkpoint inhibitors were reported.  No patient experienced 
capillary leak syndrome and no Grade 4 treatment-related AEs or treatment-related deaths were 
reported on the study. 
Fifteen patients (53.6%) reported 31 serious adverse events (SAEs) in monotherapy 
Study 15-214-01.  Eleven SAEs reported among 7 (25.0%) patients were considered related to 
treatment.  The only treatment-related SAE reported for more than 1 patient was hypotension 
(5 patients, 17.9%, 4 of 5 were Grade 3 in severity).  While no objective responses were 
observed in Study 15-214-01, 9 patients experienced tumor shrinkage between 1% and 30% and 
two patients, after progressing on multiple prior therapies, had durable stable disease over 1 year.  


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One patient with metastatic melanoma, who was previously treated with ipilimumab and a BRAF 
inhibitor, received 25 cycles of NKTR-214 and had durable stable disease for 18 months.  A 
second patient with metastatic RCC, who had progressed on high-dose IL-2 and was refractory 
to single-agent OX40 (i.e., an antibody targeting the tumor necrosis factor receptor superfamily 
member 4) and nivolumab, was treated with 19 cycles of NKTR-214 and had durable stable 
disease for 14 months.  Given the biological properties of NKTR-214 and nivolumab these 
observations further supported the rationale for combining these two agents. 
2.2.5 Nivolumab Mechanism of Action 
Cancer immunotherapy rests on the premise that tumors can be recognized as foreign rather than 
as self and can be effectively attacked by an activated immune system.  An effective immune 
response in this setting is thought to rely on immune surveillance of tumor antigens expressed on 
cancer cells that ultimately results in an adaptive immune response and cancer cell death. 
Meanwhile, tumor progression may depend upon acquisition of traits that allow cancer cells to 
evade immunosurveillance and escape effective innate and adaptive immune responses 
(Pardoll, 2003; Zitvogel, 2006; Dunn, 2002).  Current immunotherapy efforts attempt to break 
the apparent tolerance of the immune system to tumor cells and antigens by either introducing 
cancer antigens by therapeutic vaccination or by modulating regulatory checkpoints of the 
immune system.  T-cell stimulation is a complex process involving the integration of numerous 
positive as well as negative co-stimulatory signals in addition to antigen recognition by the T-cell 
receptor (TCR) (Greenwald, 2005).  Collectively, these signals govern the balance between 
T-cell activation and tolerance.  PD-1 is a member of the CD28 family of T-cell co-stimulatory 
receptors that also includes CD28, CTLA 4, inducible T-cell co-stimulator (ICOS), and B- and 
T-lymphocyte attenuator (BTLA) (Freeman, 2000).  PD-1 signaling has been shown to inhibit 
CD-28-mediated upregulation of IL-2, IL-10, IL-13, interferon-gamma (IFN-γ) and Bcl-xL. 
PD-1 expression also been noted to inhibit T cell activation, and expansion of previously 
activated cells.  Evidence for a negative regulatory role of PD-1 comes from studies of PD-1 
deficient mice, which develop a variety of autoimmune phenotypes (Sharpe, 2007).  These 
results suggest that PD-1 blockade has the potential to activate anti-self T-cell responses, but 
these responses are variable and dependent upon various host genetic factors.  Thus, PD-1 
deficiency or inhibition is not accompanied by a universal loss of tolerance to self-antigens. 
In vitro, nivolumab (BMS-936558) binds to PD-1 with high affinity (EC50 0.39-2.62 nM), and 
inhibits the binding of PD-1 to its ligands PD-L1 and PD-L2 (IC50  1 nM).  Nivolumab binds 
specifically to PD-1 and not to related members of the CD28 family such as CD28, ICOS, 
CTLA-4 and BTLA.  Blockade of the PD-1 pathway by nivolumab results in a reproducible 
enhancement of both proliferation and IFN-γ release in the mixed lymphocyte reaction.  Using a 
cytomegalovirus (CMV) re-stimulation assay with human peripheral blood mononuclear cells 
(PBMC), the effect of nivolumab on antigen specific recall response indicates that nivolumab 
augmented IFN-γ secretion from CMV specific memory T cells in a dose-dependent manner 
versus isotype-matched control.  In vivo blockade of PD-1 by a murine analog of nivolumab 


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enhances the anti-tumor immune response and result in tumor rejection in several 
immunocompetent mouse tumor models (MC38, SA1/N, and PAN02) (Wolchok, 2009). 
2.3 
Benefit/Risk Assessment 
2.3.1 Nivolumab in Renal Cell Carcinoma 
Nivolumab monotherapy has been studied in patients with advanced RCC in several 
Bristol-Meyers Squibb-sponsored studies (Phases 1 through 3): MDX1106-03, CA209009, 
CA209010, and CA209025.  MDX1106-03 was a Phase 1 refractory solid tumor trial, which 
included 34 patients with previously treated advanced RCC who received nivolumab at 1 mg/kg 
(n = 18) or 10 mg/kg (n = 16) given every 2 weeks (McDermott, 2015; Motzer, 2015b; 
Topalian, 2012).  Median PFS was 7.3 months. In both the 1 mg/kg and 10 mg/kg cohorts, 
approximately 30% of patients experienced an objective response with median duration of 
response of 12.9 months.  Responses were generally rapid with a median time to response of 
16 weeks.  Notably, responses could occur after treatment cessation and persist off treatment. 
Median overall survival was 22.4 months.  These results were promising given that many of the 
patients were heavily pre-treated with 71% having had 2 or more lines of therapy.  
Treatment-related AEs of any grade were observed in 85% of RCC patients, the most common 
being fatigue (41%), rash (27%), diarrhea (18%), and pruritus (18%).  Grade 3-4 
treatment-related AEs were observed in 18% of RCC patients.  The spectrum, frequency, and 
severity of treatment-related AEs were similar in the RCC population compared to the overall 
study population and were similar across dose levels. 
In order to identify a potential dose-response relationship in RCC, a randomized Phase 2 study 
(CA209010) was conducted in 168 patients with advanced RCC previously treated with an 
antiangiogenic therapy who received nivolumab at 0.3 mg (n = 60), 2 mg/kg (n = 24) or 
10 mg/kg (n=54) given every 3 weeks (Robert, 2017).  No dose response relationship was found 
as measured by PFS, with median PFS of 2.7, 4.0, and 4.2 months for the 0.3, 2, and 10 mg/kg 
groups, respectively (P = 0.9); ORR was 20%, 22%, and 20% in the 0.3, 2, and 10 mg/kg groups, 
respectively. Median time to achievement of an objective response was 2.8-3.0 months.  The 
median duration of response was 22.3 months (4.8, not reached) in the 10 mg/kg arm and not yet 
reached in the 2 lower dose cohorts.  Median OS was at 18.2 to 25.5 months, with a minimum of 
follow-up of 24 months.  Fatigue was the most frequent toxicity (22-35%).  No new toxicities 
were identified with 11% experiencing Grade 3-4 treatment-related AEs, none of which were due 
to pneumonitis. Treatment-related AEs led to discontinuation of study drug in 7% of patients 
A parallel biomarker-focused trial, CA209009, using the same 3 nivolumab dose levels 
(0.3, 2, and 10 mg/kg every 3 weeks) was executed to explore predictors of response and identify 
mechanisms of resistance (Spigel, 2017).  This study included 67 patients with 
previously-treated, advanced RCC who were randomized to one of the 3 nivolumab dose groups 
and 24 patients with previously-untreated RCC who received nivolumab at 10 mg/kg every 
3 weeks.  The results mirrored the efficacy and toxicity profile of CA209010 with an overall 
ORR of 18% in previously treated patients, and 13% in previously untreated patients and disease 


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stabilization in another 32% of previously treated and untreated patients.  At 24 weeks, 36% of 
patients were free from progression.  Of 56 patients with evaluable pretreatment tumor samples, 
18 (32%) had ≥ 5% PD-L1 tumor expression. ORR was 22% among those with ≥ 5% PD-L1 
tumor expression versus 8% among those with < 5% PD-L1 tumor expression. 
Based on the clinical activity of nivolumab observed in these Phase 1 and 2 studies, a large 
Phase 3 trial (CA209025) was conducted in 821 patients with advanced RCC previously treated 
with 1 or 2 antiangiogenic therapies who were randomized to receive nivolumab 3 mg/kg every 
2 weeks or everolimus 10 mg daily (Motzer, 2015a).  A planned interim analysis, after a 
minimum of follow-up of 14 months, demonstrated a statistically significant and clinically 
meaningful improvement in OS of nivolumab monotherapy vs everolimus (median OS, 
25.0 months vs 19.6 months, respectively; hazard ratio [HR] = 0.73 [98.5% CI, 0.57 to 0.93], 
p-value = 0.002). ORR was 25% for nivolumab vs 5% for everolimus.  Among 756 patients with 
quantifiable PD-L1 tumor expression in pretreatment samples, 24% had 1% PD-L1 expression.  
Among patients with ≥1% PD-L1 expression, median OS was 21.8 months in the nivolumab 
group and 18.8 months in the everolimus group (HR, 0.79; 95% CI, 0.53 to 1.17).  Among 
patients with <1% PD-L1 expression, the median OS was 27.4 months in the nivolumab group 
and 21.2 months in the everolimus group (HR, 0.77; 95% CI 0.60 to 0.97).  No new safety 
concerns were identified, and nivolumab monotherapy showed a favorable safety profile as 
compared to everolimus, evidenced by the lower rates of drug-related AEs (all grades, 79% vs 
88%; Grade 3-4, 19%-37%, respectively) and drug-related AEs leading to discontinuation (all 
grades, 8% vs 13%, respectively) in the nivolumab group.  These results were the basis for 
regulatory approval of nivolumab monotherapy in advanced RCC. 
Promising safety and efficacy results were also observed with the combination of nivolumab and 
ipilimumab in the advanced RCC population in Study CA209016 (Hammers, 2017), a Phase 1 
dose-escalation study of nivolumab in combination with vascular endothelial growth factor 
receptor (VEGFR)-TKIs or ipilimumab in patients with advanced RCC.  The dosing regimen 
including nivolumab 3 mg/kg combined with ipilimumab 1 mg/kg (N3 + I1) was chosen for 
further clinical evaluation because it exhibited similar clinical activity to nivolumab 1 mg/kg 
combined with ipilimumab 3 mg/kg (N1+ I3) but had a more favorable safety profile.  
A Phase 3 trial CA209214 evaluated nivolumab combined with ipilimumab (N3+ I1 regimen) 
against sunitinib in first-line advanced RCC. Patients were stratified according to IMDC risk 
score and region (Motzer, 2018b).  Nivolumab + ipilimumab combination therapy demonstrated 
statistically significant and superior OS compared with sunitinib monotherapy in the primary 
population which comprised intermediate- and poor-risk patients (HR: 0.63 [99.8% CI: 0.44, 
0.89]; stratified log-rank test 2-sided p-value < 0.0001) at the adjusted alpha of 0.002.  Median 
OS was not reached at the time of database lock for this report in the nivolumab + ipilimumab 
group and was 25.95 months in the sunitinib group.  Nivolumab + ipilimumab combination 
therapy demonstrated a statistically significant higher ORR using an independent radiology 
review committee (41.6% [95% CI: 36.9, 46.5]) using Response Evaluation Criteria in Solid 
Tumors version 1.1 (RECIST 1.1) than sunitinib monotherapy (26.5% [95% CI: 22.4, 31.0]) 


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p-value < 0.0001. 9.4% vs 1.2% of patients achieved a complete response (CR) in the nivolumab 
+ ipilimumab and sunitinib groups, respectively.  With a delayed separation of the PFS curves in 
Kaplan Meier analysis, the PFS HR was 0.82, [99.1% CI: 0.64-1.05], with stratified log-rank 
2-sided p-value = 0.0331, which did not meet the pre-specified α boundary of 0.009 to achieve 
statistical significance although the difference in median survival was > 3 months. 
Among 776 intermediate- and poor-risk patients who had quantifiable PD-L1 expression, 100 of 
384 patients (26%) in the nivolumab-plus-ipilimumab group and 114 of 392 patients (29%) in 
the sunitinib group had 1% or greater PD-L1 expression.  In exploratory analyses, overall 
survival among the 776 patients was longer with nivolumab plus ipilimumab than with sunitinib 
across PD-L1 expression levels. The 12-month overall survival rate with less than 1% PD-L1 
expression was 80% (95% CI, 75 to 84) with nivolumab plus ipilimumab and 75% (95% CI, 
70 to 80) with sunitinib, and the 18-month overall survival rate was 74% (95% CI, 69 to 79) and 
64% (95% CI, 58 to 70), respectively; the median overall survival was not reached in both 
groups (hazard ratio for death, 0.73; 95% CI, 0.56 to 0.96).  In patients with 1% or greater PD-L1 
expression, the 12-month overall survival rate was 86% (95% CI, 77 to 91) with nivolumab plus 
ipilimumab and 66% (95% CI, 56 to 74) with sunitinib, and the 18-month overall survival rate 
was 81% (95% CI, 71 to 87) and 53% (95% CI, 43 to 62), respectively; the median overall 
survival was not reached and 19.6 months (95% CI, 14.8 to not estimable), respectively (hazard 
ratio for death, 0.45; 95% CI, 0.29 to 0.71). 
The objective response rate among patients with less than 1% PD-L1 expression was 37% with 
nivolumab plus ipilimumab and 28% with sunitinib (P = 0.03); among patients with 1% or 
greater PD-L1 expression, the objective response rate was 58% versus 22% (P<0.001). The 
median PFS among patients with less than 1% PD-L1 expression was 11.0 months with 
nivolumab plus ipilimumab and 10.4 months with sunitinib (hazard ratio for disease progression 
or death, 1.00; 95% CI, 0.80 to 1.26); among patients with 1% or greater PD-L1 expression, the 
median PFS was 22.8 and 5.9 months, respectively (hazard ratio for disease progression or death, 
0.46; 95% CI, 0.31 to 0.67). A similar trend was observed among patients with 5% or greater 
PD-L1 expression, as compared with patients with less than 5% PD-L1 expression. 
2.3.2 Observed Events of Cerebrovascular Accident  
2.3.2.1 
Initial Analysis of Cerebrovascular Accident Events in Study 16-214-02 
(PIVOT-02) 
Serious events of cerebrovascular accident (CVA), including one fatal event, have been observed 
in patients who have received NKTR-214 in the triplet combination with nivolumab and 
ipilimumab, in the doublet combination with nivolumab, and in the combination of NKTR-214, 
nivolumab, and other anticancer therapy.  
As of 28 October 2019, 3 of 43 patients (7.0%) who received triplet therapy in Study 16-214-02 
(PIVOT-02) had CVA events, including one fatal event, all of which were considered by the 
Investigator to be related to treatment with NKTR-214, nivolumab, and ipilimumab. 
Additionally, 9 of 488 patients (1.8%) who received doublet therapy (NKTR-214 and 


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nivolumab) had 10 CVA events, which were considered by the Investigator to be related to at 
least one of the study treatments in 4 patients (3 related to the NKTR-214 and nivolumab-doublet 
therapy and 1 related to nivolumab monotherapy); and one of 10 (10.0%) patients who received 
combined NKTR-214, nivolumab, and other anticancer therapy (platinum-based chemotherapy) 
had a CVA event, which was considered by the Investigator to be unrelated to study treatment. 
2.3.2.2 
Updated Analysis of CVA Events Observed with NKTR-214 
A cumulative search of the NKTR-214 global safety database was conducted on 
28 October 2020, which included 1345 patients who received NKTR-214 in triplet combinations 
with nivolumab plus ipilimumab or with nivolumab plus NKTR-262 (a toll-like receptor agonist 
7/8); in doublet combinations with checkpoint inhibitors; in a doublet combination (NKTR-214 
with nivolumab) plus chemotherapy, and in combination with NKTR-262 from the following 
studies: 15-214-01, 16-214-02, 16-214-05, 17-214-09, 18-214-10, 20-214-29, CA045-001 
(17-214-08), CA045-009 (18-214-03), CA043-010 (18-214-14), SP-IND, and 17-262-01. 
Overall, 1.9% (26 of 1345) of patients exposed to NKTR-214 reported CVA events. Of the 
26 patients, 13 patients experienced Grade 3 or 4 events and 4 patients had a fatal outcome. The 
mean time to first CVA event was 218.7 days (range 4 to 727 days; median 158 days). Twenty of 
the 26 patients with CVA events received a doublet combination with a checkpoint inhibitor, 
which included 1.7% (19 of 1116) of patients who received nivolumab, 1.3% (1 of 76) who 
received pembrolizumab, and 0% (0 of 23) who received atezolizumab. 
Based on these events, CVA was escalated to an adverse event of special interest (AESI) in 2020 
and mitigations were put in place to reduce the risk of CVA. These mitigations include 
implementation of a CVA adverse event management algorithm (Appendix 6) and updates to the 
exclusion criteria, renal function and hydration assessment, hydration guidelines, concomitant 
and prohibited medications, dose modification guidelines, and discontinuation criteria. 
Additional information on the clinical safety and risk of CVA is found in the NKTR-214 
Investigator’s Brochure. 
2.3.3 
Mitigation Measures 
Following the comprehensive review of the entire NKTR‑214 clinical program, additional safety 
measures and analyses were implemented to mitigate the risk of CVA events and to expedite 
reporting of CVA events by identifying CVA as an AESI.  These safety measures and analyses 
are reflected in changes to the following protocol sections: study exclusion criteria (Section 4.2), 
hydration guidelines (Sections 1.2 and 5.4.2.2), CVA AE management algorithm (Appendix 6), 
 for characterization of CVA events (Sections 1.2 and 5.10.3; 
Table 6; Appendix 6), criteria to delay, resume, or permanently discontinue study drug 
(Section 5.13), management algorithms for immune‑mediated AEs (Section 5.13.8), 
anticoagulation (Section 5.15.3.3), prohibited medications (Section 5.15.3.1), and reporting 
AESIs (Section 8.11). 


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Additional details on the clinical experience with NKTR‑214 are provided in the NKTR‑214 
Investigator’s Brochure. 
2.3.4 Nivolumab and NKTR-214 in Renal Cell Carcinoma 
Preliminary data on the combination of nivolumab and NKTR-214 in 26 patients with previously 
untreated advanced RCC was recently presented (Diab, 2018a).  Patients were administered 
nivolumab at a flat dose of 360 mg every 3 weeks, in combination with NKTR-214 at 
0.006 mg/kg, both by intravenous infusion.  Patients were evaluated using Fleming 2-stage 
design, in which efficacy was assessed by ORR (local Investigator) and subsequently confirmed 
by independent radiology review.  A historical target ORR of 25% was set with a target ORR for 
the new combination of 50%.  For the first stage, at least 6 out of 11 patients needed to 
demonstrate a confirmed ORR in order to reject the null hypothesis; at the final analysis, at least 
10 out of 26 patients will be needed to reject the null hypothesis.  Important baseline 
demographics included Eastern Cooperative Oncology Group (ECOG) performance status 0 
(60%) or 1 (40%), and PD-L1 positive, negative, and unknown status at baseline equaled 29%, 
63%, and 8%, respectively.  In Stage 1, the target efficacy signal was met with 7 out of 
11 patients with a response.  Stage 2 with less mature data demonstrated 12 out of 26 patients 
with a response.  Responses were observed in patients with both PD-L1 positive tumors (2 out of 
7 patients; 29%) and negative tumors (9 out of 17 patients; 53%); 2 patients had unknown PD-L1 
status. The trial is ongoing; the final analysis will be made at a future date. 
2.3.5 NKTR-214 Safety Profile  
NKTR-214 was designed to mitigate the severe toxicities associated with rapid systemic immune 
activation seen with administration of aldesleukin.  The identified risks of NKTR-214 include 
hypotension, IL-2 mediated AEs (e.g., flu-like symptoms, rash, pruritus, fatigue, hepatic 
transaminase elevations, and serum creatinine elevations), infusion-related reactions/ 
hypersensitivity reactions, thyroid dysfunction, eosinophilia, and arthralgia.  The majority of 
these AEs are mild to moderate in severity and can be monitored and managed in the clinical 
setting.  The goal of engineering a PEGylated form of IL-2 that reduces the treatment-limiting 
toxicities of aldesleukin, that is, those necessitating in-hospital administration, appears to have 
been realized at the doses tested.  
Additional details on the clinical experience with NKTR-214 are provided in the NKTR-214 
Investigator’s Brochure. 
2.3.6 Nivolumab Safety Profile 
Extensive details on the safety profile of nivolumab are available in the Investigator’s Brochure 
and will not be repeated herein. 
Overall, the safety profile of nivolumab monotherapy as well as in combination with ipilimumab 
is manageable and generally consistent across completed and ongoing clinical trials with no 
MTD reached at any dose tested up to 10 mg/kg.  Most AEs were low-grade (Grade 1 to 2) with 


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relatively few related high-grade (Grade 3 to 4) AEs.  There was no pattern in the incidence, 
severity, or causality of AEs with respect to nivolumab dose level. 
A pattern of immune-related adverse events has been defined, for which management algorithms 
have been developed (see Section 5.13.8).  Most high-grade events were manageable with the 
use of corticosteroids or hormone replacement therapy (endocrinopathies) as instructed in these 
algorithms. 
Additional details on the safety profile of nivolumab, including results from other clinical 
studies, are also available in the nivolumab Investigator’s Brochure. 
2.3.7 NKTR-214 and Nivolumab Benefit and Risk Assessment 
NKTR-214 has been generally well-tolerated in the clinical studies to date, both as monotherapy 
as well as in combination with nivolumab, with promising evidence of clinical efficacy and a 
potentially favorable benefit-risk profile.  NKTR-214 has been safely administered in an 
outpatient setting supported by appropriate clinical monitoring.   
Hypotension has been identified as a clinically significant adverse effect of NKTR-214 and can 
be effectively mitigated by prophylaxis and hydration guidelines.  Other risks associated with 
NKTR-214 include IL-2 mediated AEs (e.g., flu-like symptoms, rash, pruritus, fatigue, hepatic 
transaminase elevations, and serum creatinine elevation), infusion-related reactions, thyroid 
dysfunction, eosinophilia, and arthralgia; these AEs are generally mild or moderate in severity 
and can be monitored and managed in the clinical setting.  Cases of thyroid dysfunction 
(hypothyroidism, hyperthyroidism, thyroiditis), dermatitis, pneumonitis, hepatitis, myocarditis, 
myositis/myasthenia gravis, and vitiligo/hypopigmentation consistent with immune-mediated 
mechanism have been observed in patients receiving NKTR-214 plus nivolumab and some of 
these cases shared clinical characteristics consistent with immune-mediated AEs associated with 
checkpoint inhibitors.  
The continued development of NKTR-214 in combination with nivolumab for the treatment of 
various cancers is warranted based on a positive benefit-risk profile.  In addition, the early 
efficacy data along with the correlative biomarker showing conversion of PD-L1 negative tumors 
to PD-L1 positive tumors suggests that the addition of NKTR-214 to a checkpoint inhibitor 
(nivolumab) may change the tumor microenvironment in PD-L1 negative tumors such that the 
combination may contribute to anti-tumor activity invoke clinically significant, durable 
responses with an acceptable safety profile. 
In conclusion, the currently available safety data demonstrates that NKTR-214 and nivolumab is 
a well-tolerated immuno-oncology combination therapy.  Given the encouraging clinical activity 
and manageable and generally non-overlapping toxicity profile, the potential for direct benefit in 
patients warrants continued evaluation of the combination NKTR-214 and nivolumab in the 
clinical setting and supports further development of combination of NKTR-214 and nivolumab 
regimens in patients with cancer. 


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2.4 
Scientific Rationale for Study Design 
2.4.1 Sunitinib in Renal Cell Carcinoma 
Sunitinib is a VEGF receptor TKI that is approved and recommended for the treatment of 
advanced RCC across prognostic groups (Escudier, 2012).  In a randomized Phase 3 trial of 
sunitinib vs IFN-α in treatment-naive patients (including 36% with favorable risk, 57% with 
intermediate risk, and 7% with poor risk per MSKCC criteria), PFS (by independent radiology 
review) was significantly improved in the sunitinib group compared to the IFN-α group (median 
PFS 11 vs 5 months, HR = 0.42; p-value < 0.001). ORR was also greater in the sunitinib group 
(31% vs 6%). Median OS was 26.4 months in the sunitinib group vs 21.8 months in the IFN- 
group (HR = 0.82; p-value = 0.051) (Motzer, 2009).  More recently, sunitinib was compared to 
pazopanib in treatment-naive patients (including 27% favorable risk, 73% intermediate risk, and 
no poor risk) in the Phase 3 COMPARZ study (Motzer, 2013).  In this non-inferiority study, 
sunitinib and pazopanib demonstrated similar median PFS (8.4 months for pazopanib vs 
9.5 months for sunitinib, HR = 1.05) and median OS (28.4 months for pazopanib vs 29.3 months 
for sunitinib, HR = 0.91, p-value = 0.28).  The ORR of pazopanib and sunitinib was 31% and 
24%, respectively.  The most common ( 20% frequency) adverse reactions include fatigue, 
asthenia, fever, diarrhea, nausea, mucositis/stomatitis, vomiting, dyspepsia, abdominal pain, 
constipation, hypertension, peripheral edema, rash, hand-foot syndrome, skin discoloration, dry 
skin, hair color changes, altered taste, headache, back pain, arthralgia, extremity pain, cough, 
dyspnea, anorexia, and bleeding (Sutent, 2019).  Other important adverse reactions include 
hepatotoxicity, QT prolongation (including Torsades de Pointes), osteonecrosis of the jaw, tumor 
lysis syndrome, and thyroid dysfunction. 
2.4.2 Cabozantinib in Renal Cell Carcinoma 
Cabozantinib is a small molecule inhibitor of the tyrosine kinases c-Met, AXL, and VEGFR2, 
and has been shown to reduce tumor growth, metastasis, and angiogenesis.  In vitro biochemical 
and/or cellular assays have shown that cabozantinib inhibits the tyrosine kinase activity of MET, 
VEGFR-1, -2 and -3, AXL, RET, ROS1, TYRO3, MER, KIT, TRKB, FLT-3, and TIE-2 
(Cabometyx, 2021).  These receptor tyrosine kinases are involved in both normal cellular 
function and pathologic processes such as oncogenesis, metastasis, tumor angiogenesis, drug 
resistance, and maintenance of the tumor microenvironment. 
Cabozantinib has been evaluated in both first-line and second-line settings in advanced RCC. In 
patients with advanced RCC who progressed after previous VEGFR-TKI treatment, the 
randomized Phase 3 METEOR trial compared the efficacy and safety of cabozantinib 
monotherapy at a daily dose of 60 mg versus the mTOR inhibitor everolimus at a daily dose of 
10 mg (Choueiri, 2015; Choueiri, 2016).  In the trial, 658 patients were randomized to receive 
cabozantinib (n = 330) or everolimus (n = 328).  After a minimum follow-up of 11 months in the 
first 375 randomized patients, the primary endpoint of PFS (by independent radiology review) 
was 7.4 months in the cabozantinib arm vs 3.8 months in the everolimus arm (HR = 0.58 [95% 
CI 0.45 to 0.75], p-value < 0.001).  Using MSKCC criteria, subgroup analyses of risk groups 


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demonstrated PFS benefit in patients with favorable risk (HR = 0.54 [95% CI 0.37, 0.79]), 
intermediate risk (HR = 0.56 [95% CI 0.37, 0.84]), and poor risk (HR = 0.84 [95% CI 0.46, 
1.53]).  ORR was 17% in the cabozantinib arm vs 5% in the everolimus arm (p < 0.001).  An 
interim OS analysis at the time of this final PFS analysis demonstrated a trend toward longer OS 
(HR = 0.67, p=0.005, with p-value ≤ 0.0019 required for statistical significance).  A subsequent 
OS analysis, performed after a median follow-up of approximately 19 months in all 658 
randomized patients, demonstrated a significant improvement in OS, with median OS of 21.4 
months in the cabozantinib arm and 16.5 months in the everolimus arm (HR = 0.66 [95% CI 
0.53-0.83]; p-value = 0.00026).  Subgroup analyses of OS according to MSKCC risk group were 
consistent with the results for the overall population.  The most common Grade 3 or 4 adverse 
events included hypertension (49 [15%] in the cabozantinib group vs 12 [4%] in the everolimus 
group), diarrhea (43 [13%] vs 7 [2%]), fatigue (36 [11%] vs 24 [7%]), palmar-plantar 
erythrodysesthesia syndrome (27 [8%] vs 3 [1%]), anemia (19 [6%] vs 53 [17%]), 
hyperglycemia (3 [1%] vs 16 [5%]), and hypomagnesemia (16 [5%] vs none).  Serious adverse 
events Grade ≥ 3 occurred in 130 (39%) patients in the cabozantinib group and in 129 (40%) in 
the everolimus group.  One treatment-related death occurred in the cabozantinib group (death; 
not otherwise specified) and two occurred in the everolimus group (1 aspergillus infection and 1 
pneumonia aspiration). 
In treatment-naive patients, cabozantinib was also evaluated in a randomized Phase 2 multicenter 
trial against sunitinib as first-line therapy in patients with advanced RCC (Choueiri, 2017).  
Patients were required to have either intermediate- or poor-risk disease according to IMDC 
criteria and were randomized in 1:1 ratio to cabozantinib (n = 79) or sunitinib (n = 78).  
Investigator-assessed PFS was the primary endpoint. Compared with sunitinib, cabozantinib 
treatment significantly increased median PFS (8.2 vs 5.6 months) and was associated with a 34% 
reduction in rate of progression or death (adjusted hazard ratio, 0.66; 95% CI, 0.46 to 0.95; 
one-sided p-value = 0.012). ORR was 46% (95% CI, 34 to 57) for cabozantinib vs 18% (95% CI, 
10 to 28) for sunitinib. Median OS was 30.3 months for cabozantinib vs 21.8 months for 
sunitinib (adjusted HR = 0.80, 95% CI 0.50, 1.26).  All-causality Grade 3 or 4 adverse events 
were 67% for cabozantinib and 68% for sunitinib and included diarrhea (cabozantinib, 10% vs 
sunitinib, 11%), fatigue (6% vs 15%), hypertension (28% vs 22%), palmar-plantar 
erythrodysesthesia (8% vs 4%), and hematologic adverse events (3% vs 22%).  
Treatment-related Grade 5 events occurred in 3 patients in the cabozantinib arm (acute kidney 
injury, sepsis, and jejunal perforation) and 3 patients in the sunitinib arm (sepsis, respiratory 
failure, and vascular disorders). 
2.4.3 Rationale for the Combination of NKTR-214 and Immune Checkpoint Inhibitors 
The ongoing PIVOT-02 study of nivolumab and NKTR-214 includes an expansion cohort in 
patients with treatment-naive advanced RCC.  The most recent analysis is summarized in 
Section 2.3.3 (Diab, 2018a).  Responses were observed in PD-L1 positive and negative patients.  
The combination of nivolumab with a safe and convenient delivery system of the CD122-biased 


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agonist (NKTR-214) may represent the highest possibility of cure and serve to fulfill unmet 
medical need. 
2.4.4 Rationale for the Comparator 
Tyrosine kinase inhibitors are one of the most commonly used first-line therapies for advanced 
RCC. Based on results of CABOSUN study (Section 2.2.2), cabozantinib has been approved as 
an accepted first standard-of-care regimen in both US and EU, in IMDC intermediate- and 
poor-risk patients.  Sunitinib is listed by the NCCN guidelines as a preferred treatment and has 
been the comparator for most advanced RCC studies in the last several years.  Although recent 
results from the CA209214, CABOSUN, and KEYNOTE-426 studies have shown superior 
efficacy of nivolumab + ipilimumab, cabozantinib, and pembrolizumab + axitinib, respectively, 
against sunitinib, patients benefit from individualized considerations for treatment options.  
Currently available combinations are associated with increased safety risks and/or rates of early 
discontinuation, and TKI monotherapy with either sunitinib or cabozantinib remains an 
acceptable option for patients with previously untreated advanced RCC. Inclusion of the most 
commonly used and preferred TKIs, sunitinib and cabozantinib, as choices in the control arm 
provide the Investigator with the ability to choose an appropriate TKI monotherapy option for 
their patients. 
2.4.5 Rationale for Endpoints  
The study will include primary endpoints of ORR and OS, to be evaluated in IMDC 
intermediate- or poor-risk patients and IMDC all-risk patients.  Either OS or PFS, as long as 
there is no detriment in OS, have been successful endpoints to support drug approvals in 
advanced RCC. Sorafenib, sunitinib, bevacizumab, axitinib, everolimus and cabozantinib were 
each approved based on improvement in PFS.  Based on improvement in OS, temsirolimus was 
approved for patients with untreated advanced RCC in a poor-risk population, the combination of 
nivolumab and ipilimumab in intermediate- and poor-risk patients, and most recently the 
combination of pembrolizumab and axitinib in patients with any IMDC risk score.  Although 
tivozanib demonstrated a statistically significant improvement in PFS, this did not lead to 
regulatory approval, as a detriment in OS was noted in patients on the tivozanib arm.  Objective 
response rate is included because of the improvement in ORR rates seen with the dual 
immunotherapy of ipilimumab combined with nivolumab in Studies CA209016 
(Hammers, 2017) and CA209214 (Motzer, 2018b), with the intent to describe the ORR of 
NKTR-214 combined with nivolumab or TKI (sunitinib or cabozantinib) monotherapy.  PFS was 
selected as a key secondary endpoint, but not as a primary endpoint as previous randomized trial 
in this population tend to show a late separation of the Kaplan Meier curves (nivolumab and 
ipilimumab versus sunitinib; Motzer, 2018b) or no separation (atezolizumab versus sunitinib; 
McDermott, 2018). 
The evaluation of primary endpoints includes IMDC intermediate and poor-risk patients, which 
comprise approximately 75% of the total treatment-naive advanced RCC population.  Inclusion 
of this large subset of patients in the primary endpoints of the study will allow for potential 


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meaningful differences in efficacy to be detected earlier than in the IMDC all-risk patient 
population.  This may allow the NKTR-214 and nivolumab combination to become available to 
larger numbers of advanced RCC patients in a more timely fashion.  Additional primary and key 
secondary endpoints include OS, ORR, and PFS in all IMDC risk (favorable, intermediate, and 
poor) patients.  Promising response rates to the combination of NKTR-214 and nivolumab were 
observed among favorable-risk patients enrolled in the Phase 1/2 Study 16-214-02 (PIVOT-02), 
suggesting that the potential benefit of this combination may not be limited to intermediate- and 
poor-risk patients.  Finally, one of the control arm agents, cabozantinib, is only approved for the 
treatment of intermediate- and poor-risk patients; whereas, the second control arm agent, 
sunitinib, is a preferred treatment option for favorable-risk patients and approved for use with all 
risks. 
2.4.6 Rationale for Open-Label Design 
The trial will have an open-label design with a blinded independent central review.  Different 
dosing schedules and use of both IV infusions and oral medications across the 2 different arms 
make blinding the trial impractical.  The complexity of including multiple visits for placebo 
infusions are burdensome for this patient population.  Nivolumab is associated with some 
toxicities that are also common to cabozantinib and sunitinib (e.g., diarrhea, hepatotoxicity), and 
the management of these common toxicities are different for immuno-oncology agents (e.g., 
typically requiring steroids) vs TKIs (e.g., typically requiring dose delay and reductions).  
Therefore, an open-label trial is preferable for patient safety as it allows the optimal management 
of toxicities. 
Due to the hydration program and the special restrictions for withholding anti-hypertensive 
medications in the NKTR-214 arm, a placebo-controlled, double-blinded design is not 
appropriate for this study. 
2.4.7 Rationale for Stratification by IMDC Prognostic Score and TKI Choice 
The IMDC prognostic score (Section 2.2.1) is known to have a profound effect on patient 
prognosis in terms of survival in advanced RCC, and the effectiveness of some treatment options 
in previously untreated advanced RCC is dependent on the different risk groups (Heng, 2013; 
Motzer, 2018b).  It was also considered important to stratify patients based on TKI used in case 
there are differences in outcomes based on TKI choice. 
2.4.8 Duration of Treatment for NKTR-214 Combined with Nivolumab 
The optimal duration of immunotherapy is an important question and continues to be 
investigated.  Clinical trials across different tumor types in the nivolumab and ipilimumab 
development program indicate that most of the responses occur early, with a median time to 
response of 2 to 4 months, and emerging data suggests that benefit can be maintained in the 
absence of continued treatment.  A recent analysis in a melanoma study suggests the majority of 


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patients who discontinue nivolumab and/or ipilimumab for toxicity maintain disease control in 
the absence of further treatment (Schadendorf, 2016).  
Accumulating data suggest that 2 years of PD-1 checkpoint inhibitor treatment may be sufficient 
for long-term benefit. CA209003, a dose-escalation cohort expansion trial evaluating the safety 
and clinical activity of nivolumab in patients with previously treated advanced solid tumors 
(including 129 patients with non-small cell lung cancer [NSCLC]), specified a maximum 
treatment duration of 2 years.  Among 16 patients with NSCLC who discontinued nivolumab 
after completing 2 years of treatment, 12 patients were alive > 5 years and remained progression-
free without any subsequent therapy. In the CA209003 NSCLC cohort, the OS curve begins to 
plateau after 2 years, with an OS rate of 25% at 2 years and 18% at 3 years (Brahmer, 2017).  
These survival outcomes are similar to Phase 3 studies in previously treated NSCLC, in which 
nivolumab treatment was continued until progression or unacceptable toxicity (2-year OS rates 
of 23% and 29%, and 3-year OS rates of 16%-18% for squamous and nonsquamous NSCLC 
respectively) (Felip, 2017). 
Similar results have been reported in clinical studies of pembrolizumab, another PD-1 inhibitor.  
Keynote-010 was a randomized Phase 3 trial of pembrolizumab (at either 2 mg/kg or 10 mg/kg 
every 3 weeks) versus docetaxel in patients with previously treated, PD-L1-positive, advanced 
NSCLC which specified a maximum treatment duration of 2 years for pembrolizumab.  OS was 
significantly longer with both pembrolizumab 2 mg/kg (HR = 0.72, p-value = 0.00017) and 
pembrolizumab 10 mg/kg (HR = 0.60, p-value < 0.00001) compared to docetaxel, with an OS 
plateau developing beyond 2 years in both pembrolizumab arms.  Among 690 patients who 
received pembrolizumab, 47 patients completed 2 years of pembrolizumab and stopped 
treatment.  Most were able to maintain their response, including those with stable disease, with 
only 2 patients (4%) having confirmed progression after stopping at 2 years (Herbst, 2016).  
Keynote-006 was a randomized Phase 3 study of pembrolizumab versus ipilimumab in patients 
with advanced melanoma, which also specified a maximum 2-year duration of pembrolizumab 
treatment.  104 (19%) of 556 patients randomized to pembrolizumab completed 2 years of 
treatment.  With a median follow-up of 9 months after completion of pembrolizumab, the 
estimated risk of progression or death was 9% in these patients (Robert, 2017).  
Taken together, these data suggest that treatment beyond 2 years is unlikely to confer additional 
clinically meaningful benefit and that the risk of progression after discontinuing treatment at 
2 years is low. 
In contrast, a shorter duration of nivolumab of only 1 year was associated with increased risk of 
progression in previously treated patients with NSCLC, suggesting that treatment beyond 1 year 
is likely needed. In CA209153, patients with previously treated advanced NSCLC who 
completed 1 year of nivolumab therapy were randomized to either continue or stop treatment, 
with the option of retreatment upon progression.  Among 163 patients still on treatment at 1 year 
and without progression, those who were randomized to continue nivolumab had significant 
improvement in PFS compared to those who were randomized to stop treatment, with median 


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PFS (post-randomization) not reached vs 10.3 months, respectively; HR = 0.42 (95% CI, 0.25 to 
0.71).  With a median follow-up of 14.9 months post-randomization, there also was a trend for 
patients on continued treatment to live longer (OS HR = 0.63 [95% CI: 0.33, 1.20]).  Of note, the 
PFS curves in both groups plateau approximately 1 year after randomization (i.e., 2 years after 
treatment initiation), suggesting that there may be minimal benefit in extending treatment beyond 
a total of 2 years (Spigel, 2017).  
Collectively, these data suggest that there is minimal if any benefit derived from continuing 
immune-oncology treatment beyond 2 years in advanced tumors.  However, even though 
immunotherapy is well tolerated, patients will be at risk for additional toxicity with longer term 
treatment.  Therefore, in this study, treatment will be given for a maximum of 2 years from 
Cycle 1 Day 1 (Arm A only). 
Given the hypothesis that co-administration of NKTR-214 with nivolumab will potentiate the 
pharmacological effects of nivolumab, the duration of NKTR-214 therapy will also be restricted 
to 2 years from Cycle 1 Day 1 (Arm A only) to match the duration of nivolumab therapy. 
2.5 
Justification for Dose  
2.5.1 Justification for Dose of NKTR-214  
The dose for NKTR-214 is 0.006 mg/kg q3w taking in consideration the clinical safety profile 
associated with the robust immune system activation observed in the PIVOT-02 study.  Refer to 
Section 2.3.2 for additional details on PIVOT-02. 
2.5.2 Justification for Dose of Nivolumab 
Nivolumab monotherapy has been extensively studied in multiple tumor types, including 
melanoma, NSCLC, RCC, classical Hodgkin’s lymphoma, head and neck, and urothelial 
carcinoma, using body weight normalized dosing (mg/kg), and has been safely administered at 
doses up to 10 mg/kg q2w. Nivolumab is currently approved for the treatment of various tumors, 
including melanoma, NSCLC, RCC, classical Hodgkin’s lymphoma, squamous cell carcinoma of 
the head and neck, and urothelial carcinoma, using a regimen of either  nivolumab 240 mg q2w 
or nivolumab 3 mg/kg q2w and nivolumab 480 mg every 4 weeks (q4w). 
Nivolumab has been shown to be safe and well tolerated up to a dose level of nivolumab 
10 mg/kg q2w.  Population pharmacokinetic (PPK) analyses have shown that the 
pharmacokinetics (PK) of nivolumab is linear with proportional exposures over a dose range of 
0.1 to 10 mg/kg; no differences in PK across ethnicities and tumor types were observed.  Using 
the PPK model, the exposures following administration of several dosing regimens of nivolumab 
administered as a flat dose were simulated, including nivolumab 360 mg q3w.  The simulated 
steady state average concentration (Cavgss) following administration of nivolumab 360 mg q3w 
are expected to be similar to those following administration of nivolumab 240 mg q2w and 
nivolumab 3 mg/kg q2w administered to patients weighing 80 kg, the approximate median 
weight of patients with NSCLC, melanoma and RCC used in the PPK analyses.  Given that the 


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Cavgss estimates for nivolumab 360 mg q3w are predicted to be similar to those for nivolumab 
240 mg q2w and nivolumab 3 mg/kg q2w, the efficacy is predicted to be similar for these 
regimens.  It should be noted that the steady state peak concentrations following nivolumab 
360 mg q3w are predicted to be less than those following the administration of nivolumab 
10 mg/kg q2w providing sufficient safety margins. Further details on nivolumab 360 mg q3w 
dosing can be found in the Investigator’s Brochure. 
Finally, nivolumab 360 mg q3w is currently being investigated in combination with a number of 
other agents, including NKTR-214 in the PIVOT-02 study, and platinum-doublet chemotherapy 
dosing, with no new or increased safety events observed to date.  By using nivolumab 360 mg 
q3w in this study, it allows for aligning doses of nivolumab at the same dosing frequency of the 
experimental agent. 
Additional details on dosing are provided in the nivolumab Investigator’s Brochure. 


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3.0 
STUDY OBJECTIVES 
3.1 
Primary Objectives 
The primary objectives are: 
• To compare the ORR by blinded independent central review (BICR) assessment using 
modified Response Evaluation Criteria in Solid Tumors (mRECIST) 1.1 of NKTR-214 
combined with nivolumab to that of TKI monotherapy (sunitinib or cabozantinib) in IMDC 
intermediate- or poor-risk patients with previously untreated advanced RCC 
• To compare the ORR by BICR using mRECIST 1.1 of NKTR-214 combined with nivolumab 
to that of TKI monotherapy (sunitinib or cabozantinib) in IMDC all-risk patients with 
previously untreated advanced RCC 
• To compare the OS of NKTR-214 combined with nivolumab to that of TKI monotherapy 
(sunitinib or cabozantinib) in IMDC intermediate- or poor-risk patients with previously 
untreated advanced RCC  
• To compare the OS of NKTR-214 combined with nivolumab to that of TKI monotherapy 
(sunitinib or cabozantinib) in IMDC all-risk patients with previously untreated advanced 
RCC 
3.2 
Secondary Objectives 
The key secondary objectives are: 
• To compare the PFS by BICR using mRECIST 1.1 of NKTR-214 combined with nivolumab 
to TKI monotherapy (sunitinib or cabozantinib) in IMDC intermediate- or poor-risk patients 
with previously untreated advanced RCC 
• To compare the PFS by BICR using mRECIST 1.1 of NKTR-214 combined with nivolumab 
to TKI monotherapy (sunitinib or cabozantinib) in IMDC all-risk patients with previously 
untreated advanced RCC  
The other secondary objectives are: 
• To estimate the incidence of AEs of NKTR-214 combined with nivolumab versus TKI 
monotherapy (sunitinib or cabozantinib) in patients with previously untreated advanced RCC 
• To evaluate whether PD-L1 expression on tumor cells (< 1% vs ≥ 1%) using the PD-L1 
immunohistochemistry (IHC) 28-8 pharmDx assay is a predictive biomarker for ORR, PFS, 
and OS in patients with previously untreated advanced RCC  
• To characterize changes in cancer-related symptoms and quality-of-life in patients with 
previously untreated advanced RCC using the National Comprehensive Cancer 
Network/Functional Assessment of Cancer Therapy (NCCN/FACT) Symptom Index for 
Kidney Cancer (FKSI-19)  




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4.0 
SELECTION OF STUDY POPULATION 
4.1 
Inclusion Criteria 
Each patient will be entered into this study only if he/she meets all of the following criteria: 
1. 
Provide written, informed consent to participate in the study and follow the study 
procedures.  The Investigator takes responsibility for ensuring that all vulnerable patients 
are protected and participate voluntarily in an environment free from coercion or undue 
influence. 
2. 
Male or female patients, age 18 years or older at the time of signing the informed consent 
form (ICF) 
3. 
Karnofsky Performance Status of at least 70% (see Appendix 2) 
4. 
Measurable disease per mRECIST 1.1 criteria (by local Investigator; See Appendix 9) 
5. 
Renal cell carcinoma diagnosis:  
a. Histological confirmation of RCC with a clear-cell component (tumors may also have 
sarcomatoid features), AND,  
b. Advanced (not amenable to curative surgery or radiation therapy) or metastatic 
(American Joint Committee on Cancer [AJCC] Stage IV) RCC  
6. 
No prior systemic therapy (including neoadjuvant, adjuvant, or vaccine therapy) for RCC 
7. 
Prior palliative radiotherapy must be completed at least 2 weeks prior to randomization. 
Patients must have recovered from all Grade 2 or higher radiation-related toxicities and 
not require corticosteroids.  
Note: Radiated lesions cannot be used as measurable lesions unless there is clear 
evidence of progression. 
8. 
Patients are included with any IMDC score, whether favorable, intermediate, or poor risk. 
For IMDC intermediate- or poor-risk patients, at least one of the following prognostic 
factors must be present (based on central laboratory results; see Appendix 1; See 
Section 8.15 for exceptions): 
a. Karnofsky performance status equal to 70%    
b. Less than 1 year from initial diagnosis (including original localized disease, if 
applicable) to randomization 
c. Hemoglobin < lower limit of normal  


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d. Corrected calcium > upper limit of normal (ULN):   
corrected calcium = measured total calcium (mg/dL) + 0.8 (4.0 − serum albumin 
[g/dL]), where 4.0 represents the average albumin level in g/dL or  
measured total calcium (mmol/L) + 0.02 (40 − serum albumin [g/L]), where 
40 represents the average albumin level in g/L 
e. Absolute neutrophil count > ULN 
f. Platelet count > ULN 
9. 
Demonstrated adequate organ function, as defined below, within 14 days of 
randomization: 
a. Absolute neutrophil count (ANC) ≥ 1500/μL (≥ 1000/μL for patients with known or 
suspected diagnosis of benign ethnic neutropenia) after at least 14 days without 
growth factor support 
b. Platelet count ≥ 100 × 103/μL after at least 14 days without transfusion 
c. Hemoglobin ≥ 9.0 g/dL after at least 14 days without transfusion or growth factor 
support 
d. Serum creatinine ≤ 1.5 × ULN (or estimated creatinine clearance ≥ 40 mL/min)  
e. Aspartate aminotransferase (AST) and alanine transaminase (ALT) ≤ 3 × ULN 
f. Total bilirubin ≤ 1.5 × ULN (total bilirubin ≤ 2 × ULN if associated with 
hepatobiliary metastases or Gilbert’s syndrome)  
g. Urine protein creatinine ratio (UPCR) < 1.0 (< 113 mg/mmol) or 24-hour urine 
protein < 1 gram (g) 
Note: Patients with severe hepatic impairment (Child-Pugh Class C) are ineligible.  
10. 
A documented left ventricular ejection fraction (LVEF) > 45% using standard 
echocardiogram or multigated acquisition (MUGA) scan test within 60 days prior to 
randomization. 
11. 
Oxygen saturation ≥ 92% on room air 
12. 
Clinically significant toxic effect(s) of any prior anticancer therapy (if applicable) must 
be Grade 1 or resolved (except alopecia and sensory neuropathy). If the patient received 
major surgery, they must have complete wound healing and recovered from any 
complication from the surgery. 
13. 
Reproductive Status 
a. Women of childbearing potential (WOCBP) must have a negative serum or urine 
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic 
gonadotropin [hCG]) within the 28 days prior to randomization 
b. Women must not be breastfeeding 


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c. Women of childbearing potential must agree to follow instructions for method(s) of 
contraception for the duration of study treatment and for 5 months post treatment 
completion. Women should use an adequate method(s) of contraception as indicated 
in Appendix 4. 
d. Men who are sexually active with WOCBP must agree to follow instructions for 
method(s) of contraception (Appendix 4) for the duration of study treatment and 
3 months post NKTR-214 completion. In addition, male patients must refrain from 
sperm donation during this time.  
Investigators shall counsel WOCBP, and male patients who are sexually active with 
WOCBP, on the importance of pregnancy prevention and the implications of an 
unexpected pregnancy.  Investigators shall advise on the use of highly effective methods 
of contraception (Appendix 4), which have a failure rate of < 1% when used consistently 
and correctly. 
14. 
Patients must not have active brain metastases or any leptomeningeal metastases:   
a. Patients with brain metastases are eligible if these have been treated and there is no 
radiographic evidence of progression for at least 4 weeks after treatment is complete 
(confirmed by the head imaging obtained within 28 days prior to randomization).  
There must also be no requirement for immunosuppressive doses of systemic 
corticosteroids (> 10 mg/day prednisone equivalents; see Appendix 5 for 
corticosteroid dose equivalents) for at least 2 weeks prior to randomization. Stable 
dose of anticonvulsants is required at least 14 days prior to randomization.  Treatment 
for central nervous system (CNS) metastases may include stereotactic radiosurgery 
(e.g., GammaKnife, CyberKnife, or equivalent) or neurosurgical resection. Patients 
who received whole brain radiation therapy are not eligible. 
b. No stereotactic radiation or craniotomy within 28 days of randomization 
c. No clinically significant symptoms secondary to brain metastases 
d. Head imaging must occur on study in accordance with Section 5.8 
15. 
Archival or fresh tumor tissue, from a site not previously irradiated and with no 
intervening treatment between time of acquisition and randomization, identified and 
available to be provided as either a formalin-fixed, paraffin-embedded tissue block or 
unstained slides sectioned from a block within 3 months prior to randomization. 
16. 
Patients must be able to swallow pills intact. 
17. 
Patients must be able and willing to comply with the study visit schedule and study 
procedures. 


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4.2 
Exclusion Criteria 
A patient will be excluded from this study if he/she meets any of the following criteria: 
1. 
Use of an investigational agent or an investigational device within 28 days of 
randomization 
2. 
Female patients who are pregnant or lactating, who plan to get pregnant, or who have a 
positive serum or urine pregnancy test 
3. 
Active, known, or suspected autoimmune disease that has required systemic treatment 
within the past 3 months; a documented history of clinically severe autoimmune disease 
that requires systemic steroids or immunosuppressive agents.  (Exceptions include any 
patient on ≤ 10 mg/day of prednisone or equivalent, patients with vitiligo, 
hypothyroidism stable on hormone replacement, Type I diabetes, Graves’ disease, 
Hashimoto's disease, alopecia areata, or eczema.) 
4. 
History of allergy to study drug components (for nivolumab, NKTR-214, sunitinib and 
cabozantinib); for cabozantinib, this includes galactose intolerance, Lapp lactase 
deficiency or glucose-galactose malabsorption.   
5. 
History of severe hypersensitivity reaction to any monoclonal antibody  
6. 
Has a known additional malignancy that is progressing or requires active treatment. 
Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin 
that has undergone potentially curative therapy, or in situ cervical cancer.  Prostate cancer 
is acceptable, provided that the following criterion is met: Stage T2N0M0 or lower.  
7. 
History of organ or tissue transplant that requires systemic use of immune suppressive 
agents 
8. 
Prior major surgery within 28 days of randomization (“major surgery” does not include 
biopsy or placement of a venous access device).   
9. 
Any tumor invading the wall of a major blood vessel. Tumor extension into the lumen of 
the renal vein or vena cava without evidence of breaching the vessel wall (by computed 
tomography [CT] or magnetic resonance imaging [MRI]) is not considered invasion. 
10. 
Any tumor invading the gastrointestinal (GI) tract or any evidence of endotracheal or 
endobronchial tumor within 28 days prior to randomization 
11. 
Active infection requiring systemic therapy within 14 days prior to randomization 
(exception: Prophylactic use of antibiotics for signs of potential asymptomatic urinary 
tract infection or treatment of uncomplicated urinary tract infection with antibiotics is 
permitted) 
12. 
Has known hepatitis B virus infection (e.g., hepatitis B surface antigen [HBsAg] reactive) 
or hepatitis C virus (HCV) infection (e.g., HCV ribonucleic acid [RNA] qualitative is 
detected) 


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13. 
Has known immunodeficiency or active human immunodeficiency virus (HIV-1/2 
antibodies) 
14. 
Prolonged Fridericia’s corrected QT interval (QTcF) > 450 ms for men and > 470 ms for 
women at Screening 
15. 
Known cardiovascular history including unstable or deteriorating cardiac disease within 
the previous 12 months prior to screening including but not limited to the following: 
a. Unstable angina or myocardial infarction 
b. Transient ischemic attack (TIA)/Cerebrovascular accident (CVA) 
c. Congestive heart failure (CHF) (New York Heart Association [NYHA] Class III or 
IV) 
d. Uncontrolled clinically significant arrhythmias 
16. 
Need for > 2 antihypertensive medications for management of hypertension (including 
diuretics).  Patients with hypertension must be on a stable anti-hypertensive regimen for 
the 14 days prior to randomization.  Note: An antihypertensive medication that contains 
2 drugs under one formulation is counted as 2 antihypertensive medications (e.g., 
angiotensin-converting-enzyme [ACE] inhibitor plus diuretic, calcium channel blocker 
plus ACE inhibitor). 
17. 
History of pulmonary embolism (PE), deep vein thrombosis (DVT) (not including 
primary renal tumor thrombus), or prior clinically significant venous or non-CVA/TIA 
arterial thromboembolic event (e.g., internal jugular vein thrombosis) within 3 months 
prior to randomization.   
a. Patients with a history of a venous or arterial thromboembolic event must be 
asymptomatic for at least 2 weeks prior to randomization and must be receiving a 
stable regimen of therapeutic anticoagulation (preferably low molecular weight 
heparin [LMWH] or direct oral anticoagulation [DOAC]; see Section 5.15.3.3 for 
further guidance). Note: unless there is a new medical contraindication observed after 
Cycle 1 Day 1, a patient with a history of venous or arterial thromboembolic event 
must be willing to maintain therapeutic anticoagulation throughout participation on 
the treatment phase of the study. 
18. 
History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess 
within 6 months prior to randomization 
19. 
Impairment of gastrointestinal function or gastrointestinal disease that may significantly 
alter the absorption of sunitinib or cabozantinib (e.g., malabsorptive disorder, ulcerative 
disease, uncontrolled nausea, vomiting, diarrhea, or small bowel resection) 
20. 
Serious, non-healing wound or ulcer 
21. 
Medically significant hemorrhage within 30 days of randomization; patients who are at 
risk of severe hemorrhage. 


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22. 
Patients who have received a live / attenuated vaccine within 30 days of randomization 
23. 
Known current drug or alcohol abuse 
24. 
Any contraindication or exclusions specific to sunitinib and cabozantinib included in the 
current Package Insert, Summary of Product Characteristics (SmPC), or the prescribing 
guidelines applicable to your country.   
25. 
Any condition including medical, emotional, psychiatric, or logistical that, in the opinion 
of the Investigator, would preclude the patient from adhering to the protocol or would 
increase the risk associated with study participation or study drug administration or 
interfere with the interpretation of safety results (e.g., a condition associated with 
diarrhea or acute diverticulitis). 
26. 
Patients with inadequately treated adrenal insufficiency  
 


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5.0 
INVESTIGATIONAL PLAN 
5.1 
Study Design 
This is a multicenter, randomized, open label, Phase 3 study that will evaluate the efficacy and 
safety of NKTR-214 combined with nivolumab compared with the Investigator’s choice of a 
TKI, either sunitinib or cabozantinib, in patients with previously untreated advanced RCC. 
The treatment period of the study is divided into multiple treatment cycles with associated 
evaluations and procedures.  One cycle of treatment is defined as 6 weeks.  Results of the 
assessments must be reviewed and documented before administering the scheduled dose of study 
drugs.  In certain circumstances, patients with progressive disease (PD) per mRECIST 1.1 but 
with otherwise stable or improved performance and clinical status may continue to be treated in 
the event of a perceived benefit per Investigator; see Section 5.4.4 for treatment beyond 
progression criteria.  This study is divided into a Screening period, a Treatment period, and a 
Long-Term Follow-Up period, which will continue until withdrawal of consent, death, loss to 
follow-up, or study termination by the Sponsor. 
Approximately 600 patients with previously untreated advanced RCC will be randomized in a 
1:1 ratio between the two treatment arms:  
• Arm A: NKTR-214 0.006 mg/kg IV q3w combined with nivolumab 360 mg IV q3w 
• Arm B: The Investigator’s choice of either one of the following treatments   
o Sunitinib 50 mg orally (po) once daily for 4 weeks followed by 2 weeks off   
OR 
o Cabozantinib 60 mg po once daily  
Randomization will be stratified by: 
• The International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) prognostic 
score (0 [favorable risk] versus 1-2 [intermediate risk] versus 3-6 [poor risk]); laboratory data 
to calculate IMDC score are based on central laboratory results; 
• TKI choice (sunitinib or cabozantinib) 
Figure 1 provides the study schematic and the study procedures are provided in the Schedules of 
Events as follows: 
• Screening Schedule of Events:  Table 1 
• On-Treatment Schedule of Events for Arm A:  Table 2 
• On-Treatment Schedule of Events for Arm B:  Table 3  
• Long-Term Follow-Up:  Table 4  


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5.2 
Screening Period 
Patients will provide written informed consent to participate in the study before completing any 
protocol-specified procedures or evaluations not considered to be part of the patient’s standard 
care. After signing the ICF, patients will be evaluated for entry criteria during the Screening 
period based on assessments outlined in Table 1.  Rescreening after screen failure will be 
allowed.  
5.3 
Screening Failure 
Screen failures are defined as patients who consent to participate in the clinical study but are not 
subsequently randomized.  A minimal set of screen failure information is required to ensure 
transparent reporting of screen failure patients, to meet the Consolidated Standards of Reporting 
Trials (CONSORT) publishing requirements, as applicable, and to respond to queries from 
regulatory authorities.  
Patient re-screening: this study permits the re-enrollment of a patient that has discontinued the 
study as a pre-treatment failure (i.e., patient has not been randomized / has not been treated).  If 
re-enrolled, the patient must be re-consented. 
Retesting of laboratory parameters and/or other assessments within any single Screening or 
Lead-in period will be permitted (in addition to any parameters that require a confirmatory 
value). 
The most current result prior to Randomization is the value by which study inclusion will be 
assessed, as it represents the patient’s most current, clinical state. 
Laboratory parameters and/or assessments that are included in Table 1 may be repeated in an 
effort to find all possible well-qualified patients.   
5.4 
Treatment Period 
Patients will be treated until a maximum of 2 years from Cycle 1 Day 1 (Arm A only), disease 
progression per mRECIST 1.1 in the absence of clinical benefit as determined by the 
Investigator, death, unacceptable toxicity, symptomatic deterioration, the Investigator’s decision 
to discontinue treatment, the patient decides to discontinue treatment or withdraw consent, the 
patient is lost to follow-up, or termination of the study by the Sponsor. 
Patients with PD per mRECIST 1.1 but with otherwise stable or improved performance and 
clinical status may continue to be treated in the event of a perceived benefit per Investigator; see 
Section 5.4.4 for treatment beyond progression.  Patients with a partial response (PR) or with 
stable disease (SD) will continue to receive study drugs until disease progression, or 
intolerability to therapy. It is at the discretion of the Investigator to continue treating patients 
with a confirmed CR, for a maximum treatment of 2 years from Cycle 1 Day 1 (Arm A only). 


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5.4.1 Administration of Study Drug 
Patients should begin study treatment within 5 calendar days following randomization. 
Table 5 provides the timing of study drug administration. 
Table 5: 
Selection and Timing of Dose 
Study Treatment 
Starting dose 
Frequency of Administration 
Route of Administration 
NKTR-214 a 
0.006 mg/kg 
Q3W 
IV 
Nivolumab  
360 mg  
Q3W 
IV 
Sunitinib 
50 mg 
A 6-week cycle, consisting of 
once daily regimen for 4 weeks 
followed by no treatment for 
2 weeks 
PO  
(with or without food) 
Cabozantinib 
60 mg 
(40 mg for patients with 
moderate hepatic 
impairment [Child-Pugh 
Class B])  
once daily 
PO 
(Food fasting is 
recommended 2 h prior and 
1 h after administration) 
a. 
NKTR-214 dose is based on IL-2 content 
 
Child-Pugh Class is assessed using total bilirubin, serum albumin, prothrombin time, ascites and 
hepatic encephalopathy (for scoring, see Renown, 2018).  Patients with mild hepatic impairment 
(Child-Pugh Class A) do not require a reduced starting dose of cabozantinib.  
Patients randomized to Arm B must agree to complete a pill diary to record oral dosing, which 
will be reviewed by the Investigator or designee at the beginning of each cycle, starting with 
Cycle 2. 
5.4.1.1 
NKTR-214 Dosing 
Each patient’s NKTR-214 dose will be determined by the patient’s weight in kilograms, which 
will be determined on the day of each NKTR-214 dosing.  If the patient’s weight is within 10% 
of the Cycle 1 Day 1 weight, the study drug doses do not need to be recalculated depending on 
institutional guidelines/preference.  If the patient’s weight has changed more than 10% from the 
Cycle 1 Day 1 weight, the dose of NKTR-214 must be recalculated and subsequent weight 
measurements should be compared with this new baseline weight to determine if further 
NKTR-214 dose recalculations are necessary. 
Patients should receive NKTR-214 at a starting dose of 0.006 mg/kg on Day 1 and Day 22 of 
each treatment cycle until progression, unacceptable toxicity, withdrawal of consent, completion 
of 2 years (Arm A only) of treatment from Cycle 1 Day 1, the study ends, or other 
protocol-specified reasons in Section 5.4.3, whichever occurs first.  Patients may be dosed no 


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less than 18 days from the previous dose. Study agent(s) should be administered in an area with 
access to resuscitation equipment. 
NKTR-214 will be administered first, before nivolumab. NKTR-214 will be administered IV 
over 30 (± 5) minutes at a starting dose of 0.006 mg/kg every 3 weeks.  The duration of infusion 
of NKTR-214 may be increased if necessary (e.g., patient history of infusion reaction) (see 
Pharmacy Manual for details). 
Patients should be carefully monitored for infusion reactions during NKTR-214 administration. 
If an acute infusion reaction is noted, patients should be managed according to Section 5.13.9. 
NKTR-214 treatment can continue for patients randomized to Arm A in the event that nivolumab 
is stopped due to toxicities. 
 
 
 
 
 
 
 
  
 
 
  
Please refer to the Pharmacy Manual/current Investigator’s Brochure for details regarding 
NKTR-214 reconstitution, preparation, storage, and administration. 
5.4.1.2 
Nivolumab Dosing 
Nivolumab administration should start at least 30 minutes after the end of the NKTR-214 
administration.  Nivolumab will be administered IV over 30 (± 5) minutes at a dose of 360 mg.  
The duration of infusion of nivolumab may be increased if necessary (e.g., patient history of 
infusion reaction) (see Pharmacy Manual for details). 
There will be no dose escalations or reductions of nivolumab allowed.  Patients may be dosed no 
less than 18 days from the previous dose. Premedications are not recommended for the first dose 
of nivolumab.  
Patients should be carefully monitored for infusion reactions during nivolumab administration.  
If an acute infusion reaction is noted, patients should be managed according to Section 5.13.9. 


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Instructions for dilution and infusion of nivolumab injection will be provided in the Pharmacy 
Manual. 
5.4.1.3 
Sunitinib and Cabozantinib Dosing 
Sunitinib will be administered on a 6-week cycle, starting at a dose of 50 mg once daily for 
4 weeks, followed by 2 weeks of no treatment.  Cabozantinib will be administered at a starting 
dose of 60 mg once daily; for patients with moderate hepatic impairment (Child Pugh Class B) 
the starting dose of cabozantinib will be 40 mg once daily.  Food fasting is recommended for 
2 hours before and 1 hour after cabozantinib administration.  Table 7 provides the permitted 
doses for sunitinib and cabozantinib. Refer to the sunitinib (Sutent®) and cabozantinib 
(Cabometyx®) US Prescribing Information and/or the corresponding SmPC for updated dosing 
guidance or further information. 
5.4.2 Monitoring Vital Signs and Hydration Guidelines 
The study site must be equipped for medical emergencies. 
5.4.2.1 
Frequent Vital Signs 
Refer to Section 8.17 for vital sign measurements, which are to be monitored according to the 
Schedule of Events (Section 1.2). 
5.4.2.2 
Hydration Guidelines for Arm A 
Important safety information and hydration instructions are to be provided to patients 
randomized to Arm A.  Details regarding intravenous and oral hydration will be captured in the 


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electronic data capture (EDC). Oral hydration details during Cycle 1 will be captured in a patient 
hydration diary.  
Adequate hydration mitigates the development of hypotension associated with NKTR-214 
administration.  Hydration and renal function must be assessed within 24 hours, or as soon as 
locally feasible, prior to NKTR-214 study drug administration see Appendix 3 for the list of 
analytes that require collection and evaluation prior to NKTR-214 study drug administration).  
For patients who must delay study treatment due to creatinine increase, see additional 
information regarding criteria to delay (Sections 5.13.1 and 5.13.2), resume (Section 5.13.7), or 
permanently discontinue study treatment (Section 5.14).  Underlying reasons for decreased oral 
intake (e.g., nausea) should be addressed and treatment (e.g., IV hydration) should be provided.  
The Investigator may modify these recommendations based on the needs of the individual 
patient.  Patients will also be provided a handout with hydration guidance.  
Patients randomized to Arm A should be administered 1 liter of IV fluid on the day of each 
dosing of NKTR-214.  Patients are to be instructed that for the next 3 days after administration of 
NKTR-214, they should drink at least 2 liters per day of self-administered oral hydration.  Avoid 
activity that may contribute to dehydration (including, but not limited to, strenuous activity, long 
hot showers, and saunas) on the day of NKTR-214 administration and for the next 3 days after 
NKTR-214 administration.   
Per clinical judgment, IV fluids may be administered at any time during any cycle.  The 
Investigator may decide to forego administering IV fluids to a patient or adjust the 
recommendation for self-oral hydration to a particular patient if this is deemed in the best interest 
of the patient (e.g., evidence of fluid overload).  Advise patients with orthostatic symptoms to 
call their treating oncologist and consider increasing oral hydration. 
Patients with pre-existing adrenal impairment requiring corticosteroid supplementation may be at 
increased risk for hypotensive episodes during treatment with NKTR-214 (See Section 5.13.5).  
Between 2 and 4 days, inclusive, following administration of the first 2 doses of NKTR-214, site 
personnel must contact the patient (by telephone or clinic visit) to remind the patient of the oral 
hydration guidelines, to assess for any symptomatology and compliance with the guidelines, and 
document compliance and symptoms from the discussion (Section 1.2).  Following subsequent 
NKTR-214 administrations, the oral hydration follow-up should be conducted as clinically 
indicated for patients receiving NKTR-214. 
5.4.3 Duration of Treatment 
Patients will remain on treatment until: 
• Disease progression in the absence of clinical benefit as determined by the Investigator 
• Death 
• Unacceptable toxicity 


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• Symptomatic deterioration 
• 2 years from Cycle 1 Day 1 (Arm A only) 
• Investigator’s decision to discontinue treatment 
• Patient decision to discontinue treatment  
• Patient withdraws consent 
• Patient is lost to follow-up 
• The Sponsor decides to terminate the study 
5.4.4 Treatment Beyond Progression 
Accumulating evidence indicates that a minority of patients with solid tumors treated with 
immunotherapy may derive clinical benefit despite initial evidence of PD (Wolchock, 2009; 
Nishino, 2015).  Study treatment decisions will be based on the Investigator’s assessment of 
tumor images and not on the BICR assessment (Section 7.4). Patients in both treatment arms will 
be permitted to continue on treatment beyond initial mRECIST 1.1-defined PD as long as they 
meet the following criteria: 
• Investigator-assessed clinical benefit 
• Patient tolerates study drug(s) 
• Patient has stable performance status 
• Treatment beyond progression will not delay an imminent intervention to prevent serious 
complications of disease progression (e.g., central nervous system metastases requiring 
immediate treatment). 
• Patient provides written informed consent prior to receiving additional study treatment. All 
other elements of the main consent including description of reasonably foreseeable risks or 
discomforts, or other alternative treatment options will still apply. 
The assessment of clinical benefit should take into account whether the patient is clinically 
deteriorating and unlikely to receive further benefit from continued treatment.  All decisions to 
continue treatment beyond initial progression, including an assessment of the risk/benefit of 
continuing with study drug(s), must be documented in the study records.  The ICF contains 
language explaining treatment beyond progression; should the Investigator recommend 
continuing treatment following disease progression, the patient must be re-consented prior to 
continuing study treatment. 
For patients who stay on treatment beyond mRECIST 1.1-defined PD, all study procedures 
(Section 1.2) should be performed continuously, including radiographic assessment by CT 
(preferred) or MRI on the described schedule in Section 7.0. CT/MRI assessments should 
continue until criteria for treatment discontinuation are met and BICR-assessed progression has 


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occurred. Tumor assessments are no longer required if subsequent anticancer therapy is started, 
even if the patient has not yet progressed. 
Treatment beyond progression should be stopped when Investigator assesses a loss of clinical 
benefit.  The criteria may include clinical disease progression, second PD of target lesions per 
mRECIST 1.1, radiographic progression of non-target lesions, or new lesions.  Discussion with 
the Medical Monitor is encouraged. 
5.5 
Discontinuation from Study Treatment  
Patients may choose to discontinue the trial at any time, for any reason, and without prejudice to 
further treatment.  Patients may discontinue treatment of all or one of the study drugs based on 
AEs (see Section 5.13).   
Reasons for discontinuation of study treatment are listed in Section 5.14. 
In the event of a patient’s withdrawal, the Investigator will promptly notify the Sponsor and 
make every effort to complete the Long-Term Follow-Up Schedule of Events specified in 
Table 4 (Section 1.2). 
A patient may also be withdrawn from investigational product/study by the Sponsor, Regulatory 
Authorities, or Institutional Review Boards (IRBs)/Independent Ethics Committees (IECs). 
5.6 
Long-Term Follow-Up 
Long-term follow-up comprises 2 Safety Follow-Up Visits and Survival Follow-Up. For patients 
who discontinue study treatment, radiographic tumor assessments will continue to be collected 
every 9 weeks (± 7 days) from randomization through (and inclusive of) Week 54 and then every 
12 weeks (± 7 days) until both BICR and Investigator’s assessments of tumor images have 
determined progression, patient withdraws consent, patient begins a subsequent anticancer 
therapy, loss to follow up, death, or study termination by the Sponsor. Additional assessments 
are described in Table 4.  
5.6.1 
Safety Follow Up  
• Safety Follow-up Visit 1 should occur 30 (± 7) days from the last dose of all study drug, or at 
the time of permanent treatment discontinuation if discontinuation is after the Safety Follow 
Up Visit 1 window.   
• Safety Follow-up Visit 2 occurs 100 (± 7) days from the last dose of all study drug. Safety 
follow-up visits should occur regardless of initiation of subsequent anticancer therapy.   
• Both Safety Follow-Up Visits should be conducted in person.   
• Per clinical judgment, the patient may come in earlier for additional follow up. 


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• Patients will also be followed for safety until resolution or permanent sequelae of all 
toxicities attributable to study drugs (NKTR-214 and/or nivolumab or TKI) as outlined in 
Sections 8.5 and 8.8.  
• For AE and SAE reporting periods, please refer to Sections 8.5 and 8.7. 
5.6.2 
Survival Follow Up 
• All patients will be contacted for survival every 12 weeks (± 14 days) following the Safety 
Follow-Up Visit 2 (or following last contact with the patient if Safety Follow-Up Visit 2 is 
missed).  
• Survival visits may be conducted in person or by telephone.  
• Information about subsequent anticancer therapy will also be collected during these contacts.   
• The Sponsor may request that survival data be collected on all treated patients outside of the 
scheduled contacts.  At the time of this request, each patient will be contacted to determine 
their survival status unless the patient has withdrawn consent for all contact or is lost to 
follow-up.  Patients are not considered lost to follow up until after demonstration of due 
diligence with follow-up efforts. Alternative methods to determine survival status may be 
used (e.g., access to medical records and public record searches) as allowed by local 
regulations and/or guidelines.   
• For patients who discontinue study treatment, radiographic tumor assessments will continue 
to be collected every 9 weeks (± 7 days) from randomization through (and inclusive of) 
Week 54 and then every 12 weeks (± 7 days) until both BICR and Investigator’s assessments 
of tumor images have determined progression, patient withdraws consent, death, initiation of 
subsequent anticancer therapy, loss to follow up, or study termination by the Sponsor. 
• Additional subsequent anticancer therapy details such as regimen, setting of the regimen, line 
of therapy, start date and end date of each regimen, best response to the regimen, and date of 
progression after next line of therapy will be collected. 
• Survival follow up should continue until patient withdrawal of consent for survival follow 
up, death, loss to follow-up, or study termination by the Sponsor.   
5.7 
End of Study 
End of study is defined as no more than 3 years after the last patient received their first dose of 
NKTR-214 or Sponsor decision to terminate the study, whichever comes first.  
5.8 
Tumor and Radiographic Assessments 
Tumor assessments for all patients will be performed as specified in Section 1.2. 
Tumor response will be evaluated using mRECIST 1.1 described in Section 7.0. 


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Radiographic assessments (chest/abdomen/pelvis) are required for all patients for tumor 
measurements. MRI of the brain without and with contrast is required for patients at baseline. CT 
of the brain (without and with contrast) can be performed if MRI is contraindicated. 
Documented tumor measurements are required using CT scans, MRI, physical examination, 
and/or digital photography, as appropriate.  Any imaging used to assess disease at any time point 
will be submitted for an independent radiology review.  Clinical information (palliative 
radiotherapy on-study, surgical excision of any lesion, details of paracentesis and 
thoracocentesis) must be provided to the BICR team. 
The same method of assessment (CT or MRI and/or digital photography) and the same technique 
for acquisition of images must be used for all study assessments (contrast must be used unless 
medically contraindicated).  Baseline imaging should be done at the same institution/facility that 
will be used to measure response during the patient’s participation in the study.  Radiographic 
assessments and efficacy analyses will be conducted by the Investigator site as well as the 
independent radiology review. 
If a patient has an unconfirmed PR or CR, an early scan is recommended 4 weeks later (e.g., if 
the initial observation of PR was seen at Week 9, a Week 13 scan should occur); subsequent 
tumor assessments must remain on the original assessment schedule (i.e., at Week 18, Week 27, 
Week 36, Week 45, etc.).  For patients with unconfirmed progressive disease, subsequent tumor 
assessments must remain on the original assessment schedule (i.e., at Week 18, Week 27, 
Week 36, etc.), unless an early scan is clinically indicated. 
ORR and PFS will be evaluated by a BICR as part of this clinical study.  Images must be 
submitted to the BICR on the schedule outlined in the Study 17-214-09/CA045002 Imaging 
Manual.  Patients who discontinue study treatment should continue to have tumor assessments 
until both BICR and Investigator’s assessments of tumor images have determined progression or 
a subsequent anticancer therapy is started (Section 5.6). Patients who continue treatment beyond 
BICR-confirmed progression (Section 5.4.4) will continue to have tumor assessments until 
documentation of PD by the Investigator. 
5.9 
Pharmacokinetic, Biomarker, 
 
For Arm A, blood samples for PK analyses of NKTR-214, its metabolites, and nivolumab will be 
collected as described in Table 6. 


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Table 6: 
Pharmacokinetic, Biomarker, 
  
Study Day of 
Sample Collection 
(1 Cycle = 6 weeks) 
Event 
Time (Relative 
to Start of 
NKTR-214 
Infusion) 
Hour: Min 
NKTR-214 
PK Blood 
Sampled 
 
 
 
Nivolumab 
PK Blood 
Sample 
 
 
 
CVA 
Biomarkers 
Cycle 1 Day 1 
Pre-dose 
00:00 
X 
 
X 
 
Xe 
EOIa 
00:30 
X 
 
 
 
 
 
4:00b 
X 
 
 
 
 
Cycle 1 Day 3c 
 
48:00 
X 
 
 
 
 
Cycle 1 Day 5c 
 
96:00 
X 
 
 
 
 
Cycle 1 Day 8c 
 
168:00 
X 
 
 
 
 
Cycle 1 Day 22 
Pre-dose 
00:00 
X 
 
X 
 
Xe 
Cycle 3 Day 1 
Pre-dose 
00:00 
X 
 
X 
 
Xe 
EOIa 
00:30 
X 
 
 
 
 
Cycle 4 Day 1 
Pre-dose 
00:00 
 
 
 
 
Xe 
Cycle 6 Day 1 
Pre-dose 
00:00 
X 
 
X 
 
Xe 
Cycle 9 Day 1 
Pre-dose 
00:00 
X 
 
X 
 
Xe 
Cycle 12 Day 1 
Pre-dose 
00:00 
X 
 
X 
 
Xe 
Cycle 15 Day 1 
Pre-dose 
00:00 
X 
 
X 
 
Xe 
Safety Follow Up 1  
 
 
 
X 
 
 
Safety Follow Up 2  
 
 
 
X 
 
 
Time of CVA event  
 
 
 
 
 
Xe 
CVA = cerebrovascular accident; EOI = end of infusion; 
; TIA = transient ischemic attack  
a. 
This sample should be taken immediately prior to the stopping NKTR-214 infusion (preferably within 
2 minutes prior to the end of infusion). If the end of infusion is delayed to beyond the nominal infusion 
duration, the collection of this sample should also be delayed accordingly. 
b. Time window is ±1 hour for this sample (i.e., range 03:00 to 05:00 hours). Sample is preferred as close to 
04:00 hours as is clinically feasible.  
c. 
Time windows: -1 day for C1D3 (24-48 hours relative to start of NKTR-214 infusion), ± 1 day for C1D5 
and -1 day for C1D8 
d. 
  
e. 
 
 
 
 
 CVA and TIA 
biomarker samples will be obtained from patients from whom a Cycle 1 Day 1 biomarker sample has been 
collected (see Section 5.10.3).  




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Serum samples will be collected and processed as outlined in the Laboratory Manual that will be 
provided to the site. 
5.10 
Biomarkers 
A variety of factors that could potentially predict clinical responses to NKTR-214 combined with 
nivolumab or to TKIs will be investigated in peripheral blood and in tumor specimens taken 
from all patients prior to, and on treatment and as outlined in Table 6 and the Schedule of Events 
(Table 1 through Table 4), respectively.  Data from these investigations will be evaluated for 
associations with response, survival (OS, PFS), and/or safety (AE) if data allows.  
 
 
  
Complete instructions on the collection, processing, handling and shipment of all samples 
described herein will be provided in the Laboratory Manual. 
Sites may only opt out of biomarker sampling if they meet one of the following criteria: inability 
to process these samples, insufficient storage facilities, or unavailable courier pickup / dry ice. 
5.10.1 Tumor Tissue Biopsy Collection 
All patients must have tumor tissue identified and available to be sent during the Screening 
period:   
• Most recent archival sample prior to randomization, from a site not previously irradiated and 
with no intervening treatment between time of acquisition and randomization  
OR 
• A fresh pre-treatment biopsy obtained during the Screening Period. 
Archival tissue should be provided in a formalin-fixed paraffin-embedded (FFPE) block or as 
unstained slides (minimum of 8 slides, preferably 20 slides) that have been sectioned within the 
3 months prior to randomization.  If 8 unstained slides are not available, fewer slides may be 
submitted; please contact the Medical Monitor for written approval.  Leftover tissue blocks, but 
not slides, will be returned upon request.  
Tumor samples must be a core biopsy, punch biopsy, excisional biopsy, or surgical specimen.  
Biopsy in bone lesion cannot be accepted.  Fine needle aspirates/biopsy or other cytology 
specimens are insufficient for randomization.  Biopsies of bone lesions that do not have a soft 
tissue component are also unacceptable for submission.  Target lesions should not be biopsied 
unless there are no other lesions suitable for biopsy.  
Collection of tissue samples in Cycle 1 between Days 14 and 21 and at the time of PD is optional 
but highly encouraged as they may help inform on the underlying biology of early 


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response/progression, and the biological mechanisms underlying acquired and/or de novo 
resistance to the drug(s) administered.  
Pre-treatment tumor samples will be submitted for central PD-L1 IHC assessment.  PD-L1 
expression is defined as the percent of tumor cell membrane staining in a minimum of 100 
evaluable tumor cells per validated Dako PD-L1 PharmDx 28-8 IHC assay.  PD-L1 stained 
tissue sections will be assessed by a pathologist and scored as PD-L1 expression ≥ 1% or PD-L1 
expression < 1% based on the frequency of tumor cell surface PD-L1 staining.  Samples that 
have < 100 evaluable cells are considered not evaluable.  Where membrane staining is obscured 
by high cytoplasmic staining, but the tumor tissue sample contains the minimum number of 
evaluable tumor cells, samples will be deemed PD-L1 indeterminate.  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 




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days spent in various wards and discharge diagnosis, as well as non-protocol specified visits 
related to study therapy, including date of visit, reason for visit, and type of visit.  The health 
care resource utilization data will be used to support subsequent economic evaluations. 
5.12 
Health-Related Quality of Life (HRQoL) 
Patients will be asked to complete the NCCN/FACT Symptom Index for Kidney Cancer 
(FKSI-19), EQ-5D-3L, and selected items from the PRO-CTCAE.  Refer to Section 7.6 for 
additional information.  
5.13 
Dosage Modification 
Every effort should be made to follow planned dosing schedules for all study drugs in both 
treatment arms. Study drug administration may be delayed or modified for toxicity as described 
below and must be discontinued as required by criteria described in Section 5.14. 
Dose modification for NKTR-214 and nivolumab in Arm A may be considered independently 
based on Investigator assessment of relationship of a toxicity to each of the study drugs.  If only 
one of the study drugs meets the criteria for dose delay, then administration of the other study 
drug may be continued or delayed at the discretion of the Investigator.  Likewise, in the event 
that one of the study drugs in Arm A is permanently discontinued due to toxicities, the other can 
continue to be administered.   
Patients who require delay of nivolumab or NKTR-214 should be re-evaluated weekly or more 
frequently if clinically indicated and should resume treatment with combination of NKTR-214 
and nivolumab when retreatment criteria are met (Section 5.13.7).  Immuno-oncology agents are 
associated with AEs that can differ in severity and duration from AEs caused by other 
therapeutic classes.  NKTR-214 and nivolumab are considered an immuno-oncology agent in 
this protocol.  Early recognition and management of AEs associated with immuno-oncology 
agents may mitigate severe toxicity.  
For patients randomized to Arm A: NKTR-214 or nivolumab administration defines a scheduled 
nominal dosing visit (i.e., Cycle X Day 1, Cycle X Day 22).  If a patient is assessed for an 
intended nominal dosing visit but study drug is not administered (e.g., due to an AE requiring 
dose delay, drug unavailable), any assessments performed during that visit should be recorded as 
“unscheduled.”  When study drug administration resumes, all assessments should be performed 
as scheduled for the next nominal dosing visit (i.e., Cycle X Day 1 or Cycle X Day 22 Visit).  
For patients randomized to Arm B: Cycle 1 Day 1 is defined by the date that the first dose of 
sunitinib or cabozantinib is administered.  Within a cycle, missed doses of sunitinib should be 
skipped and not replaced. Scheduled Cycle X Day 1 and Cycle X Day 22 visits are fixed relative 
to Cycle 1 Day 1, regardless of dose delays.  If drug dosing is delayed at the time of these 
scheduled visits (e.g., due to an AE requiring dose delay, drug unavailable), the cycle visit is not 
shifted and all assessments should be performed as scheduled. 


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Tumor assessments for all patients should continue as per protocol even if dosing is delayed. 
5.13.1 NKTR-214 Dose-Delay and Reduction Criteria 
Dose delays and reductions are permitted for NKTR-214. NKTR-214 may be delayed or reduced 
to 0.003 mg/kg based on observed drug-related toxicities.  If the NKTR-214 dose is reduced to 
0.003 mg/kg, the dose level should remain at this level throughout the remainder of the study.  
NKTR-214 should be delayed for the following reasons: 
• For persistent Grade 2 related toxicity, a dose delay or dose reduction may be implemented at 
the discretion of the Investigator. 
o Grade ≥ 2 creatinine increase  
- For patients who must delay study treatment due to Grade ≥ 2 creatinine increase due 
to a non-inflammatory cause, delay retreatment with study drug for approximately 3 
to 5 days.  After the dosing delay, the patient may resume study drug when serum 
creatinine has returned to Grade ≤ 1, as assessed within 24 hours prior to redosing.  
For further guidance, refer to renal adverse event management algorithm in current 
Nivolumab Investigator’s Brochure.   
• Grade ≥ 3 toxicity at least possibly related to NKTR-214: NKTR-214 must be delayed until 
resolution to Grade 1 or baseline (unless otherwise requiring permanent discontinuation, per 
Section 5.14.1.1) with the following exceptions: 
o Grade ≥ 3 lymphopenia 
o Grade ≥ 3 asymptomatic amylase or lipase elevation 
• Patient has acute infection (e.g., fever, upper or lower respiratory tract infection) requiring 
systemic antibiotic therapy.  Patient may resume study treatment once free of signs or 
symptoms for 72 hours after completion of antibiotic therapy (See Section 5.13.7).  
• Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of 
the Investigator, warrants delaying the dose of study medication. 
NKTR-214 dosing may resume at the same dose or at a lower dose level when toxicity resolves 
to Grade 1 or returns to baseline, except for instances where the potential recurrence of the event 
poses an undue risk for the patient.  Medical Monitor consultation is required for dose reduction. 
5.13.2 Nivolumab Dose-Delay and Reduction Criteria 
Dose reductions for nivolumab are not permitted in this study.  
Nivolumab administration should be delayed for the following: 
• Grade 2 non-skin, drug-related AE, with the exception of fatigue 
• Grade 2 drug-related creatinine, AST, ALT and/or total bilirubin abnormalities 


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• Grade 3 skin, drug-related AE 
• Grade 3 drug-related laboratory abnormality, with the following exceptions:  
o Grade 3 lymphopenia or asymptomatic amylase or lipase does not require dose delay 
o Grade ≥ 3 AST, ALT, and/or total bilirubin will require dose discontinuation (unless 
satisfying the Cycle 1 ALT/AST elevation criteria outlined in Section 5.13.3) 
• Patient has acute infection (e.g., fever, upper or lower respiratory tract infection) requiring 
systemic antibiotic therapy.  Patient may resume study treatment once free of signs or 
symptoms for 72 hours after completion of antibiotic therapy (See Section 5.13.7).  
• Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of 
the Investigator, warrants delaying the dose of study medication. 
Patients who require delay of nivolumab should be re-evaluated weekly or more frequently if 
clinically indicated and resume nivolumab dosing when retreatment criteria are met. 
5.13.3 Dose-Modification Criteria for NKTR-214 and Nivolumab for Cycle 1 ALT/AST 
Elevations 
These recommendations are for Cycle 1 only and are not intended to serve as rigid guidelines or 
to replace clinical judgment.  Subsequent cycles should follow standard Hepatic Adverse Event 
Management Algorithm (see the nivolumab Investigator’s Brochure). 
Rule out non-inflammatory etiologies.  If non-inflammatory cause, treat accordingly and 
continue NKTR-214 and nivolumab.  Consider imaging for obstruction.  
If during monitoring ALT/AST increases, follow the guidance for the highest levels. 
ALT or AST > 3.0 to ≤ 5.0 × ULN (within first cycle of NKTR-214 + nivolumab) 
Increase frequency of liver function test (LFT) monitoring to approximately every 3 days and 
delay treatment until lab abnormalities resolve to Grade 1 or baseline. 
If no improvement within 7 days, treat with 0.5-1 mg/kg/day prednisone equivalents, and taper 
steroids over at least 1 month before resuming treatment. 
ALT or AST > 5.0 to ≤ 8.0 × ULN (within first cycle of NKTR-214 + nivolumab) 
Increase frequency of monitoring to approximately every 3 days until lab abnormalities resolve 
to Grade 1 or baseline. 
Treatment must be delayed until lab abnormalities resolve to Grade 1 or baseline. 
If no improvement within 7 days (follow Hepatic Adverse Event Management Algorithm); 


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• Discontinue NKTR-214 + nivolumab 
• 1 to 2 mg/kg/day prednisone equivalents followed by corticosteroid taper over at least one 
month 
• Consult gastroenterologist 
• Consider adding non-corticosteroid immunosuppressive medication if no improvement in 
> 3-5 days, worsens or rebounds while on steroids 
ALT or AST > 8.0 × ULN (follow Hepatic Adverse Event Management Algorithm) 
• Discontinue NKTR-214 + nivolumab 
• Increase frequency of monitoring to approximately 1-2 days 
• 1 to 2 mg/kg/day prednisone equivalents followed by corticosteroid taper over at least one 
month 
• Consult gastroenterologist 
• If no improvement in > 3–5 days, worsens or rebounds, add non-corticosteroid 
immunosuppressive medication 
Please refer to Section 5.14 for discontinuation criteria. 
5.13.4 
Monitoring and Management of Elevated Hepatic Transaminases 
Elevated hepatic transaminases are an overlapping toxicity that can occur for both NKTR-214 
and nivolumab.  The elevations in hepatic transaminases associated with NKTR-214 typically 
occur at the time of peak active cytokine concentration in the blood (Days 4-8) and are often 
accompanied by other IL-2 mediated AEs such as flu-like symptoms, rash or pruritus.  The 
transient elevations in hepatic transaminases are usually asymptomatic, mild or moderate in 
severity, not associated with increased total bilirubin and alkaline phosphatase, resolve 
spontaneously without treatment, and predominantly occur in Cycle 1 and Cycle 2; the 
transaminase elevations are considered to occur in the context of IL-2 mediated AEs.  For 
transaminase elevations occurring in Cycle 1 consistent with a cytokine-related effect without 
alternative etiologies, follow the Cycle 1 hepatic adverse event management guideline 
(Section 5.13.3). 
Hepatic events, including elevated LFTs, have also been observed for nivolumab.  Most cases 
were of low or moderate severity.  Higher grade abnormalities are concerning for 
immune-mediated hepatitis, and typically occur with a later onset (median time to onset of 
3.3 months).  Immune-mediated hepatitis generally results in a quick rise in LFTs and responds 
to corticosteroids or immune-modulating agents.  For transaminase elevations occurring in 
Cycle 2 onwards potentially involving an immune-mediated mechanism, follow the 
immune-mediated hepatic adverse event management guidelines in the nivolumab Investigator’s 
Brochure or product labeling for appropriate management.  


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5.13.5 
Monitoring and Management of Adrenal Insufficiency and Hypophysitis  
Adrenal insufficiency and hypophysitis have been observed in patients receiving NKTR-214 and 
nivolumab. Consider prompt evaluation when patients have signs or symptoms of hypophysitis 
or adrenal insufficiency which includes levels of early-morning adrenocorticotropic hormone, 
cortisol, thyroid stimulating hormone (TSH), and free thyroxine (T4).  Co-management with an 
endocrinologist is recommended for patients with pre-existing adrenal insufficiency. 
5.13.6 
Monitoring and Management of Eosinophilia 
5.13.6.1 
NKTR-214-induced Eosinophilia 
Frequent and significant eosinophilia has been observed in patients receiving NKTR-214, 
primarily starting at Cycle 2 with levels plateauing after Cycle 3, consistent with the known 
pharmacodynamic effect of IL-2 therapy.  The eosinophilia pattern demonstrates a cyclic waxing 
and waning pattern whereby eosinophil levels peak approximately 7 days after each infusion and 
wane before the patient’s next infusion.  Isolated cases of hypereosinophilic syndrome and other 
eosinophilic disorders have been reported.   
Absolute eosinophil count (AEC) should be closely monitored per protocol.  If a study patient is 
suspected to have eosinophilic disorder (symptoms may involve skin, lungs, digestive tract, 
heart, blood, and nervous systems) with AEC at or above the 5000/µL (5 × 109/L) level, delaying 
NKTR-214 treatment may be considered while evaluating and treating the patient as clinically 
indicated.  
5.13.6.2 
Eosinophilic Disorders 
Isolated cases of hypereosinophilic syndrome and drug reaction with eosinophilia and systemic 
symptoms have been reported. If there is clinical concern for an eosinophilic disorder, the 
Investigator is encouraged to contact the Medical Monitor. 
Additional details regarding eosinophilia and eosinophilic disorders are provided in the 
NKTR-214 Investigator’s Brochure. 
5.13.7 
Criteria to Resume NKTR-214 and/or Nivolumab 
Patients will be permitted to resume study drug(s) at the same dose level(s) following resolution 
of an AE to Grade ≤ 1 or to baseline within 8 weeks after the last dose unless the Medical 
Monitor is consulted and agrees with the rationale for resuming therapy after 8 weeks, and with 
the exception of patients who meet criteria for permanent discontinuation as specified in 
Section 5.14.1.1.  If patients required steroids to treat an AE, the taper must be completed and 
dose should be < 10 mg prednisone per day.  Patients who meet criteria for permanent 
discontinuation must not receive further study therapy. 
Patients may resume treatment with study treatment when the drug-related AE(s) resolve to 
Grade ≤ 1 or baseline value, with the following exceptions: 


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• Patients who delayed dosing for acute infection requiring systemic antibiotic therapy must be 
free of signs or symptoms of infection for 72 hours after completion of antibiotic therapy 
prior to resuming study treatment.  
• Patients may resume study treatment in the presence of Grade 2 fatigue 
• Patients who have not experienced a Grade 3 drug-related skin AE may resume study 
treatment in the presence of Grade 2 skin toxicity 
• For patients with Grade 2 AST, ALT, and/or total bilirubin abnormalities, dosing may 
resume when laboratory values return to baseline and management with corticosteroids, if 
needed, is complete. 
• Drug-related pulmonary toxicity, diarrhea, or colitis must have resolved to baseline before 
treatment is resumed. Patients with persistent Grade 1 pneumonitis after completion of a 
steroid taper over at least 1 month may be eligible for retreatment if discussed with and 
approved by the Medical Monitor. 
• Drug-related endocrinopathies adequately controlled with only physiologic hormone 
replacement may resume treatment after consultation with the Medical Monitor. Grade ≥ 3 
adrenal insufficiency or Grade ≥ 4 hypophysitis require discontinuation regardless of control 
with hormone replacement (see Section 5.14.1 for permanent treatment discontinuation 
criteria). Hospitalization for diagnostic workup of adrenal insufficiency without severe 
symptoms should not require discontinuation. 
• For patients who must delay study treatment due to Grade ≥ 2 creatinine increase due to a 
non-inflammatory cause (see Sections 5.13.1 and 5.13.2) delay retreatment with study drug 
for approximately 3 to 5 days.  After the dosing delay, the patient may resume study drug 
treatment when serum creatinine has returned to Grade ≤ 1, as assessed within 24 hours, or as 
soon as locally feasible, except where permanent discontinuation of study drug is required 
(see Section 5.14.1.1). 
Dose delay of NKTR-214 combined with nivolumab that results in treatment delay of > 8 weeks 
requires treatment discontinuation, with exceptions as noted in Section 5.14.1.1.  However, if the 
toxicity resolves to Grade ≤ 1 or baseline > 8 weeks after the last dose, but the patient does not 
otherwise meet the criteria for permanent discontinuation (see Section 5.14.1.1), and the 
Investigator believes that the patient is deriving clinical benefit, then the patient may be eligible 
to resume the study drug(s) following the approval of the Medical Monitor. 
5.13.8 
Management Algorithms for Immune-Mediated AEs and Cytokine Release 
Syndrome 
5.13.8.1 
Management Algorithms for Immune-Mediated AEs Associated with 
Immuno-Oncology Agents  
Immuno-oncology agents are associated with AEs that can differ in severity and duration from 
AEs caused by other therapeutic classes.  Nivolumab and NKTR-214 are considered 
immuno-oncology agents in this protocol.  Early recognition and management of AEs associated 


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with immuno-oncology agents may mitigate severe toxicity.  Management Algorithms including 
the use of systemic corticosteroids (see the nivolumab Investigator’s Brochure) have been 
developed to assist Investigators in assessing and managing the following groups of AEs 
(including, but may not be limited to): 
• Gastrointestinal 
• Renal 
• Pulmonary 
• Hepatic 
• Endocrinopathy 
• Skin 
• Neurological (see Appendix 6)  
• Myocarditis 
5.13.8.2 
Cytokine Release Syndrome 
Events of CRS have been reported after NKTR-214 exposure (5 patients). The majority of CRS 
events reported in these trials were Grade 1 or Grade 2 and resolved. Two Grade 3 events of 
CRS were reported and resolved. These cases either co-reported IL-2 mediated symptoms or 
were confounded (i.e., infectious etiology). 
CRS is a clinical diagnosis with a constellation of symptoms often characterized by fever, 
tachypnea, headache, tachycardia, hypotension, rash, and/or hypoxia caused by the release of 
cytokines. In addition, diarrhea and end organ dysfunction can be seen in CRS. Many of these 
symptoms overlap with known AEs seen in NKTR-214 and nivolumab combination therapy 
(i.e., pyrexia and hypotension). These symptoms may be seen in infusion reactions as well as 
other known syndromes, such as tumor lysis syndrome and macrophage activation syndrome.  
Manifestations of infusion reactions are provided in Section 5.13.9. 
For suspected cases of CRS Grade 3 or higher, the Investigator is encouraged to contact the 
Medical Monitor. An algorithm for CRS management is provided in Appendix 7. 
5.13.9 
Treatment of NKTR-214 or Nivolumab-Related Infusion Reactions 
Infusion reactions have been reported during infusions with NKTR-214 and nivolumab. If such a 
reaction were to occur with either the NKTR-214 or nivolumab infusion, it might manifest with 
fever, chills, rigors, headache, rash, pruritus, arthralgias, hypotension, hypertension, 
bronchospasm, or other allergic-like reactions.  Infusion reactions should be graded as outlined 
below (consistent with Common Terminology Criteria for Adverse Events [CTCAE] v5.0 
grading of infusion-related reaction; please also refer to Section 8.3). 


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Treatment recommendations are provided below and may be modified based on local treatment 
standards and guidelines, as appropriate: 
For Grade 1 symptoms (mild reaction; infusion interruption not indicated; intervention not 
indicated): 
• Remain at the bedside and monitor the patient until recovery from symptoms. The following 
prophylactic premedications are recommended for future infusions: diphenhydramine 50 mg 
(or equivalent) and/or acetaminophen/paracetamol 325 to 1000 mg at least 30 minutes before 
subsequent infusions. Subsequent infusions may be administered at a reduced rate (e.g., 50% 
of the original infusion rate). 
For Grade 2 symptoms (moderate reaction requires therapy or infusion interruption but responds 
promptly to symptomatic treatment [e.g., antihistamines, non-steroidal anti-inflammatory drugs, 
narcotics, corticosteroids, bronchodilators, IV fluids]; prophylactic medications indicated for 
≤ 24 hours): 
• Stop the NKTR-214 or nivolumab infusion, begin an IV infusion of normal saline, and treat 
the patient with diphenhydramine 50 mg IV (or equivalent) and/or 
acetaminophen/paracetamol 325 to 1000 mg; remain at the bedside and monitor the patient 
until resolution of symptoms.  Corticosteroid and/or bronchodilator therapy may also be 
administered as appropriate.  If the infusion is interrupted, then restart the infusion at 50% of 
the original infusion rate when symptoms resolve; if no further complications ensue after 
30 minutes, the rate may be increased to 100% of the original infusion rate.  If symptoms 
recur after restarting the NKTR-214 or nivolumab infusion, then no further drug will be 
administered at that visit.  Administer diphenhydramine 50 mg IV, remain at the bedside, and 
monitor the patient until resolution of symptoms. 
• For future infusions, the following prophylactic premedications are recommended: 
diphenhydramine 50 mg (or equivalent) and/or acetaminophen/paracetamol 325 to 1000 mg 
administered at least 30 minutes before the infusion.  If necessary, corticosteroids (up to 
25 mg of methylprednisolone or equivalent) may be used (see Appendix 5 for corticosteroid 
dose equivalents). Subsequent infusions may be administered at a reduced rate (e.g., 50% of 
the original infusion rate). 
For Grade 3 or Grade 4 symptoms (severe reaction, Grade 3: prolonged [i.e., not rapidly 
responsive to symptomatic medication and/or brief interruption of infusion]; recurrence of 
symptoms following initial improvement; hospitalization indicated for other clinical sequelae 
[e.g., renal impairment, pulmonary infiltrates].  Grade 4: life-threatening; pressor or ventilatory 
support indicated): 
• Immediately discontinue infusion of NKTR-214 or nivolumab. Begin an IV infusion of 
normal saline and treat the patient as follows: recommend bronchodilators, epinephrine 0.2 to 
1 mg of a 1:1000 solution for subcutaneous administration or 0.1 to 0.25 mg of a 1:10,000 
solution injected slowly for IV administration, and/or diphenhydramine 50 mg IV with 


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methylprednisolone 100 mg IV (or equivalent), as needed.  NKTR-214 or nivolumab will be 
permanently discontinued. The patient should be monitored until the Investigator is 
comfortable that the symptoms will not recur. Investigators should follow their institutional 
guidelines for the treatment of anaphylaxis. Remain at the bedside and monitor the patient 
until recovery of the symptoms. 
In case of late-occurring hypersensitivity symptoms (e.g., appearance of a localized or 
generalized pruritus within 1 week after treatment), symptomatic treatment may be given 
(e.g., oral antihistamine or corticosteroids). 
5.13.10 
Sunitinib or Cabozantinib Dosing-Delay Criteria  
Sunitinib or cabozantinib dosing should be delayed for the following:  
• If UPCR ≥ 2.0 [≥ 227 mg/mmol] urine dipstick protein ≥ 3+, obtain 24-hour urine protein to 
determine if dosing should be delayed. 
o Dosing may proceed if 24-hour urine protein < 3 g. 
o Delay dosing if 24-hour urine protein ≥ 3 g (see Section 5.13.11 for criteria to resume). 
o Recurrent 24-hour urine protein ≥ 3 g after dose reduction requires study drug 
discontinuation (refer to Sections 5.14.1.2 and 5.14.1.3). 
• Clinical manifestations of CHF 
• LVEF > 20% but < 50% below baseline 
• Any Grade 2 drug-related hemorrhage  
• Any Grade 2 or 3 drug-related venous thrombosis requiring anticoagulation, with the 
following exception: 
o Any recurrent or worsening venous thromboembolic event after restarting sunitinib or 
cabozantinib will require discontinuation  
• Any Grade 3 drug-related adverse event or Grade 3 drug-related laboratory abnormality (e.g., 
AST, ALT, total bilirubin) that persists for more than 1 week or worsens despite supportive 
care management, with the following exceptions: 
o Grade ≥ 2 drug-related arterial thromboembolic events, including cerebrovascular 
ischemia, cardiac ischemia, or peripheral or visceral arterial ischemia, require 
discontinuation. 
o Grade  3 drug-related hemorrhage requires discontinuation (Section 5.14.1.2). 
o Drug-related AST or ALT > 8 × ULN requires discontinuation (Section 5.14.1.2). 


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o Concurrent AST or ALT > 3 × ULN (> 2 × baseline AND > 3 × ULN for patients with 
baseline elevation) and total bilirubin > 2 × ULN (> 2 × baseline AND > 2 × ULN for 
patients with baseline elevation), consistent with potential drug-induced liver injury (see 
Section 8.10), requires discontinuation.  
o Grade 3 drug-related amylase or lipase abnormalities that are not associated with 
symptoms or clinical manifestations of pancreatitis do not require dose delay.  In such 
cases, more frequent monitoring (e.g., weekly) of amylase and lipase is recommended. If 
amylase or lipase worsens to Grade 4 severity or the patient develops symptoms or 
clinical manifestations of pancreatitis, dosing should be delayed. 
• Sustained Grade 3 drug-related hypertension (systolic blood pressure  160 mm Hg or 
diastolic blood pressure  100 mm Hg).  Note: Stopping or reducing the dose of sunitinib or 
cabozantinib is expected to cause a decrease in blood pressure.  The treating physician should 
monitor the patient for hypotension and adjust the number and dose of antihypertensive 
medications accordingly. 
• Grade 4 drug-related amylase or lipase abnormalities require dose delay.  Patients should be 
monitored for development of symptoms or clinical manifestations of pancreatitis. 
• Grade 4 drug-related electrolyte abnormalities require dose delay.  Electrolyte correction 
with supplementation/appropriate management should be promptly initiated. 
• Grade 4 drug-related neutropenia, lymphopenia, leukopenia, anemia, or thrombocytopenia 
• Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of 
the Investigator, warrants delaying sunitinib or cabozantinib dosing 
• For patients scheduled for major surgery, including dental surgery which may impact bone 
healing, sunitinib or cabozantinib dosing should be delayed at least 28 days prior to 
scheduled surgery.  The treating physician should use clinical judgment with regard to the 
risks and benefits of the planned surgical procedure if it is not possible to delay cabozantinib 
or sunitinib dosing for 28 days prior to the procedure.  A delay of cabozantinib and sunitinib 
dosing of 5 to 7 days is recommended for healing for minor surgery. 
As a general approach, all AEs related to sunitinib or cabozantinib should be managed with 
supportive care, when possible, at the earliest signs of toxicity.  Calcium, magnesium, potassium, 
and phosphorus should be kept above the lower limits of the laboratory normal values.  Please 
refer to the sunitinib or cabozantinib prescribing information for additional information 
regarding dose modifications and AE management. 
5.13.11 
Criteria to Resume Sunitinib or Cabozantinib 
Patients may resume treatment with sunitinib or cabozantinib when the drug-related AE(s) 
resolve to Grade  1 or baseline value, with the following exceptions: 
• Patients may resume dosing in the presence of Grade 2 fatigue. 


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• Patients who delayed dosing due to 24-hour urine protein ≥ 3.0 g may resume dosing at one 
dose level reduction when UPCR < 2.0 [< 227 mg/mmol].  Repeat episodes of urine protein 
≥ 3 g despite dose reductions require study drug discontinuation (refer to Section 5.14.1.2). 
• Patients who delayed dosing due to Grade 3 hypertension may resume dosing at the same 
dose or at one dose level reduction, at the discretion of the Investigator, when hypertension 
has improved to Grade  2. 
• Patients who delayed dosing due to Grade 4 lipase or amylase abnormalities may resume 
dosing upon resolution to Grade  2. 
• Patients who develop a pulmonary embolism and/or DVT should have study treatment 
delayed until therapeutic anticoagulation is established.  Treatment with sunitinib may be 
resumed in patients with pulmonary embolism or DVT if it is determined that the event is 
uncomplicated and that the patient is deriving clinical benefit from sunitinib treatment and 
that anticoagulation does not place them at a significant risk that outweighs the benefit of 
resuming treatment per discretion of the Investigator. 
• Patients who delayed dosing due to  Grade 2 hemorrhage may resume dosing if bleeding is 
under control (recovered to at least Grade 1 level) and has a low risk of recurrence. 
• Patients who delayed dosing due to major surgery should not resume sunitinib until complete 
wound healing has taken place.  Following sunitinib resumption, patients should be 
monitored for wound dehiscence, wound infections, and other signs of impaired wound 
healing. 
5.13.12 
Sunitinib or Cabozantinib Dose Reduction and Escalation 
Table 7 outlines the permitted doses for sunitinib and cabozantinib. 
Table 7: 
Sunitinib and Cabozantinib—Permitted Doses 
 
Sunitinib 
Cabozantinib 
0 (starting dose) 
50 mg daily 
60 mg daily 
-1 
37.5 mg daily 
40 mg daily 
-2 
25 mg daily 
20 mg daily 
5.13.12.1 Sunitinib 
Sunitinib dose reductions are permitted as per the approved product label for safety reasons or 
when a concomitant strong cytochrome P450 3A4 (CYP3A4) inhibitor is needed (Appendix 8).  
Selection of an alternative concomitant medication with minimal or no enzyme inhibition 
potential is recommended whenever possible.  
After toxicity requiring a dose delay has improved and meets the criteria to resume dosing 
(Section 5.13.11), patients should resume sunitinib at one dose level reduction.  Dose reductions 


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should occur in 12.5 mg decrements.  No more than 2 dose reductions are allowed.  If more than 
two dose reductions are necessary (i.e., reduction to less than 25 mg daily), the patient must be 
permanently discontinued (Section 5.14.1.2). 
Patients who required a dose delay due to Grade 3 hypertension, which improved with 
antihypertensive medications, or any Grade 2 or 3 drug-related adverse event or asymptomatic 
laboratory abnormality that improved to Grade ≤ 1 within 7 days with supportive medical care 
may resume sunitinib at the same dose or a reduced dose, at the discretion of the Investigator. 
Patients who required a dose delay due to 24-hour urine protein ≥ 3 g, may resume study 
treatment at a reduced dose once UPCR is < 2 (< 227 mg/mmol).  Repeat episodes of urine 
protein ≥ 3 g despite dose reductions require study drug discontinuation (refer to 
Section 5.14.1.2). 
At the time a dose reduction is considered, also refer to Section 5.13.10 for dose delay 
recommendations and Section 5.14 for discontinuation criteria. 
Sunitinib dose re-escalations are permitted as per the approved product label when a concomitant 
CYP3A4 inducer is needed (Appendix 8); however, escalation above the starting dose is not 
allowed.  Selection of an alternative concomitant medication with minimal or no enzyme 
induction potential is recommended whenever possible. 
5.13.12.2 Cabozantinib 
Reduce the starting dose of cabozantinib to 40 mg once daily in patients with moderate hepatic 
impairment (i.e., Child-Pugh Class B); refer to the cabozantinib (Cabometyx®) US Prescribing 
Information and/or the corresponding SmPC for updated dosing guidance or further information. 
For patients receiving a concomitant strong CYP3A4 inducer or inhibitor, follow the dosing 
guidelines in the Package Insert, SmPC, or local health authority guidelines applicable to your 
country.   
Dose reductions for adverse event management are allowed for cabozantinib (Table 7). 
Cabozantinib doses will not be re-escalated once reduced, unless a concomitant strong CYP3A4 
inducer is started (see Section 5.13.12.3); however, escalation above the starting dose is not 
allowed. 
After toxicity requiring a dose delay has improved and meets the criteria to resume dosing 
(Section 5.13.11), patients who were receiving cabozantinib 40 mg daily prior to the delay will 
resume cabozantinib at 20 mg daily.  If more than 2 dose reductions are necessary (i.e., reduction 
to less than 20 mg daily) or more than 1 dose reduction in patients with Child-Pugh Class B 
(i.e., starting dose 40 mg daily), cabozantinib must be permanently discontinued 
(Section 5.14.1.3).  


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Patients who required a dose delay due to 24-hour urine protein ≥ 3 g, may resume study 
treatment at a reduced dose once UPCR is < 2 [< 227 mg/mmol].  Recurrent 24-hour urine 
protein ≥ 3 g after dose reduction requires study drug discontinuation (refer to Section 5.14.1.3). 
Patients who required a dose delay due to Grade 3 hypertension, which improved with 
antihypertensive medications, or any Grade 2 or 3 drug-related adverse event or asymptomatic 
laboratory abnormality that improved to Grade ≤ 1 within 7 days with supportive medical care 
may resume cabozantinib at the same dose or a reduced dose, at the discretion of the 
Investigator. 
Patients with asymptomatic Grade 2 drug-related AST, ALT or total bilirubin elevation, or 
Grade 3 drug-related lipase or amylase abnormalities that are not associated with symptoms or 
clinical manifestations of pancreatitis may reduce cabozantinib by 1 dose level, without delaying 
dosing, at the discretion of the Investigator. 
5.13.12.3 For Patients Who Start Taking a Concomitant Strong CYP3A4 Inhibitor 
Reduce the daily dose of cabozantinib or sunitinib by one dose level.  Resume the dose that was 
used prior to initiating the CYP3A4 inhibitor 2 to 3 days after discontinuation of the strong 
inhibitor (see Prescribing Information for cabozantinib and sunitinib). 
5.14 
Discontinuation Criteria 
5.14.1 
Discontinuation from Study Treatment 
Patients MUST discontinue investigational product (and non-investigational product at the 
discretion of the Investigator) for any of the following reasons: 
• Patient’s request to stop study treatment.  Patients who request to discontinue study treatment 
will remain in the study and must continue to be followed for protocol specified follow-up 
procedures.  The only exception to this is when a patient specifically withdraws consent for 
further assessments or contact with him/her or persons previously authorized by patient to 
provide this information. 
• 2 years since Cycle 1 Day 1 (Arm A only) 
• Any clinical AE, laboratory abnormality, or intercurrent illness which, in the opinion of the 
Investigator, indicates that continued participation in the study is not in the best interest of 
the patient 
• See additional study treatment discontinuation criteria specific to NKTR-214 and nivolumab 
(Section 5.14.1.1), sunitinib (Section 5.14.1.2), and cabozantinib (Section 5.14.1.3) due 
to AEs. 
• Termination of the study by the Sponsor 


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• Loss of ability to freely provide consent through imprisonment or involuntarily incarceration 
for treatment of either a psychiatric or physical (e.g., infectious disease) illness. (Note: Under 
specific circumstances, a patient who has been imprisoned may be permitted to continue as a 
patient. Strict conditions apply and Sponsor approval is required.) 
• Disease progression in the absence of clinical benefit as determined by the Investigator 
• Occurrence of a clinically significant AE found to be unacceptable or nonresolution of a 
clinically significant AE for > 8 weeks 
• Symptomatic deterioration in the absence of tumor progression per mRECIST 1.1. 
• Noncompliance of the patient with protocol-mandated procedures based on the judgment and 
agreement of both the Investigator and Sponsor 
If a patient has not progressed following discontinuation of study drug(s), every effort should be 
made to continue to obtain radiographic tumor assessments (until the patient has documented 
progression by both the BICR and Investigator’s assessment or begins a subsequent anticancer 
therapy).  
A patient may also be withdrawn from investigational product/study by the Sponsor, Regulatory 
Authorities, or IRBs/IECs.  
Patients may choose to discontinue the study at any time, for any reason, and without prejudice 
to further treatment. 
Refer to the Schedule of Events (Table 4) for data to be collected at the time of treatment 
discontinuation and follow-up and for any further evaluations that can be completed. 
If a female patient becomes pregnant, administration of the study drug(s) must be discontinued 
immediately, and the Investigator must notify the Sponsor within 24 hours of awareness of the 
pregnancy. Refer to Section 8.12.2 (Pregnancy).  
All patients who discontinue study treatment should comply with protocol specified follow-up 
procedures as outlined in Table 4.  The only exception to this requirement is when a patient 
withdraws consent for all study procedures including post-treatment study follow-up or loses the 
ability to consent freely (i.e., is imprisoned or involuntarily incarcerated for the treatment of 
either a psychiatric or physical illness). 
If study treatment is discontinued prior to the patient’s completion of the study, the reason for the 
discontinuation must be documented in the patient’s medical records and entered on the 
appropriate CRF page. 
5.14.1.1 
NKTR-214 Combined with Nivolumab Discontinuation Criteria 
Patients meeting any of the following criteria will be required to permanently discontinue all 
assigned study drug(s).  However, per Investigator assessment, NKTR-214 or nivolumab may be 


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continued as a monotherapy if the toxicities listed below are considered related to only one of the 
study drugs, once the criteria to resume are met (Section 5.13.7).  For CVA events and suspected 
TIA events, follow the criteria described below (additional details are provided in the CVA 
management algorithm in Appendix 6). 
NKTR-214 combined with nivolumab treatment should be permanently discontinued for the 
following: 
• Any ≥ Grade 2 drug-related uveitis, eye pain or blurred vision that does not respond to 
topical therapy and does not improve to Grade 1 severity within the retreatment period OR 
requires systemic treatment  
• Grade 3 or 4 infusion reaction of any duration that occurs during the: 
o NKTR-214 infusion or prior to the nivolumab infusion requires discontinuation of 
NKTR-214. 
o Nivolumab infusion or later requires discontinuation of both NKTR-214 and nivolumab. 
• Any Grade 3 non-skin, drug-related AE lasting > 7 days or recurs, with the following 
exceptions for laboratory abnormalities, drug-related uveitis, pneumonitis, bronchospasm, 
neurologic toxicity, hypersensitivity reactions, and endocrinopathies 
o Grade 3 drug-related uveitis, pneumonitis, bronchospasm, neurologic toxicity, 
myocarditis, or hypersensitivity reaction of any duration requires discontinuation 
o Grade 3 drug-related endocrinopathies (excluding adrenal insufficiency) adequately 
controlled with only physiologic hormone replacement do not require discontinuation.  
- 
Note: For adrenal insufficiency of Grade ≥ 3, treatment needs to be discontinued 
regardless of control with hormone replacement (hospitalization for diagnostic 
workup of adrenal insufficiency without severe symptoms should not require 
discontinuation). 
o Grade 3 drug-related laboratory abnormalities do not require treatment discontinuation 
except: 
- 
Grade 3 drug-related thrombocytopenia > 7 days or associated with bleeding requires 
discontinuation  
- 
Any drug-related LFT abnormality that meets the following criteria require 
discontinuation (also see Hepatic Adverse Event Management Algorithm, in 
nivolumab Investigator’s Brochure): 
 Treatment-emergent ALT or AST > 3 times ULN (> 2 × baseline AND 
> 3 × ULN for patients with baseline elevation) AND 
 Total bilirubin > 2 times ULN (> 2 × baseline AND > 2 × ULN for patients 
with baseline elevation) or clinical jaundice, without initial findings of 
cholestasis (e.g., elevated serum alkaline phosphatase) (see Section 8.10) 


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In most cases of Grade 3 AST or ALT elevation that do not improve with hepatic AE 
management, study treatment will be permanently discontinued (see Section 5.13 for 
more details).  If the Investigator determines a possible favorable benefit/risk ratio 
that warrants continuation of study treatment, a discussion between the Investigator 
and the Medical Monitor must occur. For IL-2 mediated ALT/AST elevations 
< 8.0 × ULN in Cycle 1 only, study treatment does not need to be discontinued. 
• Any Grade 4 drug-related adverse event or laboratory abnormality (including but not limited 
to creatinine, AST, ALT, or total bilirubin), except for the following events which do not 
require discontinuation: 
o Grade 4 neutropenia  7 days 
o Grade 4 lymphopenia or leukopenia or asymptomatic amylase or lipase 
o Isolated Grade 4 electrolyte imbalances/abnormalities that are not associated with clinical 
sequelae and are corrected with supplementation/appropriate management within 
72 hours of their onset 
o Grade 4 drug-related endocrinopathy adverse events (except adrenal insufficiency or 
hypophysitis), such as, hyper- or hypothyroidism, or glucose intolerance, which resolve 
or are adequately controlled with physiologic hormone replacement (corticosteroids, 
thyroid hormones) or glucose-controlling agents, respectively, may not require 
discontinuation after discussion with and approval from the Medical Monitor. 
o Note: For Grade ≥ 3 adrenal insufficiency and/or Grade ≥ 4 hypophysitis, treatment needs 
to be discontinued regardless of control with hormone replacement (hospitalization for 
diagnostic workup of adrenal insufficiency without severe symptoms should not require 
discontinuation). 
• Any event that leads to delay in dosing lasting > 8 weeks from the previous dose requires 
discontinuation, with the following exceptions: 
o Dosing delays to allow for prolonged steroid tapers to manage drug-related adverse 
events are allowed.  Prior to re-initiating treatment in a patient with a dosing delay lasting 
> 8 weeks, the Medical Monitor must be consulted and agree with the rationale for 
resuming therapy.  Tumor assessments should continue as per protocol even if dosing is 
delayed.  Periodic study visits to assess safety and laboratory studies should also continue 
every 3 weeks or more frequently if clinically indicated during such dosing delays. 
• Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of 
the Investigator, presents a substantial clinical risk to the patient with continued nivolumab 
dosing. 
• Any new CVA event confirmed by imaging (diffusion-weighted imaging [DWI] MRI 
preferred unless contraindicated), regardless of neurological symptoms, and for suspected 
TIA without clear alternative etiology (see Appendix 6). 


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5.14.1.2 
Sunitinib Discontinuation Criteria 
Treatment with sunitinib should be permanently discontinued for any of the following: 
• Any requirement for more than 2 sunitinib dose reductions 
• Any Grade drug-related arterial thrombosis 
• Grade ≥ 3 drug-related hemorrhage or recurrent Grade 3 drug-related hemorrhage after dose 
reduction 
• Grade 4 drug-related symptomatic venous thrombosis 
• LVEF reduction ≥ 50% from baseline 
• Grade 4 drug-related cardiac toxicity 
• Any other Grade ≥ 2 drug-related arterial or venous thromboembolic events including 
cerebrovascular ischemia, cardiac ischemia, or peripheral or visceral arterial ischemia 
• Erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis or necrotizing 
fasciitis 
• Thrombotic microangiopathy 
• Nephrotic syndrome or repeat episodes of urine protein ≥ 3 g despite dose reductions  
• Angioedema due to hypersensitivity 
• Two or more symptomatic episodes of hypertension despite modification of antihypertensive 
medication(s) and reduction of sunitinib dose 
• Any drug-related LFT abnormality that meets the following criteria require discontinuation: 
o Treatment-emergent ALT or AST > 3 times ULN (> 2 × baseline AND > 3 × ULN for 
patients with baseline elevation) 
o Total bilirubin > 2 times ULN (> 2 × baseline AND > 2 × ULN for patients with baseline 
elevation) or clinical jaundice, without initial findings of cholestasis (e.g., elevated serum 
alkaline phosphatase) (see Section 8.10) 
o Sunitinib should be interrupted for Grade 3 or 4 drug-related hepatic adverse reactions 
and discontinued if there is no resolution within 7 days.  Sunitinib should be permanently 
discontinued if a patient subsequently experiences Grade 3 or 4 changes in LFT or have 
other signs and symptoms of liver failure. 
• Any dosing delay lasting > 8 weeks unless the Medical Monitor is consulted and agrees with 
the rationale for resuming therapy after a delay > 8 weeks.  Note that tumor assessments 
should continue as per protocol even if dosing is delayed. 
• Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of 
the Investigator, presents a substantial clinical risk to the patient with continued sunitinib 
dosing. 


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5.14.1.3 
Cabozantinib Discontinuation Criteria 
Permanently discontinue cabozantinib for patients with any of the following: 
• Any requirement for more than 2 cabozantinib dose reductions (i.e., reduction to less than 
20 mg) 
• Acute myocardial infarction or new CVA event (including TIA) confirmed by imaging (DWI 
MRI preferred; refer to Appendix 6)  
• Any other Grade ≥ 2 drug-related arterial or venous thromboembolic events including 
cerebrovascular ischemia, cardiac ischemia, or peripheral or visceral arterial ischemia 
• LVEF reduction ≥ 50% from baseline 
• Any Grade ≥ 3 hemorrhage 
• Grade 4 hypertension or persistent Grade 3 hypertension despite optimal medical 
management and cabozantinib dose reduction 
• Reversible posterior leukoencephalopathy syndrome 
• Development of GI perforation or drug-related fistula  
• Nephrotic syndrome or recurrent nephrotic range proteinuria (i.e., recurrent 24-hour urine 
protein ≥ 3 g after dose reduction) 
• Any drug-related LFT abnormality that meets the following criteria requires discontinuation: 
o Treatment-emergent ALT or AST > 3 times ULN (> 2 × baseline AND > 3 × ULN for 
patients with baseline elevation) 
o Total bilirubin > 2 times ULN (> 2 × baseline AND > 2 × ULN for patients with baseline 
elevation) or clinical jaundice, without initial findings of cholestasis (e.g., elevated serum 
alkaline phosphatase) (see Section 8.10) 
• Any Grade 4 drug-related adverse event or laboratory abnormality, with the following 
exceptions: 
o Grade 4 neutropenia ≤ 7 days 
o Grade 4 lymphopenia or leukopenia 
o Grade 4 amylase or lipase abnormalities that are not associated with symptoms or clinical 
manifestations of pancreatitis 
o Isolated Grade 4 electrolyte abnormalities that are not associated with clinical sequelae 
and are corrected with supplementation/appropriate management within 72 hours of their 
onset 
• Any dosing delay lasting > 8 weeks unless the Medical Monitor is consulted and agrees with 
the rationale for resuming therapy after a delay > 8 weeks.  Note that tumor assessments 
should continue as per protocol even if dosing is delayed. 


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• Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of 
the Investigator, presents a substantial clinical risk to the patient with continued cabozantinib 
dosing. 
5.15 
Prior and Concomitant Medications 
Complications, including fatal events, have occurred in patients who received allogeneic 
hematopoietic stem cell transplantation before or after nivolumab. 
Recording of prior medications should include prior cancer treatments:  previous 
immunotherapy, chemotherapy, targeted therapy, radiation, over-the-counter (OTC) medications, 
herbs, and dietary supplements. 
All medications (prescription and OTC), vitamin and mineral supplements, and/or herbs taken by 
the patient from 30 days prior to randomization through the last Safety Follow-Up Visit will be 
documented and recorded, including start and stop date, dose and route of administration, 
frequency, and indication.  Medications taken for a procedure (e.g., biopsy) should also be 
included. 
5.15.1 
Premedication 
Premedications should not be administered prior to the initial administration of NKTR-214, 
nivolumab, sunitinib, or cabozantinib, but if a patient reports symptoms (such as nausea and/or 
vomiting), prophylactic use of anti-emetics may be used. 
If a patient experiences a Grade 1-2 infusion reaction during any infusions with NKTR-214 or 
nivolumab, prophylactic premedications may be administered for subsequent infusions (see 
Section 5.13.9 for further details on management and prevention of infusion reactions). 
Please refer to Section 5.15.2 for additional recommendations on prophylaxis. 
5.15.2 
Permitted Concomitant Treatment 
5.15.2.1 
Steroids 
Patients are permitted the use of topical, ocular, intra-articular, intranasal, and inhalational 
corticosteroids (with minimal systemic absorption).  Patients with pre-existing adrenal 
impairment requiring corticosteroid supplementation may be at increased risk for hypotensive 
episodes during treatment with NKTR-214 and may require co-management with an 
endocrinologist (see Section 5.13.5).  A brief course of corticosteroids for prophylaxis (e.g., 
contrast dye allergy) or for treatment of non-autoimmune conditions (e.g., pneumonia, 
delayed-type hypersensitivity reaction caused by a contact allergen) is permitted.  Use of 
corticosteroids for the management of autoimmune conditions (as outlined in the Investigator’s 
Brochure for nivolumab) is permitted. 


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5.15.2.2 
Prophylaxis 
Prophylaxis for flu-like symptoms with either acetaminophen (paracetamol) or ibuprofen is 
permitted on study per the Investigator’s discretion.  Prophylaxis for flu-like symptoms 
(acetaminophen or non-steroidal anti-inflammatory agents) can be initiated on either the day of 
NKTR-214 administration or the day after administration and may continue for 4 days after 
administration or longer as needed. 
Prophylaxis for rash and/or pruritus with anti-histamines is permitted on study per the 
Investigator’s discretion.  Prophylaxis for rash and/or pruritus can be initiated on either the day 
of NKTR-214 administration or the day after administration and may continue for 4 days after 
administration or longer as needed. 
Prophylactic use of antibiotics for signs of potential asymptomatic urinary tract infection is 
permitted.   
5.15.2.3 
Palliative and Supportive Care 
Palliative (limited-field) radiation therapy and palliative surgical resection are permitted if 
required but should be avoided unless the patient has a BICR-confirmed progression.  Palliative 
therapy must be clearly documented as such in the study record and shared with the BICR 
vendor if performed prior to BICR-confirmed disease progression. 
Concomitant palliative and supportive care for disease-related symptoms (including 
bisphosphonates and RANK-L inhibitors) is allowed.   
5.15.3 
Prohibited and/or Restricted Concomitant Medications 
5.15.3.1 
Prohibited Medications 
• Immunosuppressive agents 
• Immunosuppressive doses of systemic corticosteroids (except as stated in Section 5.15.2) 
defined as a daily dose of greater than 10 mg prednisone equivalents  
• Any antineoplastic therapy (i.e., chemotherapy, hormonal therapy, immunotherapy, extensive 
non-palliative radiation therapy, or investigational agent) is prohibited during the study.  
• Any botanical preparation (e.g., herbal supplements or traditional Chinese medicines) 
intended to treat the disease under study or provide supportive care.  Use of marijuana and its 
derivatives for treatment of symptoms related to cancer or cancer treatment are permitted if 
obtained by medical prescription or if its use (even without a medical prescription) has been 
legalized locally. 


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• Any live / attenuated vaccine (e.g., varicella, zoster, yellow fever, rotavirus, oral polio, and 
measles-mumps-rubella, or Flumist® Quadrivalent) during treatment and until 100 days post 
last dose of nivolumab. Note: all vaccines against severe acute respiratory syndrome 
coronavirus 2 (SARS-CoV-2; COVID-19) are allowed on treatment. For any questions about 
the COVID vaccines, please contact the Medical Monitor. 
5.15.3.2 
Blood Pressure Medications 
Consideration should be given to withholding antihypertensive medications including diuretics, 
as well as other drugs with hypotensive properties (e.g., alpha blockers for benign prostatic 
hypertrophy) prior to each dose of NKTR-214, particularly when therapy involves multiple 
antihypertensive drugs and classes other than thiazide diuretics.  If withholding antihypertensive 
medications, withhold no less than 12 hours and no more than 48 hours prior to each dose of 
NKTR-214.  
Patients who are on medications with antihypertensive effects for the treatment of coronary 
artery disease (e.g., β-blockers, Ca channel blockers, nitrates, etc.) should be able to withhold 
these drugs prior to initiation of treatment (i.e., based on blood pressure monitoring results).  
Antihypertensive medications may be reinitiated in between doses of NKTR-214 at any time as 
clinically indicated (i.e., based on blood pressure monitoring results). 
For patients receiving β-blockers, consider a step-wise tapering of doses before initiation of 
NKTR-214 to avoid reflex tachycardia.  If Grade ≥ 2 hypertension is observed in any cycle, 
patients should be monitored more frequently (at least weekly) until a new stable 
antihypertensive regimen is identified.  Patients may be monitored more frequently at the 
discretion of the Investigator as clinically warranted. 
5.15.3.3 
Anticoagulation 
Patients with a history of a venous or arterial thromboembolic event must be receiving a stable 
regimen of therapeutic anticoagulation (preferably LMWH or DOAC).  Unless there is a new 
medical contraindication observed after Cycle 1 Day 1, a patient with a history of venous or 
arterial thromboembolic event must be maintained on therapeutic anticoagulation throughout the 
patient’s participation on study (i.e., through discontinuation of all study drugs). 
Use of coumadin is permitted; however, therapeutic dosing should target a specific international 
normalized ratio (INR) stable for at least 4 weeks prior to randomization.  NKTR-214 has the 
potential to down-regulate metabolizing enzymes for coumadin for approximately 1 week after 
administration of each dose of NKTR-214.  Due to the possibility of drug-drug interactions 
between coumadin and NKTR-214, frequent monitoring of INR and ongoing consideration of 
dose adjustments are warranted throughout the patient’s participation on study. 
Acetylsalicylic acid should not be combined with LMWH or DOAC due to increased risk of 
hemorrhage. 


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5.15.3.4 
Cytochrome P450 Potential Drug Interactions 
Sunitinib and cabozantinib are metabolized by CYP3A4. Co-administration of strong inducers of 
the CYP3A4 family (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, 
phenobarbital, dexamethasone, and St. John’s Wort) may significantly decrease sunitinib or 
cabozantinib concentrations and chronic use of CYP3A4 inducers must be avoided.  Selection of 
alternate concomitant medications with no or minimal CYP3A4 enzyme induction potential is 
recommended.  Caution must be used when discontinuing treatment with a strong CYP3A4 
inducer in a patient who has been concurrently receiving a stable dose of sunitinib or 
cabozantinib, as this could significantly increase the exposure to sunitinib or cabozantinib. 
Co-administration of strong inhibitors of the CYP3A4 family (Appendix 8) may significantly 
increase sunitinib or cabozantinib concentrations and may increase the risk of toxicities related to 
these study drugs.  If alternative concomitant therapies are not available, doses or sunitinib or 
cabozantinib may be interrupted or reduced to mitigate the risk of increased toxicities (see 
Sections 5.13.12.1 and 5.13.12.2). Grapefruit, grapefruit juice, and other foods that are known to 
inhibit CYP3A4 should be avoided during treatment with sunitinib or cabozantinib.  
5.15.3.5 
Effect of NKTR-214 on PK of Concomitant Medications   
NKTR-214 causes transient increases in circulating cytokines lasting for about one week after 
NKTR-214 dosing in the q3w dosing schedule. Several of these cytokines (IFN-γ, IL-6, IL-10) 
have the potential to decrease the activity of multiple drug metabolizing enzymes and drug 
transporters. Consequently, treatment with NKTR-214 may lead to a temporary decrease in 
clearance of drugs that are substrates of metabolizing enzymes or drug transporters.  Where 
indicated based on decreased tolerability or the occurrence of adverse effects related to a 
concomitant drug, reduce the dosage of the concomitant drug per the product label during Days 3 
to 8 of each cycle of NKTR-214.  
5.15.3.5.1 
Potential Interaction of NKTR-214 and Warfarin 
For patients receiving warfarin (coumadin), therapeutic dosing should target a specific INR that 
is stable for at least 4 weeks prior to NKTR-214 administration.  NKTR-214 has the potential to 
down‑regulate metabolizing enzymes for warfarin for approximately 1 week after administration 
of each dose of NKTR-214.  Due to the possibility of drug-drug interactions between warfarin 
and NKTR-214, frequent monitoring of INR and ongoing consideration of dose adjustments are 
warranted during NKTR-214 administration. 
5.16 
Adverse Events 
All AEs, either reported by the patient or observed by study staff, will be recorded until the last 
Safety Follow-up Visit (see Section 5.6).  This study will use the Medical Dictionary for 
Regulatory Activities (MedDRA) for coding all AEs.  AEs will be summarized by preferred 
term, system organ class, grade of severity, and relationship to each study drug (NKTR-214 
and/or nivolumab and/or sunitinib and/or cabozantinib). 


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5.17 
Treatment Assignment and Patient Number Assignment 
Each patient will be assigned a unique patient number after signing the ICF.  Patient numbers 
will be used on all patients’ study information.  Patient numbers will not be reassigned.  
An Interactive Response Technology (IRT) will be employed to manage patient randomization. 
Randomization stratification factors are described in Section 5.1. 
For all countries, Nektar will supply NKTR-214 and nivolumab from a central source. With 
Sponsor approval, and depending on local health authority guidelines and drug availability, 
nivolumab, sunitinib, and cabozantinib may be obtained through commercial supply, the site 
pharmacy, or through a central source. Sunitinib and cabozantinib must both be approved by the 
local Competent Authority and commercially available (local sourcing of these agents may be 
permitted on an ad hoc basis).  Choice of TKI for an individual patient randomized to Arm B 
will depend on what drug products are available at each medical center and the Investigator's 
choice.  Selection of a drug product should be based on what would have been offered to that 
patient, should the patient not be participating in this trial.  Agents that are not routinely available 
in the pharmacy at each medical center will not be considered “available therapy.”  The 
Investigator must have prior clinical experience with the control arm for the treatment of a 
patient with renal cell carcinoma. 


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6.0 
INVESTIGATIONAL PRODUCT(S)/STUDY DRUGS 
Table 8 provides the study treatments that will be administered in the study. Not all of the 
capsule/tablet strengths for sunitinib and cabozantinib may be available.  Final available 
capsule/tablet strengths will be listed in the Pharmacy Manual.  
Table 8: 
Investigational Products  
Product Description 
Strength 
Packaging / Appearance 
Storage Conditions 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.1 
NKTR-214  
6.1.1 
Drug Description and Formulation 
 
 
 
 
  
 
  
6.1.2 
Drug Packaging and Labeling 
 
 
 Each 


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vial will be labeled with the study drug number/name, strength, name of the Sponsor, storage 
condition, lot number, and the required cautionary statement. 
6.1.3 
Drug Reconstitution and Handling 
 
 
 
   
Refer to the Pharmacy Manual for detailed handling and administration information. 
6.1.4 
Drug Storage 
 
 
6.1.5 
Drug Shipment 
 
.  Refer to the Pharmacy Manual for additional details for 
ordering drug supply. 
6.2 
Nivolumab, Sunitinib, and Cabozantinib Formulation, Preparation, Storage, and 
Packaging 
Refer to the Pharmacy Manual for details. 
6.3 
Study Drug Accountability and Reconciliation 
NKTR-214 and nivolumab will be supplied to the Investigator by Nektar Therapeutics or its 
designee. With Sponsor approval, and depending on local health authority guidelines and drug 
availability, nivolumab, sunitinib, and cabozantinib may be obtained through commercial supply, 
the site pharmacy, or through a central depository.  Depending on source of supply per specific 
country requirements, the packaging and labeling may vary.  Products will be labeled to meet 
local country requirements. Please refer to the Pharmacy Manual for detailed information. 
Study drug supplies must be kept in an appropriate, secure, locked area and stored in accordance 
with the conditions specified on the labels.  Depending on local health authority guidelines, 
intravenous fluids and associated supplies (IV administration sets, in-line filters, calibrated 
pumps) may be obtained through commercial supply, the site pharmacy, or through a central 
depository. 
The Investigator, pharmacist, or designee must maintain an accurate record of dispensing the 
study drug in a Drug Accountability Log, a copy of which must be given to Nektar Therapeutics. 
In addition, (for those patients randomized to Arm B), the patient must agree to complete a pill 


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diary to record oral dosing, which will be reviewed by the Investigator or designee at the 
beginning of each cycle, starting with Cycle 2. 
The Drug Accountability Log may record specifics to study drug dispensation such as: 
• Records of product delivery, inventory, temperature monitoring, destruction, and return as 
per Sponsor’s instructions. 
• Doses prepared, time prepared, doses dispensed. 
• Doses and/or vials destroyed. 
The Drug Accountability Log will be reviewed by the monitor during site visits and at the 
completion of the study. 


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7.0 
ASSESSMENT OF EFFICACY 
Response and progression will be determined by BICR using mRECIST 1.1. 
7.1 
Imaging Assessments for the Study 
Images will be submitted to an imaging core lab and will be reviewed by the BICR on an 
ongoing basis.  Sites should be qualified prior to scanning the first patient and understand the 
image acquisition guidelines and submission process as outlined in the Study 17-214-09/ 
CA045002 Imaging Manual provided by the imaging core lab. 
Tumor assessments should be acquired as outlined in Section 1.2 (Schedule of Events) and as 
described below. 
• For patients who are on treatment, contrast-enhanced CT of the chest and contrast-enhanced 
CT or MRI of the abdomen, pelvis, and all other known and suspected sites of disease should 
be performed every 9 weeks (± 7 days) from randomization through (and inclusive of) 
Week 54 and then every 12 weeks (± 7 days).  
o Tumor assessment schedule is relative to the date of randomization and will be 
maintained regardless of dose delays. 
• Patients who have not progressed, as determined by both BICR and Investigator assessment, 
should continue tumor assessments according to the protocol-specified schedule, or sooner if 
clinically indicated.   
• If patients discontinue treatment without radiographic progression, tumor assessments will 
continue according to the protocol-specified schedule, as noted in Section 1.2, until 
progression has been confirmed by both BICR and Investigator assessment.   
• Patients who are treated beyond Investigator-assessed disease progression should continue 
tumor assessments until the criteria for treatment discontinuation are met and BICR-assessed 
progression has occurred.  
• Tumor assessments are no longer required if subsequent anticancer therapy is started, even if 
the patient has not yet progressed. 
Tumor assessments at other time points may be performed if clinically indicated and should be 
submitted to the central imaging vendor as soon as possible.  Unscheduled CT/MRI and bone 
scan should be submitted to central imaging vendor.  X-Ray scans that clearly demonstrate 
interval progression of disease, most commonly as unequivocal lesions that are unmistakably 
new since the prior CT/MRI, should be submitted to central imaging vendor.  Otherwise, 
radiographs do not need to be submitted centrally. 
7.2 
Methods of Measurement 
Contrast-enhanced CT of the chest and contrast-enhanced CT or MRI of the abdomen, pelvis, 
and all other known and suspected sites of disease should be performed for tumor assessments.  


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Images should be acquired with slice thickness of 5 mm or less with no intervening gap 
(contiguous).  Every attempt should be made to image each patient using an identical acquisition 
protocol on the same scanner for all imaging time points.  Tumor measurements should be made 
by the same Investigator or radiologist for each assessment whenever possible.  Change in tumor 
measurements and tumor response to guide ongoing study treatment decisions will be assessed 
by the Investigator using the mRECIST 1.1 criteria. 
Should a patient have contraindication for CT intravenous contrast, a non-contrast CT of the 
chest and a contrast-enhanced MRI of the abdomen, pelvis, and other known/suspected sites of 
disease should be obtained. 
Should a patient have contraindication for both MRI and CT intravenous contrasts, a 
non-contrast CT of the chest and a non-contrast MRI of the abdomen, pelvis, and other 
known/suspected sites of disease should be obtained. 
Should a patient have contraindication for MRI (e.g., incompatible pacemaker) in addition to 
contraindication to CT intravenous contrast, a non-contrast CT of the chest, abdomen, pelvis, and 
other known/suspected sites of disease is acceptable.  
Use of CT component of a positron emission tomography (PET)-CT scanner: Combined 
modality scanning such as with PET-CT is increasingly used in clinical care, and is a 
modality/technology that is in rapid evolution; therefore, the recommendations outlined here may 
change rather quickly with time.  At present, low dose or attenuation correction CT portions of a 
combined PET-CT are of limited use in anatomically-based efficacy assessments and it is 
therefore suggested that they should not be substituted for dedicated diagnostic contrast-
enhanced CT scans for anatomically-based mRECIST 1.1 measurements.  However, if a site can 
document that the CT performed as part of a PET-CT is of identical diagnostic quality to a 
diagnostic CT (with IV and oral contrast) then the CT portion of the PET-CT can be used for 
mRECIST1.1 measurements.  Note, however, that the PET portion of the CT introduces 
additional data which may bias an Investigator if it is not routinely or serially performed. 
Bone scan or PET scan is not adequate for assessment of mRECIST 1.1 response in target 
lesions.  In selected circumstances where such modalities are the sole modality used to assess 
certain non-target organs, those non-target organs may be evaluated less frequently.  For 
example, bone scans may need to be repeated only when complete response is identified in target 
disease or when progression in bone is suspected. 
MRI of brain without and with contrast should be acquired as outlined in Section 1.2 (Schedule 
of Events).  CT of the brain without and with contrast can be performed if MRI is 
contraindicated. 
Bone scans may be collected per local standards, as clinically indicated.  Digital photography 
should be performed and submitted, if clinically indicated. 


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7.3 
Imaging and Clinical Assessment 
Tumor assessments should continue even if dosing is delayed or discontinued. Changes in tumor 
measurements and tumor responses will be assessed by the same Investigator using 
mRECIST 1.1 criteria.  Investigators will report the number and size of new lesions that appear 
while on study.  The time point of tumor assessments will be reported on the electronic CRF 
(eCRF) based on the Investigator’s assessment using mRECIST 1.1 criteria (See Appendix 9 for 
specifics of mRECIST 1.1 criteria to be utilized in this study).  Assessments of PR and CR are 
recommended to be confirmed at least 4 weeks (28 days) after initial response.  A Best Overall 
Response of SD requires a minimum of 56 days on study from randomization to the date of the 
first imaging assessment. 
All patients must have measurable disease to be eligible for this study. To achieve ‘unequivocal 
progression’ on the basis of the non-target disease, there must be an overall level of substantial 
worsening in non-target disease such that, even in the presence of SD or PR in target disease, the 
overall tumor burden has increased sufficiently to merit discontinuation of therapy.  A modest 
‘increase’ in the size of one or more non-target lesions is usually not sufficient to qualify for 
unequivocal progression status.  The designation of overall progression solely on the basis of 
change in non-target disease in the face of SD or PR of target disease will therefore be extremely 
rare (Eisenhauer, 2009). 
7.4 
Central Imaging 
Sites should submit all scans to the imaging core lab on the schedule outlined in the Study 
17-214-09/CA045002 Imaging Manual, throughout the duration of the study. BICR of scans will 
occur on a rolling basis, blinded to treatment arm, clinical data, and Investigator assessment of 
submitted scans.  Clinical information (palliative radiotherapy on-study, surgical excision of any 
lesion, details of paracentesis and thoracocentesis) must be provided to the BICR team.  All 
details on the timelines and associated process requirements will be outlined in the Imaging 
Manual. 
All study treatment decisions will be based on the Investigator’s assessment of tumor images and 
not on the BICR assessment.  The BICR assessment of progression is only relevant for 
determining when tumor assessments for a given patient are no longer required to be submitted 
to the imaging vendor. 
7.5 
Additional Imaging Assessments for the Study 
Any additional imaging that may demonstrate tumor response or progression (including scans 
performed at unscheduled time points and/or at an outside institution) should be collected for 
mRECIST 1.1 tumor assessment and submitted to the BICR. 


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7.6 
Patient-Reported Outcomes 
The evaluation of patient-reported outcomes is an increasingly important aspect of clinical 
efficacy in oncology trials.  Such data provide an understanding of the impact of treatment from 
the patient’s perspective and offer insights into patient experience that may not be captured 
through physician reporting.  Additionally, generic health-related quality of life measures 
provide data needed for calculating utility values to inform health economic models. 
Patients will be asked to complete the NCCN/FACT Symptom Index for Kidney Cancer 
(FKSI-19), EQ-5D-3L, and selected items from the Patient-Reported Outcomes version of the 
Common Term Criteria for Adverse Events (PRO-CTCAE).  Patients will complete the patient-
reported outcome measures as outlined in the schedules of events: Table 1 provides information 
regarding the timing of patient-reported outcomes assessments during the Screening period.  
Table 2 and Table 3 provide information regarding the timing of patient-reported outcomes 
assessments during the on-treatment period for Arms A and B, respectively.  Table 4 provides 
information regarding the timing of patient-reported outcomes assessments during the follow-up 
period. 
7.6.1 
FKSI-19 
The National Comprehensive Cancer Network/Functional Assessment of Cancer Therapy–
Kidney Symptom Index-19 (FKSI-19) is a 19-item self-reported questionnaire with a total score 
and four subscales that assess disease-related symptoms (DRS), treatment side effects (TSE), and 
function/well-being associated with advanced kidney cancer.  It captures symptom severity and 
interference in activity and general health perceptions.  The FKSI-19 comprises four subscales 
(DRS-Physical, DRS-Emotional, TSE, and Function/Well-Being).  Each of the items is scored on 
a five-point scale from zero (not at all) to four (very much).  Higher FKSI-19 scores indicate 
improvement (Rothrock, 2013).   
The FKSI-19 uses a recall period of “the past 7 days.” 
7.6.2 
EQ-5D-3L 
The EQ-5D-3L is a standardized instrument used to measure self-reports of health status and 
functioning.  The instrument’s descriptive system consists of 5 dimensions: mobility, self-care, 
usual activities, pain/discomfort, and anxiety/depression.  Each dimension has 3 levels, reflecting 
“no health problems,” “moderate health problems,” and “extreme health problems.”  A 
dimension for which there are no problems is said to be at level 1, while a dimension for which 
there are extreme problems is said to be at level 3.  Thus, the vectors 11111 and 33333 represent 
the best health state and the worst health state, respectively, as described by the EQ-5D-3L.  
Altogether, the instrument describes 35 = 243 health states (EuroQol, 1990). 
Empirically-derived weights can be applied to an individual’s responses to the EQ-5D-3L 
descriptive system to generate an index measuring the value to society of his or her current 
health.  Such preference-weighting systems have been developed for the UK, US, Spain, 


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Germany, and numerous other populations.  Utility index values range from a 1 (full health) 
to 0 (dead) with negative values indicating a state considered worse than being dead.  In addition, 
the EQ-5D-3L includes a visual analog scale that allows respondents to rate their own current 
health on a 101-point scale ranging from “best imaginable” to “worst imaginable” health.  
The EQ-5D-3L uses a recall period of “today.” 
7.6.3 
PRO-CTCAE 
The PRO-CTCAE is a patient-reported outcome measure developed to evaluate symptomatic 
toxicity in patients participating in oncology clinical trials.  It was designed to be used as a 
companion to the CTCAE, the standard lexicon for adverse event reporting in cancer trials. 
PRO-CTCAE includes an item library of 124 items representing 78 symptomatic toxicities 
drawn from the CTCAE. PRO-CTCAE provides a systematic yet flexible tool for descriptive 
reporting of symptomatic treatment side effects in cancer clinical trials.  Selected items from the 
PRO-CTCAE will be administered.  Patients will complete the PRO-CTCAE patient to the 
availability of language translations (Basch, 2014).  
The PRO-CTCAE uses a recall period of “the last 7 days.” 


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8.0 
ASSESSMENT OF SAFETY 
8.1 
AE Definition and Assessment 
An AE is defined as any untoward medical occurrence in a clinical investigation patient 
administered a pharmaceutical product, at any dose, not necessarily related to the treatment. 
An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product.  An AE can also arise from any use of the drug and from any route of 
administration, formulation, dose, or overdose.  This definition includes intercurrent illnesses or 
injuries, and exacerbation of pre-existing conditions.  Clinical laboratory, vital sign, or physical 
examination abnormalities will only be reported as AEs if they are deemed clinically significant 
by the Investigator (e.g., associated with signs and symptoms, require treatment, or require 
follow-up).  The Investigator should attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis will be documented as 
the AE and/or SAE and not the individual signs/symptoms. 
An AE does not include: 
• A medical or surgical procedure (e.g., surgery, endoscopy, tooth extraction, or transfusion); 
an AE is the underlying condition that leads to the procedure. 
• Pre-existing diseases or conditions present or detected before start of study drug(s) 
administration that do not worsen or increase in severity or frequency after the administration 
of study drug(s). 
• Situations where an untoward medical occurrence has not occurred (e.g., hospitalization for 
elective surgery for a condition that has not worsened on study, social and/or convenience 
admissions to grant families a respite in caring for a patient). 
• Overdose of either study drug(s) or concomitant medication without any signs or symptoms. 
8.2 
Monitoring AEs 
All AEs will be assessed by the Investigator and recorded, including but not limited to, the 
following: the event term, the date of onset and resolution, seriousness, severity, relationship to 
study drug(s), outcome, treatment of the event, and action taken with the study drug(s).  AEs will 
be reported starting immediately after the patient has been administered the first dose of study 
drug(s) until 100 days after the last dose of all study drug(s).  For treatment-related SAEs, 
additional reporting requirements also apply (see Section 8.7). 
An event occurring after the patient has provided informed consent, but before the first dose of 
study treatment or confirmed screen failure, will be collected as medical history unless the event 
is either new and attributed to protocol-mandated procedures by the Investigator or there is a 
significant change in the rate of occurrence or an increase in the severity of the pre-existing 
condition which is judged to be clinically important and attributed to the protocol-mandated 


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procedures by the Investigator. Under the latter 2 circumstances, the event will be considered an 
AE and will be captured as such. 
• Example 1: Thrombophlebitis associated with a blood draw for assessments required prior to 
dosing per protocol is an event that is related to protocol-mandated procedures.  In this 
scenario, the event of “thrombophlebitis” will be captured as an AE, and it will be 
documented as being “unrelated” to study drug(s), as applicable. 
• Example 2: An ankle sprain following an unexpected fall from a flight of stairs while at 
home, after the patient has provided informed consent, but before the first dose of study 
drug(s), is clearly unrelated to any protocol-mandated procedures and would therefore be 
captured as medical history. 
8.3 
Grading of AEs 
The severity of an event and the seriousness are not to be considered synonymous.  The severity 
is grading the intensity of an event.  The seriousness of event is based on the patient/event 
outcome or action criteria.  All AEs will be assessed for severity using the National Cancer 
Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 
guidelines.  If a particular AE is not listed in the NCI-CTCAE, the following criteria will be 
used: 
• Grade 1 = Mild (event results in mild or transient discomfort, not requiring or needing only 
minimal intervention or treatment; does not limit or interfere with daily activities [e.g., 
insomnia, mild headache]). 
• Grade 2 = Moderate (event is sufficiently discomforting so as to limit or interfere with daily 
activities; may require interventional treatment [e.g., fever requiring antipyretic medication]). 
• Grade 3 = Severe (event results in significant symptoms that prevent normal daily activities; 
may require hospitalization or invasive intervention). 
• Grade 4 = Life threatening or disabling. 
• Grade 5 = Death. 
AEs will be reported with an individual start and stop date for each level of severity. 
8.4 
Causality Relationship of AEs 
The relationship of each AE to each study drug (NKTR-214 and/or nivolumab, sunitinib or 
cabozantinib) as applicable will be evaluated by the Investigator using the following definitions: 
• Not related:  An AE that does not follow a reasonable temporal sequence from administration 
of study drug(s), and/or that can be reasonably explained by other factors such as the 
patient’s pre-existing medical condition, underlying disease, concurrent illness, or 
concomitant medications/therapies. 


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• Related:  There is a reasonable possibility that an AE is caused by the study drug(s).  A 
plausible temporal sequence exists between the time of administration of the study drug(s) 
and the development of the AE.  The AE cannot be reasonably explained by the known 
characteristics of the patient’s clinical state or other concomitant therapies or interventions 
administered to the patient.  
8.5 
AE Reporting and Follow-up 
After initiation of study drug treatment, all AEs except for SAEs (Section 8.7 and 8.8) will be 
reported from the time of first study drug(s) administration until 100 days after the last dose of 
all study drug(s) (see Section 5.6).  
All ongoing non-serious AEs will be followed until resolution, the patient is lost to follow-up, 
patient death, or until the last Safety Follow-Up Visit.  If the AE has not completely resolved by 
the last Safety Follow-Up Visit, the final outcome of these ongoing AEs will be captured as “Not 
Recovered/Not Resolved” or “Recovering/Resolving”, whichever is applicable. 
For specific instructions on identifying and reporting SAEs, see Sections 8.6 and 8.7. 
8.6 
Serious AE Definition 
An SAE is defined as any untoward medical occurrence that at any dose: 
• Results in death. 
• Is life threatening, i.e., in the opinion of the Investigator, the AE places the patient at 
immediate risk of death from the event as it occurred; it does not include a reaction that, had 
it occurred in a more severe form, might have caused death. 
• Requires inpatient hospitalization or prolongation of an existing hospitalization that occurs 
during the course of a patient’s participation in a clinical study, except for those due to the 
following: 
o A surgery or procedure that was planned before the patient entered the study and which is 
part of the planned study procedure. 
o Nonmedical reasons (e.g., elective hospitalization for social reasons or due to long travel 
distances or for prophylactic patient observation), in the absence of an AE. 
• Results in persistent or significant disability or incapacity. 
• Is a congenital anomaly or birth defect. 
• Is an important medical event that, based upon appropriate medical judgment, may 
jeopardize the patient and may require medical or surgical intervention to prevent one of the 
other outcomes listed above. 
Death is an outcome of an AE and not an AE in itself.  All events leading to death, regardless of 
relationship to study drugs, that occur during the protocol-specified reporting period, must be 


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reported with the exception of deaths attributed to disease progression (refer to Section 8.9).  An 
efficacy failure is not considered an SAE. “Life-threatening” means that the patient was at 
immediate risk of death from the event as it occurred.  This does not include an event that might 
have led to death if it had occurred with greater severity. “Inpatient hospitalization” means the 
patient has been admitted to a hospital for medical reasons for any length of time.  The 
Investigator should attempt to establish a diagnosis of the event based on signs, symptoms, 
and/or other clinical information.  In such cases, the diagnosis will be documented as the AE 
and/or SAE and not the individual signs/symptoms. 
8.7 
Serious AE Reporting 
Serious AEs occurring after the patient has provided informed consent, but before the first dose 
of study treatment or confirmed screen failure, will be collected as medical history unless the 
event is either new and attributed to protocol-mandated procedures by the Investigator or there is 
a significant change in the rate of occurrence or an increase in the severity of the pre-existing 
condition which is judged to be clinically important and attributed to the protocol-mandated 
procedures by the Investigator.  Any new or clinically significant changes in the patient’s 
medical and/or cancer history that occur after the first dose of drug and meet the SAE criteria 
will be recorded as SAEs.  All SAEs, regardless of causality or starting subsequent anticancer 
therapy, with an onset within 100 days after the last dose of all study drug(s) will be reported to 
Nektar Therapeutics Drug Safety immediately (i.e., no more than 24 hours after learning of the 
event). 
In addition, all SAEs that occur beyond 100 days after last dose of all study drug(s) that are 
assessed by the Investigator as related to study drug(s) will also be reported to Nektar 
Therapeutics Drug Safety within 24 hours of awareness of the event. 
SAEs must be reported to Nektar Therapeutics Drug Safety via email or Safety Fax as listed at 
the beginning of this protocol.  Nektar Therapeutics may transition to reporting of SAEs via EDC 
while the study is ongoing.  If this occurs, all sites will receive documented instructions 
regarding how to enter SAEs into EDC.  If the study were to transition to reporting of SAEs in 
EDC, sites would continue to submit SAEs via email or Safety Fax as a backup system should 
there be EDC system access issues. 
The Investigator must complete the SAE Report Form, assess the causality relationship to the 
study treatment as applicable, and send the completed SAE form via email or fax to Nektar 
Therapeutics Drug Safety within 24 hours of awareness.  A follow-up SAE report and any 
additional records (including but not limited to, hospital records, consultant reports, autopsy 
findings, and records needed to address queries sent from Sponsor) will be emailed or faxed to 
Nektar Therapeutics Drug Safety within 24 hours of awareness.  Any medication or other 
therapeutic measures used to treat the event will be recorded. 
All SAEs will be followed as described in Section 8.8. 


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Reporting of SAEs to the IRB/IEC will be done in accordance with the standard operating 
procedures (SOPs) and policies of the IRB/IEC.  Adequate documentation must be provided to 
Nektar Therapeutics, showing that the IRB/IEC was properly notified.  Serious AEs will be 
reported by Nektar Therapeutics or designee to the Regulatory Authorities, per local regulations. 
8.8 
Serious AE Follow-up 
All study treatment-related SAEs that have not resolved by the last Safety Follow-Up visit 
(Section 5.6) will be followed until any of the following occur (whichever comes first): 
• The event resolves. 
• The event has stabilized. 
• The event returns to baseline, if a baseline value is available. 
• It is unlikely that any additional information can be obtained (e.g., patient or health care 
practitioner refuses to provide additional information; lost to follow-up after demonstration 
of due diligence with follow-up efforts). 
• The patient dies or is lost to follow-up. 
All ongoing SAEs assessed as unrelated to study drug(s) will be followed until resolution or until 
the last Safety Follow-Up Visit (Section 5.6.1), whichever is earlier.  In the case where an 
unrelated SAE has not completely resolved by the last Safety Follow-Up Visit, the final outcome 
of these ongoing unrelated SAEs will be captured as “Not Recovered/Not Resolved” or 
“Recovering/Resolving”, whichever is applicable. 
8.9 
Disease Progression and Death Due to Disease Progression – Not Reportable as an 
AE/SAE 
It is anticipated that during this study a proportion of patients will experience disease progression 
prior to study discontinuation.  Disease progression should not be reported as an AE or SAE.  In 
some patients, disease progression may result in clinical manifestations (e.g., pleural effusion) 
that meet “seriousness” criteria (e.g., hospitalization). These manifestations may be reported as 
non-fatal SAEs.  
For all SAEs assessed as clinical manifestations associated with fatal disease progression, the 
following criteria will apply: 
• Seriousness Criteria cannot equal Death 
• Severity cannot equal Grade 5 
• Outcome = Ongoing at time of Death 
Deaths that are attributed solely to disease progression by the Investigator should not be reported 
as SAEs. 


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8.10 
Immune-mediated Adverse Events and Other Monitored Events  
Immune-mediated AEs (imAEs) are AEs consistent with an immune-mediated mechanism or 
immune-mediated component for which non-inflammatory etiologies (e.g., infection or tumor 
progression) have been ruled out. imAEs can include events with an alternate etiology which 
were exacerbated by the induction of autoimmunity.  Investigators should use clinical judgment 
characterizing an AE as immune mediated, including the requirement for steroid treatment, and 
are encouraged to rule out neoplastic, infectious, metabolic, toxic, or other etiologies to the 
extent possible, before characterizing an event as immune mediated. Information supporting the 
assessment of imAEs will be collected on the case report form. 
Additional information may also be collected on select AEs primarily related to NKTR-214, 
including cytokine release syndrome and capillary leak syndrome.  
8.11 
Adverse Events of Special Interest  
The AEs listed below are considered AESIs. Regardless of the assessment of whether the AESI 
is serious or nonserious, all AESIs are required to follow the timeline for SAE reporting (within 
24 hours as described in Section 8.7) from the sites to Nektar Drug Safety: 
pharmacovigilance@nektar.com.   
• CVA events (including TIA; any grade; CVA Management Guidelines are provided in 
Appendix 6) 
8.12 
Pregnancy Tests/Pregnancy 
8.12.1 
Pregnancy Tests 
Serum or urine pregnancy tests will be performed on WOCBP during screening. Serum or urine 
pregnancy tests will be performed by a local laboratory on women within 24 hours of Day 1 of 
each cycle prior to dosing. Urine pregnancy tests should have a minimum sensitivity of 25 IU/L 
or equivalent units of hCG. A negative pregnancy test result must be obtained before the 
administration of the study drug(s). 
A pregnancy test does not need to be performed on women who are postmenopausal (see 
Appendix 4) for at least 1 year or surgically sterile for at least 3 months before signing the ICF. 
If a female patient becomes pregnant, administration of the study drug(s) must be discontinued 
immediately. Requirements for reporting a pregnancy are provided in Section 8.12.2. 
8.12.2 
Pregnancy 
8.12.2.1 
Pregnancies in Female Patients 
The Sponsor must be notified immediately without undue delay, under no circumstances later 
than 24 hours following knowledge of the initial report and any follow-up reports of a female 
patient becoming pregnant during the course of the study and for 5 months post treatment 


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completion for female patients.  All reports should be submitted via the Pregnancy Notification 
Form.  Pregnancy, although reportable, is not considered an AE/SAE unless a female patient 
experiences signs or symptoms of pregnancy complications; however, the contact information 
for pregnancy reporting is the same as for SAE reporting and listed in Section 8.7.  Female 
patient(s) who become pregnant will be followed until the outcome of the pregnancy is known.  
Pregnancy follow-up should describe the outcome of the pregnancy, including any voluntary or 
spontaneous termination, details of the birth, and the presence or absence of any congenital 
abnormalities or birth defects in the offspring. 
If a female patient becomes pregnant, administration of the study drug(s) must be discontinued 
immediately. 
8.12.2.2 
Pregnancies in Female Partners of Male Patients 
Any pregnancy occurring during the course of the study and for 3 months after the last dose of 
NKTR-214 in a female partner of a male patient must be reported to the Sponsor.  The Sponsor 
must be notified immediately without undue delay, under no circumstances later than 24 hours 
following knowledge of the initial report and any follow-up information.  All reports should be 
submitted via the Pregnancy Notification Form. In order for the Sponsor or designee to collect 
any pregnancy surveillance information, the pregnant patient or partner must sign an informed 
consent form (See Section 12.2). 
Pregnancy, although reportable, is not considered an AE/SAE unless a female partner of male 
patient experiences signs or symptoms of pregnancy complications; however, the contact 
information for pregnancy reporting is the same as for SAE reporting and listed in Section 8.7.  
Attempts should be made to collect and report details of the course and outcome of any 
pregnancy in the partner of a male patient exposed to study drug with the authorization from the 
pregnant partner.  Pregnancy follow-up should describe the outcome of the pregnancy, including 
any voluntary or spontaneous termination, details of the birth, and the presence or absence of any 
congenital abnormalities or birth defects in the offspring. 
8.13 
Potential Drug-Induced Liver Injury 
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur prior to the reporting of a potential drug-induced liver injury (DILI) event.  All 
occurrences of potential DILIs, meeting the defined criteria, must be reported as SAEs (see 
Section 8.7 for reporting details). 
Potential DILI is defined as: 
1) Treatment-emergent ALT or AST > 3 times ULN, 
AND 


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2) Total bilirubin > 2 times ULN or clinical jaundice, without initial findings of cholestasis 
(elevated serum alkaline phosphatase), 
AND 
3) No other immediately apparent possible causes of elevated liver enzymes and 
hyperbilirubinemia, including, but not limited to, viral hepatitis, pre-existing chronic or acute 
liver disease, or the administration of other drug(s) known to be hepatotoxic. 
8.14 
Emergency Medical Support and Patient Card 
Patients enrolled in this clinical trial will be provided with Emergency Medical Support cards 
during their trial participation, which will be furnished by the Sponsor.  The Emergency Medical 
Support card is based on the need to provide clinical trial patients with a way of identifying 
themselves as participating in a clinical trial, and subsequently to give health-care providers 
access to the information about this participation that may be needed to determine the course of 
the patient’s medical treatment. 
This service is designed to provide information to health care providers who are not part of the 
clinical trial.  Clinical trial Investigators, who are already aware of the clinical trial protocol and 
treatment, have other means of accessing the necessary medical information for the management 
of emergencies occurring in their patients. 
The first point of contact for all emergencies will be the clinical trial Investigator caring for the 
affected patient.  The Investigator agrees to provide his or her emergency contact information on 
the card for this purpose.  If the Investigator is available when an event occurs, he/she will 
answer any questions.  Any subsequent action will follow the standard processes established for 
the Investigators.  In cases where the Investigator is not available, the Sponsor will provide a 
24-hour contact number, whereby health care providers are given access to a physician 
designated by the Sponsor who can assist with the medical emergency. 
8.15 
Clinical Laboratory Tests 
Clinical laboratory tests will be conducted according to the Schedule of Events (Section 1.2).  
Clinical laboratory tests will be performed by the central laboratory.  In addition, local laboratory 
testing within 24 hours, or as soon as locally feasible, is required prior to each study drug 
administration or dispensation or as clinically indicated.  A list of the clinical laboratory analytes 
to be tested is provided in Appendix 3.  All blood and urine samples will be collected and sent to 
the central laboratory on the day of collection unless otherwise instructed. Laboratory samples 
may be split (or 2 sets of samples collected) to allow a local laboratory analysis in addition to the 
central laboratory.  Eligibility will be based on central laboratory results.  However, for 
randomization, if the central laboratory tests are cancelled, lost, or considered inadequate for 
analysis, the site may forward local laboratory results for eligibility review and IMDC score 
calculation (with central laboratory testing repeated prior to the first dose of study drug).  If local 


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laboratory results are determined to be acceptable during eligibility review, randomization may 
proceed. During the Treatment Period, treatment decisions and assessment of adverse events may 
be based on local laboratory test data (see Appendix 3 for details on minimum required local 
laboratory tests for scheduled treatment visits), although central lab sample collection still 
applies.  The Investigator or qualified Sub-Investigator will review clinical laboratory test data, 
including at minimum Screening central laboratory data and both local and central laboratory 
results for all post-randomization assessments.  Additional clinical laboratory tests may be 
ordered at the Investigator’s or qualified Sub-Investigator’s discretion. 
The Investigator or qualified Sub-Investigator will review all laboratory results (both local and 
central) for clinical significance. Any laboratory result deemed clinically significant (i.e., is 
associated with signs and symptoms, requires treatment, or requires follow up) will be recorded 
as an AE as described in Section 8.1. 
8.16 
Physical Examinations 
Physical examinations should be conducted according to the Schedule of Events (Table 1).  Full 
physical examinations should be conducted at screening, and targeted, symptom-directed exams 
on Day 1 of each cycle, (evaluate all major organ systems, including the following categories:  
general, head, eyes, ears, mouth/throat, neck, heart, lungs, abdomen, lymph nodes, joints, 
extremities, integumentary, neurologic, and psychiatric).  Other examinations may be focused, at 
the discretion of the Investigator, to identify changes from baseline or evaluate changes based on 
the patient’s clinical symptoms. 
8.17 
Vital Signs 
Vital sign measurements will be recorded according to the Schedule of Events (Section 1.2).  
Vital signs include heart rate, systolic and diastolic blood pressure, and temperature.  It is 
preferred that the same arm be used for all blood pressure readings, if possible.  Pulse oximetry 
will also be included during Screening and as clinically indicated.  Weight is to be reported at 
each vital sign visit, height at screening visit only. 
8.18 
Electrocardiograms 
All patients will have 12-lead electrocardiogram (ECG) done during Screening as specified in 
the Schedule of Events.  After randomization, patients with clinically significant cardiac toxicity 
should have this assessment repeated as indicated.  For patients receiving sunitinib or 
cabozantinib, periodic monitoring with on-treatment electrocardiograms should be considered 
per its product labeling information. 
8.19 
Echocardiograms 
Standard echocardiogram will be performed at screening to assess cardiac function and LVEF 
according to the Schedule of Events.  A MUGA scan can be performed to assess cardiac function 


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and LVEF if a standard echocardiogram cannot be performed.  After randomization, patients 
with clinically significant cardiac toxicity should have this assessment repeated as indicated.   


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9.0 
STATISTICAL PLAN 
9.1 
General Considerations 
In general, continuous data will be summarized by descriptive statistics, including number of 
patients, mean, standard deviation, median, minimum, and maximum.  Categorical data will be 
summarized by the number and percentage of patients.  Unless otherwise specified, data will be 
summarized by treatment arm. 
The efficacy endpoints will be analyzed using the IMDC intermediate- or poor-risk population, 
and IMDC all-risk population.  All safety endpoints will be summarized using the Safety 
Population. 
A detailed description of analysis methods will be provided in the statistical analysis plan (SAP). 
9.2 
Determination of Sample Size 
The sample size of the study accounts for the following primary efficacy endpoints: ORR in 
IMDC intermediate- or poor-risk and IMDC all-risk populations, and OS in IMDC intermediate- 
or poor-risk and IMDC all-risk populations.  The overall alpha for this study is 0.05, which is 
split with 0.001 to evaluate ORR and 0.049 to evaluate OS.  All alpha levels are two-sided.  The 
test in IMDC all-risk population is gated by the one in IMDC intermediate- or poor-risk 
population for both ORR and OS.  That is, ORR in IMDC all-risk population will not be tested 
unless ORR in IMDC intermediate- or poor-risk population is statistically significant; and 
similarly, OS in IMDC all-risk population will not be tested unless OS in IMDC intermediate- or 
poor-risk population is statistically significant. 
In addition, a fallback approach will be used to reallocate alpha from ORR to OS. If ORR is 
significant in IMDC intermediate- or poor-risk and IMDC all-risk populations, the alpha of 0.001 
will be passed to OS. OS in IMDC intermediate- or poor-risk population can then be tested at 
0.05 (instead of 0.049) level. If it is significant, the alpha of 0.05 will be passed to OS in IMDC 
all-risk population.  The testing procedure of ORR and OS is described in Figure 2.  The total 
planned sample size is 600 patients. It is estimated that at least 500 IMDC intermediate- or 
poor-risk and approximately 100 IMDC favorable-risk, previously untreated advanced RCC 
patients will be randomized into the two treatment arms (NKTR-214 combined with nivolumab 
vs TKIs) in a 1:1 ratio.  


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Figure 2: 
Statistical Testing Procedure 
 
 
9.2.1 
Sample Size Justification for ORR  
Given a two-sided alpha of 0.001, 500 patients in the IMDC intermediate- or poor-risk 
population will provide approximately 82% power to detect an 18% difference in ORR between 
the 2 treatment arms using a Chi-square test, assuming an ORR of 27% for TKIs.  If the observed 
ORR difference is greater than 13.9%, the result will be statistically significant.  Six hundred 
patients in the IMDC all-risk population will provide approximately 89% power to detect an 18% 
difference in ORR between 2 treatment arms using a Chi-square test, assuming an ORR of 32% 
for TKIs.  If the observed ORR difference is greater than 13.2%, the result will be statistically 
significant.  If ORR is significant in IMDC intermediate- or poor-risk population, the alpha of 
0.001 will be passed to ORR in IMDC all-risk population. 
This ORR analysis will occur at the time of the interim analysis of OS. Based on the average 
accrual rate of 28 patients per month, at the time of OS interim analysis, it is estimated that 
600 patients in the IMDC all-risk population would have been enrolled and followed for 
6 months of which at least 500 patients will be IMDC intermediate- or poor-risk.  
9.2.2 
Sample Size Justification for OS 
The study is powered to detect an improvement in OS for NKTR-214 combined with nivolumab 
as compared to TKIs.  Due to the long duration of OS and potential subsequent non-protocol 
therapies, there may be confounding issues for the OS endpoint.  Thus, it is critically important 
to use interim OS results to efficiently power the OS endpoint and conduct the final analysis as 
early as possible using an adaptive approach.  The interim analysis will be triggered when at 
least 156 OS events in IMDC intermediate- or poor-risk population are observed.  All primary 
endpoints will be tested at this interim analysis.  Two parallel sequential tests will be conducted: 
(1) ORR in IMDC intermediate- or poor-risk and IMDC all-risk populations at α = 0.001 and (2) 
OS in IMDC intermediate- or poor-risk and IMDC all-risk populations at α = 0.01.  Within (1), 


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ORR in IMDC all-risk population will only be tested at 0.001 if ORR in IMDC intermediate- or 
poor-risk is statistically significant at 0.001.  Within (2), OS in IMDC all-risk population will 
only be tested at 0.01 if OS in IMDC intermediate- or poor-risk is statistically significant at 0.01.   
The overall Type I error rate is 0.05 for the primary OS analysis in IMDC intermediate- or poor-
risk and IMDC all-risk populations assuming ORR is significant in both IMDC intermediate- or 
poor-risk and IMDC all-risk populations.  The alpha of 0.01 will be spent at interim and the 
remaining alpha of 0.04 will be spent at final analysis corresponding to the statistical 
significance level of 0.047 calculated based on the correlation of the interim and final CHW test 
statistic. If ORR is not statistically significant in either population, an overall alpha of 0.049 will 
be used for OS where 0.01 will be spent at interim and the remaining alpha of 0.039 will be spent 
at final analysis corresponding to the statistical significance level of 0.046. The detailed 
calculation is provided in the SAP. 
If OS in the IMDC intermediate-or poor-risk population is not statistically significant, 
conditional power will be calculated based on this population.  The adaptive method in Liu and 
Hu (2016), and Mehta and Pocock (2011) will be used to determine the number of OS events in 
IMDC intermediate- or poor-risk population needed to target approximately 85% to 90% 
conditional power for the final analysis.  The final analysis will be triggered when this 
re-estimated number of OS events in IMDC intermediate- or poor-risk is reached.  The test of OS 
in IMDC all-risk population will be also performed at this time regardless of number of events 
observed in this group. 
If OS in the IMDC intermediate- or poor-risk population is statistically significant, but not in the 
IMDC all-risk population, then the conditional power will be calculated for the IMDC all-risk 
population.  The adaptive method in Liu and Hu (2016), and Mehta and Pocock (2011) will be 
used to determine the number of OS events in IMDC all-risk population needed to target 
approximately 85% to 90% conditional power for the final analysis. 
The minimum and maximum number of OS events in IMDC intermediate- or poor-risk 
population for the final analysis are 200 and 308, respectively.  The minimum event size is 
calculated to achieve 90% power with alpha = 0.049 (two-sided) assuming an exponential 
distribution in each treatment arm and a HR = 0.63 with median OS for the TKI arm of 
26 months in IMDC intermediate-or poor-risk population.  The maximum event size is 
determined based on the minimum clinically meaningful effect.  
The detailed sample size adaptation rules based on conditional power will be described in an 
appendix of the Data Monitoring Committee (DMC) Charter, which will not be accessible to the 
study team or sites to prevent introduction of any potential bias; however, the operational 
procedures will be described in the DMC charter, which is accessible to the study team.   
The key secondary endpoint of PFS in IMDC intermediate- or poor-risk population and IMDC 
all-risk population will be tested hierarchically given statistical significance of OS.  Further 
details of the testing procedure will be described in the SAP. 


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Figure 3 provides the study flow and decision-making time points for the primary endpoints. 
Figure 3: 
Study Flow and Decision-Making Time Points 
 


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9.3 
Analysis Sets 
For the purposes of analysis, the following populations are defined: 
Population 
Description 
Intent-to-Treat (ITT) IMDC 
Intermediate- or Poor-risk 
Population  
All patients who are randomized and are classified as the intermediate- or 
poor-risk according to the IMDC prognostic score. Patients are grouped by the 
treatment to which they were randomized. 
Intent-to-Treat IMDC All-risk 
Population 
All patients who are randomized. Patients are grouped by the treatment to which 
they were randomized. 
Safety IMDC Intermediate- or 
Poor-risk Population 
All patients who receive at least 1 dose (or partial dose) of study drug and are 
classified as the intermediate- or poor-risk according to the IMDC prognostic 
score. Patients are grouped according to the treatment they actually received.  
Safety IMDC All-risk Population All patients who receive at least 1 dose (or partial dose) of study drug. Patients 
are grouped according to the treatment they actually received.  
ORR IMDC Intermediate- or 
Poor-risk Population 
All randomized patients classified as the intermediate- or poor-risk according to 
the IMDC prognostic score who have at least 6 months of follow-up at the time 
point of the ORR analysis. A patient’s follow-up time is defined here as the 
time between randomization date and clinical data cut-off date regardless of 
patient disposition (i.e., ITT principle). Patients are grouped by the treatment to 
which they were randomized 
ORR IMDC All-risk Population 
All randomized patients who have at least 6 months of follow-up at the time 
point of the ORR analysis. A patient’s follow-up time is defined here as the 
time between randomization date and clinical data cut-off date regardless of 
patient disposition (i.e., ITT principle). Patients are grouped by the treatment to 
which they were randomized. 
Pharmacokinetic Population 
All patients in the Safety Population who have evaluable analysis 
concentration-time profiles that allow for computation of meaningful PK 
parameter values 
 
9.4 
Demographics and Baseline Characteristics 
A descriptive summary of demographics and key baseline characteristics will be provided.  
Details will be included in the SAP.   






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9.6 
Safety Analyses 
Endpoint 
Statistical Analysis Methods 
Other Secondary Safety analyses will be performed in all treated patients. Descriptive statistics of safety will be 
presented using National Cancer Institute (NCI) Common Terminology Criteria for Adverse 
Events (CTCAE) version 5.0 by treatment group. All on-study AEs, treatment-related AEs, 
SAEs, and treatment-related SAEs will be tabulated using worst grade per NCI CTCAE v 5.0 
criteria by system organ class and preferred term. On study lab parameters including 
hematology, chemistry, liver function, and renal function will be summarized using worst grade 
NCI CTCAE v 5.0 criteria. 
9.7 
Interim and Final Analyses 
• Interim Analysis (ORR & OS interim and OS events re‑estimation): when at least 156 OS 
events in IMDC intermediate- or poor-risk population have been observed.  
• Final Analysis (OS final): timing will be determined based on the Interim Analysis efficacy 
results.   
The SAP will further describe the planned interim analyses. 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 


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9.9 
Data Monitoring Committee  
When required, adjudicated events will be submitted to a DMC and Health Authorities for 
review.  The DMC will be comprised of qualified clinicians and a biostatistician, all independent 
from the Sponsor and investigational sites, selected to avoid conflict(s) of interest.  The DMC 
will review the results of the interim analyses as well as assess accumulating safety data and 
emerging risk/benefit balance at regular intervals and on an ad-hoc basis as detailed in the DMC 
charter.  The DMC will also conduct the OS events re-estimation; details will be provided in the 
DMC charter. 
The DMC’s specific activities will be detailed in a mutually agreed upon charter, which will 
define the relevant processes, including meeting proceedings and structure, data assessments, 
documentation and recordkeeping, process for DMC recommendations, and regulatory reporting, 
as applicable.  The charter will contain procedures to ensure the minimization of bias, such as 
maintaining confidentiality of any interim data. 


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10.0 
STUDY OR STUDY SITE TERMINATION 
The Sponsor has the right to suspend or terminate the study. Sponsor reasons for suspension or 
termination of the study may include, but are not limited to the following: 
• Study is terminated due to safety concerns (i.e., the benefit-risk balance is unacceptable) 
• Lack of efficacy or not meeting the study objectives 
• Development of NKTR-214 is terminated 
If an Investigator suspends or terminates their study site, the Investigator will promptly (if 
possible, within 24 hours) inform the Sponsor and the IRB/IEC and provide them with a detailed 
written explanation. Upon study completion, the Investigator will provide the Sponsor, IRB/IEC, 
and regulatory agency with final reports, summaries, and other documentation as required by 
health authorities, IRB/IEC, and other regulatory requirements. 


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11.0 
QUALITY CONTROL AND QUALITY ASSURANCE 
The Sponsor will implement and maintain quality control and quality assurance procedures with 
written SOPs to ensure that the study is conducted and data are generated, documented, and 
reported in compliance with the protocol, Good Clinical Practice (GCP), and applicable 
regulatory requirements. 
11.1 
Changes to the Protocol 
The Investigator may not deviate from the protocol without a formal protocol amendment having 
been established and approved by an appropriate IRB/IEC and the regulatory agency, as required 
by regulations, except when necessary to eliminate immediate hazards to the patient or when the 
change(s) involve only logistical or administrative aspects of the study.  Any deviation may 
result in the patient having to be withdrawn from the study and rendering that patient 
nonevaluable.  All protocol deviations and the reasons for such deviations are to be documented 
and reported to the Sponsor promptly. 
11.2 
Monitoring 
In accordance with Code of Federal Regulations 21 CFR 312.56, International Council for 
Harmonisation (ICH) GCP, and local regulations, the clinical monitor will periodically inspect 
all eCRFs, study documents, research facilities, and clinical laboratory facilities associated with 
this study at mutually convenient times during and after completion of the study. As required by 
21 CFR 312 Subpart D (Responsibilities of Sponsors and Investigators), ICH GCP, and local 
regulations, the monitoring visits provide the Sponsor with the opportunity to evaluate the 
progress of the study; verify the accuracy and completeness of eCRFs; ensure that all protocol 
requirements, applicable FDA, ICH GCP, local regulations, and Investigator’s obligations are 
being fulfilled; and resolve any inconsistencies in the study records. This includes inspection of 
all documents and records that are required to be maintained by the Investigator, including but 
not limited to medical records (office, clinic, or hospital) for the patients in this study. The names 
and identities of all research patients will be kept in strict confidence and will not appear on 
eCRFs or other records provided to or retained by the Sponsor. The Investigational New Drug 
(IND) Application regulations and ICH GCP guidelines also require the Investigator to allow 
authorized representatives of the Sponsor, IRB/IEC, FDA, and other relevant regulatory 
authorities direct access to study source records, and to inspect and make copies of the same 
records. The names and identities of the patients need not be divulged to the Sponsor; however, 
the records must nevertheless be available to be inspected for review. This can be accomplished 
by blacking out the patient’s name and replacing the name with the patient’s study identification 
number. If these requirements are in conflict with local regulatory restrictions or institutional 
requirements, the Investigator must inform the Sponsor of these restrictions before initiation of 
the study. 


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11.3 
Direct Access to Source Data/Documents for Audits and Inspections 
The Sponsor or designees may conduct auditing activities of a clinical site at any time during or 
after completion of the study.  The Investigator will be informed of such activities. 
Representatives of the FDA or other regulatory agencies, including IRB/IEC representatives, 
may also conduct an inspection or perform an audit of the study.  The 
Investigator(s)/institution(s) will permit trial-related audits, IRB/IEC review, and regulatory 
inspection(s) by providing direct access to source data/documents and study records.  If informed 
of such an inspection, the Investigator shall notify the Sponsor immediately.  The Investigator 
will ensure that the inspectors and auditors have access to the clinical supplies, study site 
facilities, and laboratory, and that all data (including original source documentation) and all 
study files are available, if requested. 


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12.0 
ETHICAL CONSIDERATIONS 
This study will be conducted to be consistent with the principles that have their origin in 
Declaration of Helsinki and in accordance with FDA regulations (21 CFR § 11, 50, 54, 56, and 
312), with ICH GCP, as well as with any applicable regulatory authority, federal, state and/or 
local laws and regulations. 
12.1 
IRB/IEC Approval 
Before enrollment of patients into the study, as required by FDA regulations (21 CFR § 56), ICH 
GCP, applicable regulatory authority requirements, and local regulations, the current protocol, 
Investigator’s Brochure, and ICF will be reviewed and approved by the applicable regulatory 
authority and/or competent IRB/IEC.  A letter documenting the IRB/IEC approval must be 
received by the Sponsor before the initiation of the study at a clinical site.  Amendments to the 
protocol will be subject to the same requirements as the original protocol in accordance with 
Section 11.1. 
The Investigator, Sponsor, or their designees will submit a progress report at least once yearly to 
the IRB/IEC, or more frequently if required by the IRB/IEC.  As soon as possible after 
completion or termination of the study, the Investigator will submit a final report to the IRB/IEC 
per the IRB/IEC requirements, and in compliance with FDA regulations, applicable regulatory 
authority requirements, and ICH GCP. 
The Investigator, the Sponsor, or their designees shall promptly notify the IRB/IEC of any SAEs, 
suspected unexpected serious adverse reactions (SUSARs), or any other information that may 
affect the safe use of the study drug(s) during the study, per the IRB/IEC local requirements, and 
in compliance with FDA regulations, regulatory authority regulations, and ICH GCP. 
12.2 
Written Informed Consent 
A freely and voluntarily written documentation of informed consent must be obtained from each 
patient or if the patient is an incapacitated person or a minor their legal representative before 
entering the study. The content and approval of the ICF must meet requirements of regulations 
and ICH GCP. Patients will be informed of all aspects of the study that are relevant to the 
patient’s decision to participate, and the ICF must be presented to each patient in the language in 
which the patient is fluent. 
Informed consent will be obtained from and documented for each patient prior to the conduct of 
any protocol-specific procedures. Signed and dated ICFs will be retained by the Investigator with 
the study records. Each patient will be given a copy of the signed and dated ICF. 
Any pregnancy that occurs in a study patient or the female partner of a male study patient should 
be reported to the Sponsor or designee. Only if a pregnant patient or partner has signed an 
informed consent form for disclosure information will the Sponsor or designee be able to collect 


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any pregnancy surveillance information. Information on this pregnancy will be collected on the 
Pregnancy Surveillance Form (see Section 8.12.2). 


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13.0 
DATA HANDLING AND RECORD KEEPING 
13.1 
Data Collection Instruments and Source Documents 
13.1.1 
Study Records 
During the study, the Investigator/institution should maintain adequate and accurate source 
documents and trial records that include all pertinent observations on each of the site’s trial 
patients.  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 (e.g., via an audit trail).  The Investigator should ensure the 
accuracy, completeness, legibility, and timeliness of the data reported to the Sponsor in the CRFs 
and in all required reports.  The Investigator/institution should, at a minimum, maintain the trial 
documents as specified in Essential Documents for the Conduct of a Clinical Trial (ICH E6 
Section 8) and as required by the applicable regulatory requirement(s).  The 
Investigator/institution should take measures to prevent accidental or premature destruction of 
these documents. 
13.1.2 
Data Collection Instruments 
Data collection instruments (DCIs) (e.g., eCRFs, electronic clinical outcomes assessments 
[eCOAs], and paper forms) will be used in this study.  These instruments are used to transmit the 
information collected during the performance of this study to the Sponsor or Sponsor’s designee 
and regulatory authorities.   
The Investigator must review the DCIs for completeness and accuracy and must approve all data, 
including any changes made.  Furthermore, the Investigator retains full responsibility for the 
appropriateness and accuracy of all data collected in the DCIs. 
13.2 
Retention of Essential Documents 
The Essential Documents contained in the clinical trial master files shall be retained for 25 years 
or per local and regional regulations and guidelines, whichever is longer. These documents 
should be retained for a longer period, however, if required by an agreement with the Sponsor. 
At all times, the retention must meet applicable data protection laws. It is the responsibility of the 
Sponsor to inform the Investigator/institution in writing as to when these documents no longer 
need to be retained.  
The Investigator shall archive the clinical trial master file securely and in a way that ensures that 
it is readily available and accessible, upon request, to the regulatory authorities. Sites must 
inform the Sponsor in writing if documents will be disposed of per Institutional Policy. 
The Investigator will contact the Sponsor before transferring or destroying any study records. 
The Investigator will also promptly notify the Sponsor in writing in the event of accidental loss 
or destruction of any study records. 


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13.3 
Confidentiality 
Patient confidentiality will be maintained per legal and regulatory requirements and ICH GCP.  
To comply with GCP guidelines and requirements, patient records will be reviewed during 
monitoring visits and audits conducted by the Sponsor, Sponsor's representatives, or health 
authorities.  During these activities, every reasonable effort will be made to keep medical 
information, including patient identifying information, as confidential as possible as required by 
law. 
Study data given to, and used by, Nektar are protected by the use of a patient identification 
number. The assignment of unique patient identification number to each patient IRT system 
enables de-identification. 
Demographic identifiers that will be collected as part of Study Data include year of birth, age, 
gender, race, and ethnicity provided this is permitted under applicable laws. Exact date of birth 
and patient name/initials are not collected. 
The study site is not to attach the names or other directly identifying information of the patients 
to any Study Data or biological samples that will be transferred to Nektar. Only pseudonymized / 
key-coded Study Data and biological samples will be transferred to Nektar, and only the study 
site will be able to connect the patient identification number to a patient’s personal data. 
13.4 
Security Measures 
Sites will employ both technical and organizational measures (such as, but not limited to, 
controlling access to personal patient data to only those with a need to know such data, data 
encryption, data anonymization and pseudonymization, and so forth) to ensure patient and 
patient data privacy. Sites will adhere to a “privacy by design” and “privacy by default” 
approach in collecting, storing, and processing personal patient data. 
In the event of a breach of the security measures used by the Site to ensure patient and patient 
data privacy, the Site will immediately notify the Sponsor. 


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14.0 
PUBLICATION PLAN 
All data are the property of the Sponsor. Any formal presentation or publication of data from this 
study will be considered for joint publication by the Sponsor personnel and Investigator(s). 
Any publications or abstracts arising from this study must adhere to the publication requirements 
set forth in the clinical trial agreement governing participation in the study. Study data shared by 
Nektar will not contain patient identifiable information. 
The Investigator may be required to sign the clinical study report if it is to be used in a 
registration submission to the health authorities of some countries. 


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15.0 
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Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus ipilimumab versus 
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APPENDIX 1: 
INTERNATIONAL METASTATIC RCC DATABASE 
CONSORTIUM (IMDC) PROGNOSTIC CRITERIA 
Adverse Prognostic Factors 
Clinical 
Karnofsky Performance Status < 80 
Time from initial diagnosis to randomization < 1 year 
Laboratory (central)a 
Hemoglobin < LLN 
Corrected calcium > ULN b, c 
Absolute neutrophil count > ULN 
Platelet count > ULN 
LLN = lower limit of normal; ULN = upper limit of normal 
a.  Based on most recent central laboratory results prior to randomization. If the central laboratory test results prior 
to randomization are unevaluable, the last local laboratory results prior to randomization may be used for 
eligibility review and IMDC score calculation (See Section 8.15). 
b.  Corrected calcium (mg/dL) = measured total Ca (mg/dL) + 0.8 (4.0 - serum albumin [g/dL]), where 
4.0 represents the average albumin level in g/dL. 
c. 
Corrected calcium (mmol/L) = measured total Ca (mmol/L) + 0.02 (40 - serum albumin [g/L]), where 
40 represents the average albumin level in g/L. 
 
Risk Group Based on Number of Adverse Prognostic Factors 
Number of Adverse Prognostic Factors Present 
Risk Groups 
0 
Favorable 
1 – 2 
Intermediate 
3 – 6 
Poor 
Heng, 2009 
 
 


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APPENDIX 2: 
PERFORMANCE STATUS CRITERIA 
Karnofsky Performance Status Scale 
Percent 
Description 
100 
Normal, no complaints, no evidence of disease. 
90 
Able to carry on normal activity; minor signs or symptoms of disease. 
80 
Normal activity with effort; some signs or symptoms of disease. 
70 
Cares for self, unable to carry on normal activity or to do active work. 
60 
Requires occasional assistance, but is able to care for most of his/her needs. 
50 
Requires considerable assistance and frequent medical care. 
40 
Disabled, requires special care and assistance. 
30 
Severely disabled, hospitalization indicated. Death not imminent. 
20 
Very sick, hospitalization indicated. Death not imminent. 
10 
Moribund, fatal processes progressing rapidly. 
0 
Dead 
Schag, 1984 
 


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APPENDIX 3: 
CLINICAL LABORATORY TESTS 
Local Clinical Laboratory Tests Obtained Prior to Study Drug Administration or 
Dispensation 
Laboratory Tests Required for Treatment Decisions 
• 
AST (SGOT) 
• 
ALT (SGPT) 
• 
Serum Creatinine 
• 
Blood urea nitrogen (BUN) 
• 
Total bilirubin 
• 
Sodium 
• 
Potassium 
• 
Pregnancy test (for WOCBP) 
• 
Any additional clinically-relevant test related to 
individual patient monitoring 
WOCBP = women of child-bearing potential 
Laboratory tests must be assessed by a local laboratory within 24 hours, or as soon as locally feasible, prior to each study 
drug administration or dispensation. 
 
Clinical Laboratory Test Panel 
Hematology 
Chemistry 
Serology (screening only)  
• 
Hemoglobin (Hgb) 
• 
Hematocrit (HCT) 
• 
Platelet count 
• 
White blood cell (WBC) 
count 
• 
Neutrophils 
• 
Lymphocytes 
• 
Monocytes 
• 
Eosinophils 
• 
Basophils 
• 
AST (SGOT) 
• 
ALT (SGPT) 
• 
Alkaline phosphatase (ALP) 
• 
Albumin 
• 
Creatinine  
• 
Calculated creatinine clearance 
• 
Calcium 
• 
Glucose (non-fasting) 
• 
Total protein (TP) 
• 
Total bilirubin 
• 
Sodium  
• 
Potassium  
• 
Chloride  
• 
CO2 content or bicarbonate  
• 
Blood urea nitrogen (BUN) or 
serum urea  
• 
Lactate dehydrogenase (LDH) 
• 
Uric acid 
• 
Hepatitis B surface antigen (HBsAg)  
• 
Hepatitis C virus antibody (anti-HCV)  
• 
Human immunodeficiency virus (HIV) 
antibody  
Additional Labs 
• 
Creatine kinase 
• 
Serum or urine pregnancy (hCG) for 
WOCBP 
• 
FSH a 
• 
Thyroid stimulating hormone (TSH)  
• 
Free thyroxine (T4)  
• 
Free or total triiodothyronine (T3)  
• 
Lipase  
• 
Amylase  
• 
C-reactive protein (Screening only)  
Coagulation 
• 
Partial thromboplastin time 
(PTT) 
• 
Prothrombin time (PT) 
Urinalysis 
• 
Specific gravity 
• 
pH 
• 
Glucose 
• 
Protein 
• 
Bilirubin 
• 
Ketones 
• 
Leukocyte esterase 
• 
Blood  
• 
Creatinine 
For positive protein, white blood cell or blood, a microscopic examination including: 
• 
Red blood cells 
• 
White blood cells 
• 
Epithelial cells 
• 
Bacteria 
• 
Crystals 
• 
Casts 
 
For urine protein, UPCR is required at Screening, and if UPCR ≥ 1.0 [≥113 mg/mmol], measurement of 24-hour urine 
protein is required to confirm patient meets eligibility criteria (see Inclusion Criteria 9). 
 
Post-randomization, UPCR or dipstick analysis is acceptable; if UPCR ≥ 2.0 [≥ 227 mg/mmol] or dipstick protein ≥ 3+, 
measurement of 24-hour urine protein is required 
a. 
Post-menopausal females under the age of 55 years must have a serum follicle-stimulating hormone (FSH) level 
> 40 mIU/mL to confirm menopause (see Appendix 4). 


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APPENDIX 4: 
WOMEN OF CHILDBEARING POTENTIAL, DEFINITIONS AND 
METHODS OF CONTRACEPTION 
DEFINITIONS 
Women of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile. Permanent sterilization methods include hysterectomy, bilateral 
salpingectomy, and bilateral oophorectomy. 
Women in the following categories are not considered WOCBP: 
• Premenarchal 
• Premenopausal female with 1 of the following: 
o Documented hysterectomy 
o Documented bilateral salpingectomy 
o Documented bilateral oophorectomy 
Note: Documentation can come from the site personnel’s review of the patient’s medical 
records, medical examination, or medical history interview. 
• Postmenopausal female 
o A postmenopausal state is defined as 12 months of amenorrhea in a woman over age 
45 years in the absence of other biological or physiological causes. In addition, females 
under the age of 55 years must have a serum follicle-stimulating hormone (FSH) level 
> 40 mIU/mL to confirm menopause. 
CONTRACEPTION GUIDANCE FOR FEMALE PATIENTS OF CHILDBEARING 
POTENTIAL 
One of the highly effective methods of contraception listed below is required during study 
duration and until the end of relevant systemic exposure, defined as 5 months after the end of 
study treatment (Note:  local laws and regulations may require use of alternative and/or 
additional contraception methods). 
Highly Effective Contraceptive Methods That Are User Dependent  
Failure rate of <1% per year when used consistently and correctly.a 
Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of 
ovulationb  
• 
oral  
• 
intravaginal  
• 
transdermal  


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Progestogen-only hormonal contraception associated with inhibition of ovulationb  
• 
oral  
• 
injectable  
Highly Effective Methods That Are User Independent  
• 
Implantable progestogen-only hormonal contraception associated with inhibition of ovulationb 
• 
Hormonal methods of contraception including oral contraceptive pills containing a combination of estrogen 
and progesterone, vaginal ring, injectables, implants and intrauterine hormone-releasing system (IUS)c 
• 
Intrauterine device (IUD)c 
• 
Bilateral tubal occlusion 
• 
Vasectomized partner  
A vasectomized partner is a highly effective contraception method provided that the partner is the sole male 
sexual partner of the WOCBP and the absence of sperm has been confirmed.  If not, an additional highly 
effective method of contraception should be used.  
• 
Sexual abstinence  
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 drug. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle 
of the patient. 
• 
It is not necessary to use any other method of contraception when complete abstinence is elected.  
• 
WOCBP patients who choose complete abstinence must continue to have pregnancy tests, as specified in 
Section 1.2.  
• 
Acceptable alternate methods of highly effective contraception must be discussed in the event that the 
WOCBP patients chooses to forego complete abstinence  
NOTES:  
a. Typical use failure rates may differ from those when used consistently and correctly. Use should be 
consistent with local regulations regarding the use of contraceptive methods for patients participating in 
clinical studies.  
b. Hormonal contraception may be susceptible to interaction with the study drug, which may reduce the efficacy 
of the contraceptive method.  Hormonal contraception is permissible only when there is sufficient evidence 
that the IMP and other study medications will not alter hormonal exposures such that contraception would be 
ineffective or result in increased exposures that could be potentially hazardous.  In this case, alternative 
methods of contraception should be utilized.  
c. Intrauterine devices and intrauterine hormone releasing systems are acceptable methods of contraception in 
the absence of definitive drug interaction studies when hormone exposures from intrauterine devices do not 
alter contraception effectiveness 
 


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Unacceptable Methods of Contraceptiona 
• 
Male or female condom with or without spermicide.  Male and female condoms cannot be used 
simultaneously 
• 
Diaphragm with spermicide 
• 
Cervical cap with spermicide 
• 
Vaginal Sponge with spermicide 
• 
Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the primary mechanism 
of action 
• 
Periodic abstinence (calendar, symptothermal, post-ovulation methods) 
• 
Withdrawal (coitus interruptus). 
• 
Spermicide only 
• 
Lactation amenorrhea method (LAM) 
a. 
Local laws and regulations may require use of alternative and/or additional contraception methods. 
 
CONTRACEPTION GUIDANCE FOR MALE PATIENTS WITH PARTNER(S) OF 
CHILDBEARING POTENTIAL 
Male patients with female partners of childbearing potential are eligible to participate if they 
agree to the following during the treatment and until the end of relevant systemic exposure. 
• Inform any and all partner(s) of their participation in a clinical drug study and the need to 
comply with contraception instructions as directed by the Investigator. 
• Male patients are required to use a condom for study duration and until the end of relevant 
systemic exposure defined as 3 months after the last dose of NKTR-214. 
• Female partners of males participating in the study to consider use of effective methods of 
contraception until the end of relevant systemic exposure, defined as 3 months after the last 
dose of NKTR-214 in the male patient. 
• Male patients 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 
during the treatment and until 3 months after the last dose of NKTR-214.  
• Refrain from donating sperm for the duration of the study treatment and until 3 months after 
the last dose of NKTR-214. 
COLLECTION OF PREGNANCY INFORMATION 
Guidance for collection of Pregnancy Information is provided in Section 8.12.2. 


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APPENDIX 5: 
CORTICOSTEROID DOSE EQUIVALENTS 
Equivalent Dose 
Steroid 
1.2 mg 
Betamethasone 
1.5 mg 
Dexamethasone 
8 mg 
Methylprednisolone 
8 mg 
Triamcinolone 
10 mg 
Prednisone 
10 mg 
Prednisolone 
40 mg 
Hydrocortisone 
50 mg 
Cortisone 
Mager, 2003; Webb, 2005 
 


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APPENDIX 6: 
CEREBROVASCULAR ACCIDENT ADVERSE EVENT 
MANAGEMENT ALGORITHM (ARM A AND ARM B) 
The table below provides a management algorithm for possible signs/symptoms of 
cerebrovascular accident (CVA) for patients in Arm A treated with the combination of 
NKTR-214 with a checkpoint inhibitor and patients in Arm B receiving sunitinib or 
cabozantinib. This general guideline constitutes guidance to the Investigator and may be 
supplemented by clinical judgment of the Investigator and/or discussions with the Medical 
Monitor representing the Sponsor. 
For unexplained neurological symptoms (such as hemiparesis, confusion, dysarthria, or visual disturbances) that 
may be associated with CVA:  
• 
Recommend following the Advanced Cardiac Life Support (ACLS) Adult Suspected Stroke Algorithm that 
includes time-sensitive assessment and rtPA use guidanceª.  
• 
Perform neurological imaging with DWI MRI as soon as feasible after the initial presentation of symptoms, 
preferably within 24 hours, or as indicated following an acute intervention. DWI MRI is preferred, but if 
contraindicated, alternative imaging modalities may be used.  
If imaging is consistent with a CVA, proceed to the following: 
1 
For any new CVA event confirmed by imaging (DWI MRI preferred unless contraindicated), regardless 
of neurological symptoms (e.g., cryptogenic CVA), and for suspected TIA without clear alternative 
etiology:  
• 
Discontinue study treatment for patients in Arm A receiving NKTR-214 in combination with a 
checkpoint inhibitor (i.e., nivolumab) and patients in Arm B receiving sunitinib or cabozantinib. 
2 
Neurology consultation recommended. 
3 
Perform pertinent laboratory assessments including coagulation (D-dimer, complete blood count with 
differential, serum blood urea nitrogen, and creatinine) 
 
 preferably by central 
laboratory testing. Local laboratory testing is allowed when central laboratory testing is not possible. 
4 
Consider cardiac echocardiogram (trans-esophageal as appropriate) to evaluate for potential source of 
emboli. 
Abbreviations: CVA = cerebrovascular accident; DWI = diffusion-weighted imaging; MRI = magnetic resonance 
imaging; rtPA = recombinant tissue plasminogen activator; TIA = transient ischemic attack. 
a. 
ACLS-algorithms.com. Adult Stroke Algorithm, (ACLS) Advanced Cardiac Life Support [Internet]; 2021 
[cited 5 May 2021]. Available from: https://acls-algorithms.com/adult-stroke-algorithm/.  
 
 


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APPENDIX 7: 
CYTOKINE RELEASE SYNDROME MANAGEMENT 
ALGORITHM 
The following treatment management guidelines are provided for general guidance. These 
guidelines should not substitute for a more individualized, tailored approach to managing a 
patient experiencing cytokine release syndrome (CRS). 
Cytokine Release Syndrome Management Measures/Algorithm 
As a general principle, differential diagnoses should be diligently evaluated according to standard medical practice. 
Non-inflammatory etiologies should be considered and appropriately treated.  
For patients with suspected CRS:  
• 
For Grade 1 or Grade 2 events, implement supportive care, including management of isolated symptoms based 
on institutional practices. 
• 
Consider admitting the patient for monitoring and providing supportive care, including management of 
isolated symptoms based on institutional practices and protocol management guidelines (e.g., hydration 
management guidelines, Section 5.4.2.2). 
• 
For patients with a persistent or worsening clinical condition after initial treatment of CRS, reevaluate for 
other contributing conditions. It is particularly important to reassess the patient for coexisting infections and 
cardiac, pulmonary, thromboembolic, and other complications. 
Grading Assessment per CTCAE v.5.0 Treatment Measures Recommended 
Grade 3 CRS 
• Hypotension 
managed with one 
pressor 
• Hypoxia requiring 
> 40% O2 
• Vasopressin administration should be considered if the hypotensive 
event is refractory to > 3L of fluid resuscitation 
• Oxygen therapy (nasal canula, non-invasive positive pressure 
ventilation, etc.) for respiratory symptoms with consideration of 
intubation for a patient with severe respiratory manifestations 
• Supportive care for renal, hepatic, and other organ function 
deteriorations 
• Steroid therapy should be considered (e.g., hydrocortisone 100 mg 
every 8 hours, dexamethasone 10 mg up to 4 times daily, 
methylprednisone 1-2 mg/kg/day IV or PO equivalent) 
• High-dose steroid (e.g., methylprednisolone 2 mg/kg up to 1 gram 
daily for 3 days) may be considered for severe CRS that failed to 
respond after repetitive steroid treatments 
• For severe CRS cases that require simultaneously aggressive 
management of hypotension, oxygenation, and cardiac telemetry, 
consult intensivist for ICU evaluation 
Grade 4 CRS 
• Life-threatening 
consequences 
• Pressor or 
ventilatory 
support indicated  
Abbreviations: CRS = cytokine release syndrome; CTCAE = Common Terminology Criteria for Adverse Events; 
ICU = intensive care unit; IV = intravenous; O2 = oxygen; po = orally 


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APPENDIX 8: 
INDUCERS AND STRONG INHIBITORS OF CYP3A4 
Inducers and Strong Inhibitors of CYP3A4a 
CYP3A4 Inducers 
Phenytoin 
Carbamazepine 
Rifampin 
Rifabutin 
Rifapentine 
Phenobarbital 
Dexamethasone 
St. John’s Wort 
Strong CYP3A4 Inhibitors 
Ketoconazole 
Itraconazole 
Posaconazole 
Voriconazole 
Clarithromycin 
Erythromycin 
Telithromycin 
Nefazodone 
Saquinavir 
Lopinavir/ritonavir 
Ritonavir 
Atazanavir 
Indinavir 
Nelfinavir 
Boceprevir 
Conivaptan 
Cabometyx, 2021; Sutent, 2019 
a. 
Notes: Lists may not be exhaustive. Grapefruit, grapefruit juice and other foods that are known to inhibit 
CYP3A4 activity should be avoided during treatment. St. John’s Wort (Hypericum perforatum) is known to be 
an inducer of CYP3A4 and should be avoided during treatment. 
 


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APPENDIX 9: 
RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
GUIDELINES (VERSION 1.1) WITH BRISTOL-MEYERS SQUIBB 
MODIFICATIONS 
1. 
EVALUATION OF LESIONS 
Solid tumors will be evaluated using Response Evaluation Criteria In Solid Tumors version 1.1 
(RECIST 1.1) guideline with Bristol-Meyers Squibb modifications (Eisenhauer, 2009). 
At baseline, tumor lesions/lymph nodes will be categorized as measurable or non-measurable as 
follows: 
1.1 
Measurable  
Tumor lesions: Must be accurately measured in at least one dimension (longest diameter in the 
plane of measurement is to be recorded) with a minimum size of: 
10 mm by CT/MRI scan (scan slice thickness no greater than 5 mm), or ≥ 2x slice thickness if 
greater than 5mm. 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph 
node must be ≥ 15 mm in short axis when assessed by CT/MRI scan (scan slice thickness 
recommended to be no greater than 5 mm). 
Lymph nodes merit special mention since they are normal anatomical structures which may be 
visible by imaging even if not involved by tumor.  Pathological nodes which are defined as 
measurable and may be identified as target lesions must meet the criterion of a short axis of 
≥ 15 mm by CT/MRI scan.  Only the short axis of these nodes will contribute to the baseline 
sum. The short axis of the node is the diameter normally used by radiologists to judge if a node is 
involved by solid tumor.  Nodal size is normally reported as two dimensions in the plane in 
which the image is obtained (for CT scan this is almost always the axial plane; for MRI the plane 
of acquisition may be axial, sagittal or coronal).  The smaller of these measures is the short axis. 
For example, an abdominal node which is reported as being 20 mm x 30 mm has a short axis of 
20 mm and qualifies as a malignant, measurable node.  In this example, 20 mm should be 
recorded as the node measurement.  All other pathological nodes (those with short axis ≥ 10 mm 
but < 15 mm) should be considered non-target lesions.  Nodes that have a short axis < 10 mm are 
considered non-pathological and should not be recorded or followed. 
Note: Lesions on X-Ray are not to be selected as Target or Non-Target Lesions. 
1.2 
Non-Measurable 
All other lesions are considered non-measurable, including small lesions (longest diameter 
< 10mm or pathological lymph nodes with ≥ 10 to < 15 mm short axis) as well as truly 
non-measurable lesions.  Lesions considered truly non-measurable include: leptomeningeal 


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disease, inflammatory breast disease, lymphangitic involvement of skin or lung, abdominal 
masses/abdominal organomegaly identified by physical exam that is not measurable by 
reproducible imaging techniques. 
Note: Lesions on X-Ray are not to be selected as Target or Non-Target Lesions. 
1.3 
Special Considerations Regarding Lesion Measurability 
1.3.1 Bone lesions 
• Bone scan, positron emission tomography (PET) scan and plain films are not considered 
adequate imaging techniques to measure bone lesions. However, these techniques can be 
used to confirm the presence or disappearance of bone lesions. 
• Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, 
that can be evaluated by cross sectional imaging techniques such as CT or MRI can be 
considered as measurable lesions if the soft tissue component meets the definition of 
measurability described above. 
• Blastic bone lesions are non-measurable. 
1.4 
Baseline Documentation of ‘Target’ and ‘Non-Target’ Lesions 
When more than one measurable lesion is present at baseline all lesions up to a maximum of 
5 lesions total (and a maximum of two lesions per organ) representative of all involved organs 
should be identified as target lesions and will be recorded and measured at baseline (this means 
in instances where patients have only one or two organ sites involved a maximum of two and 
four lesions respectively will be recorded). 
Note: A maximum of two lesions can be selected per organ system.  For example, a maximum of 
two lung lesions can be selected (selected from one lung or one lesion from each).  A maximum 
of two lymph nodes can be selected at baseline, as the lymphatic system is considered one organ. 
Target lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, but in addition should be those that lend themselves to 
reproducible repeated measurements.  It may be the case that, on occasion, the largest lesion does 
not lend itself to reproducible measurement in which circumstance the next largest lesion which 
can be measured reproducibly should be selected. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters.  If lymph nodes are to be 
included in the sum, then as noted above, only the short axis is added into the sum.  The baseline 
sum diameters will be used as reference to further characterize any objective tumor regression in 
the measurable dimension of the disease. 


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All other lesions (or sites of disease) including pathological lymph nodes should be identified as 
non-target lesions and should also be recorded at baseline.  Measurements are not required and 
these lesions should be followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal progression’ 
(more details to follow). In addition, it is possible to record multiple non-target lesions involving 
the same organ as a single item on the case record form (e.g., ‘multiple enlarged pelvic lymph 
nodes’ or ‘multiple liver metastases’). 
2. 
RESPONSE CRITERIA 
2.1 
Evaluation of Target Lesions 
• Complete Response (CR): Disappearance of all target lesions. Any pathological lymph 
nodes (whether target or non-target) must have reduction in short axis to < 10 mm. 
• Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, 
taking as reference the baseline sum diameters. 
• Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate 
an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is 
also considered progression). 
• Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study. 
• Not Evaluable (NE): If one or more target lesions cannot be measured or adequately 
assessed as either fully resolved or too small to measure (due to missing or poor-quality 
images), and the sum of diameters of the remaining measured target lesions (if any) has not 
increased sufficiently to meet PD as defined above. 
2.1.1 Special Notes on the Assessment of Target Lesions 
2.1.1.1 Lymph Nodes 
 Lymph nodes identified as target lesions should always have the actual short axis measurement 
recorded (measured in the same anatomical plane as the baseline examination), even if the nodes 
regress to below 10 mm on study.  This means that when lymph nodes are included as target 
lesions, the ‘sum’ of lesions may not be zero even if CR criteria are met, since a normal lymph 
node is defined as having a short axis of < 10 mm.  Case report forms or other data collection 
methods may therefore be designed to have target nodal lesions recorded in a separate section 
where, in order to qualify for CR, each node must achieve a short axis < 10 mm.  For PR, SD, 
and PD, the actual short axis measurement of the nodes is to be included in the sum of target 
lesions. 


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2.1.1.2 Target Lesions that Become ‘Too Small to Measure’ 
While on study, all lesions (nodal and non-nodal) recorded at baseline should have their actual 
measurements recorded at each subsequent evaluation, even when very small (e.g., 2 mm).  
However, sometimes lesions or lymph nodes which are recorded as target lesions at baseline 
become so faint on CT scan that the radiologist may not feel comfortable assigning an exact 
measure and may report them as being ‘too small to measure’.  When this occurs it is important 
that a value be recorded on the case report form. If it is the opinion of the radiologist that the 
lesion has likely disappeared, the measurement should be recorded as 0 mm.  If the lesion is 
believed to be present and is faintly seen but too small to measure, a default value of 5 mm 
should be assigned as the reference diameter.  (Note: It is less likely that this rule will be used for 
lymph nodes since they usually have a definable size when normal and are frequently surrounded 
by fat such as in the retroperitoneum; however, if a lymph node is believed to be present and is 
faintly seen but too small to measure, a default value of 5 mm should be assigned in this 
circumstance as well).  This default value is derived from the 5 mm CT slice thickness (but 
should not be changed with varying CT slice thickness).  The measurement of these lesions is 
potentially non-reproducible, therefore providing this default value will prevent false responses 
or progressions based upon measurement error.  To reiterate, however, if the radiologist is able to 
provide an actual measure, that should be recorded, even if it is below 5 mm. 
2.1.1.3 Lesions that Split or Coalesce on Treatment 
 When non-nodal lesions ‘fragment’, the longest diameters of the fragmented portions should be 
added together to calculate the target lesion sum.  Similarly, as lesions coalesce, a plane between 
them may be maintained that would aid in obtaining maximal diameter measurements of each 
individual lesion. If the lesions have truly coalesced such that they are no longer separable, the 
vector of the longest diameter in this instance should be the maximal longest diameter for the 
‘coalesced lesion’. 
2.2 
Evaluation of Non-Target Lesions 
This section provides the definitions of the criteria used to determine the tumor response for the 
group of non-target lesions.  While some non-target lesions may actually be measurable, they 
need not be measured and instead should be assessed only qualitatively at the time points 
specified in the protocol. 
• Complete Response (CR): Disappearance of all non-target lesions.  All lymph nodes must 
be non-pathological in size (< 10mm short axis). 
• Non-CR/Non-PD: Persistence of one or more non-target lesion(s) 
• Progressive Disease (PD): Unequivocal progression of existing non-target lesions. 


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2.2.1 Special Notes on Assessment of Progression of Non-Target Disease 
The concept of progression of non-target disease requires additional explanation as follows: 
2.2.1.1 When the Patient Also has Measurable Disease 
In this setting, to achieve ‘unequivocal progression’ on the basis of the non-target disease, there 
must be an overall level of substantial worsening in non-target disease such that, even in 
presence of SD or PR in target disease, the overall tumor burden has increased sufficiently to 
merit discontinuation of therapy A modest ‘increase’ in the size of one or more non-target 
lesions is usually not sufficient to qualify for unequivocal progression status.  Pleural effusions, 
pericardial effusions and ascites will not be followed as target or non-target lesions and will not 
contribute to response or progression.  The designation of overall progression solely on the basis 
of change in non-target disease in the face of SD or PR of target disease will therefore be 
extremely rare. 
2.2.1.2 When the Patient Also has Non-Measurable Disease 
This circumstance arises in some trials when it is not a criterion of study entry to have 
measurable disease.  The same general concepts apply here as noted above, however, in this 
instance there is no measurable disease assessment to factor into the interpretation of an increase 
in non-measurable disease burden.  Because worsening in non-target disease cannot be easily 
quantified (by definition: if all lesions are truly non-measurable) a useful test that can be applied 
when assessing patients for unequivocal progression is to consider if the increase in overall 
disease burden based on the change in non-measurable disease is comparable in magnitude to the 
increase that would be required to declare PD for measurable disease: i.e., an increase in tumor 
burden representing an additional 73% increase in ‘volume’ (which is equivalent to a 20% 
increase diameter in a measurable lesion).  Examples include, an increase in lymphangitic 
disease from localized to widespread, or may be described as ‘sufficient to require a change in 
therapy’.  If ‘unequivocal progression’ is seen, the patient should be considered to have had 
overall PD at that point.  While it would be ideal to have objective criteria to apply to 
non-measurable disease, the very nature of that disease makes it impossible to do so; therefore, 
the increase must be substantial. 
2.2.2 New Lesions 
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important.  There are no specific criteria for the 
identification of new radiographic lesions; however, the finding of a new lesion should be 
unequivocal: i.e., not attributable to differences in scanning technique, change in imaging 
modality or findings thought to represent something other than tumor (for example, some ‘new’ 
bone lesions may be simply healing or flare of pre-existing lesions).  This is particularly 
important when the patient’s baseline lesions show partial or complete response. For example, 


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necrosis of a liver lesion may be reported on a CT scan report as a ‘new’ cystic lesion, which it is 
not. 
NOTE: Fluid collections (pleural effusions, pericardial effusions, and ascites) will not be 
considered new lesions and will not contribute to response or progression.  In the event a new 
fluid collection is seen on a post-baseline imaging exam, a comment may be made, but the 
appearance of a new fluid collection alone should not result in an assessment of PD.  A lesion 
identified on a follow-up study in an anatomical location that was not scanned at baseline is 
considered a new lesion and will indicate disease progression.  An example of this is the patient 
who has visceral disease at baseline and while on study has a CT or MRI brain ordered which 
reveals metastases.  The patient’s brain metastases are considered to be evidence of PD even if 
he/she did not have brain imaging at baseline.  A lesion identified on Chest X-Ray that was not 
present in prior CT can be considered a new lesion and will result in PD. 
If a new lesion is equivocal, for example because of its small size, continued follow-up 
evaluation will clarify if it represents truly new disease.  If repeat scans confirm there is 
definitely a new lesion, then progression should be declared using the date of the initial scan. 
While fluorodeoxyglucose-positron emission tomography (FDG-PET) response assessments 
need additional study, it is sometimes reasonable to incorporate the use of FDG-PET scanning to 
complement CT scanning in assessment of progression (particularly possible ‘new’ disease). 
New lesions on the basis of FDG-PET imaging can be identified according to the following 
algorithm: 
1. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD based 
on a new lesion. 
2. No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive FDG-PET at 
follow-up corresponds to a new site of disease confirmed by CT, this is PD. If the positive 
FDG-PET at follow-up is not confirmed as a new site of disease on CT, additional follow-up 
CT scans are needed to determine if there is truly progression occurring at that site (if so, the 
date of PD will be the date of the initial abnormal FDG-PET scan). If the positive FDG-PET 
at follow-up corresponds to a pre-existing site of disease on CT that is not progressing on the 
basis of the anatomic images, this is not PD. 
2.3 
Response Assessment 
2.3.1 Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the study treatment until 
disease progression or the last response recorded, taking into account any requirement for 
confirmation and censoring rules regarding subsequent therapy.  The patient’s best overall 
response assignment will depend on the findings of both target and non-target disease and will 
also take into consideration the appearance of new lesions.  Furthermore, depending on the 
nature of the study and the protocol requirements, it may also require confirmatory measurement. 


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2.3.2 Time Point Response 
At each protocol specified time point, a response assessment occurs.  Table 9 provides a 
summary of the overall response status calculation at each time point for patients who have 
measurable disease at baseline.  When patients have non-measurable (therefore non-target) 
disease only, Table 10 is to be used. 
Table 9: 
Time Point Response: Patients With Target (± Non-Target) Disease 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all evaluated 
No 
PR 
SD 
Non-PD or not all evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR = complete response; NE = not evaluable; PD = progressive disease; PR = partial response; SD = stable disease 
 
Table 10: 
Time Point Response: Patients with Non-Target Disease Only 
Non-Target Lesions  
New Lesions  
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/Non-PDa 
Not all evaluated 
No 
NE 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
CR = complete response; NE = not evaluable; PD = progressive disease  
a. 
Non-CR/non-PD is preferred over SD for non-target disease since SD is increasingly used as endpoint for 
assessment of efficacy in some trials so to assign this category when no lesions can be measured is not advised. 
 
2.3.3 Best Overall Response 
Best response determination of complete or partial response requires confirmation: Complete or 
partial responses may be claimed only if the criteria for each are met at a subsequent time point 
of ≥ 4 weeks (28 days) later. In this circumstance, the best overall response can be interpreted as 


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in Table 11.  When SD is believed to be best response, it must meet the protocol specified 
minimum time from the date of first treatment or randomization date. 
For example, if the first scheduled follow-up imaging visit is Week 6 (± 7 days) for a particular 
protocol, a Best Response of SD can only be made after the patient is on-study for a minimum of 
6 weeks (42 days) minus 7 days, for an absolute minimum time on-study of 56 days from the 
reference start date (reference date is considered Day 1 on study).  If the patient is not on-study 
for at least this amount of time, any tumor assessment indicating SD before this time period will 
have a Best Response of NE unless PD is identified. 
Special note on response assessment: When nodal disease is included in the sum of target lesions 
and the nodes decrease to ‘normal’ size (< 10 mm), they may still have a measurement reported 
on scans.  This measurement should be recorded even though the nodes are normal in order not 
to overstate progression should it be based on increase in size of the nodes.  As noted earlier, this 
means that patients with CR may not have a total sum of ‘zero’ on the case report form (CRF). 
Table 11: 
Best Overall Response (Confirmation of CR and PR Required) 
Overall Response First 
Time Point 
Overall Response 
Subsequent Time Point 
Best Overall Response 
CR 
CR 
CR 
CR 
PR 
SD, PD, or PRa 
CR 
SD 
SD provided minimum criteria for SD duration met, 
otherwise PD 
CR 
PD 
SD provided minimum criteria for SD duration met, 
otherwise PD 
CR 
NE 
SD provided minimum criteria for SD duration met, 
otherwise, NE 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD provided minimum criteria for SD duration met, 
otherwise, PD 
PR 
NE 
SD provided minimum criteria for SD duration met, 
otherwise, NE 
NE 
NE 
NE 
CR = complete response; NE = not evaluable; PD = progressive disease; PR = partial response; SD = stable disease  
a. 
If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease meeting 
PR criteria relative to baseline, makes the disease PD at that point (since disease must have reappeared after 
CR). Best response would depend on whether minimum duration for SD was met.  However, sometimes ‘CR’ 
may be claimed when subsequent scans suggest small lesions were likely still present and in fact the patient had 
PR, not CR at the first time point.  Under these circumstances, the original CR should be changed to PR and the 
best response is PR. 


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2.3.4 Confirmation Scans 
Verification of Response: To be assigned a status of CR or PR, changes in tumor measurements 
must be confirmed by consecutive or subsequent repeat assessments that should be performed no 
less than 28 days after the criteria for response are first met.  Subsequent documentation of a CR 
may provide confirmation of a previously identified CR even with unlimited intervening NEs 
(e.g., CR NE CR or CR NE NE CR).  Subsequent documentation of a PR may provide 
confirmation of a previously identified PR even with an intervening NE or SD (e.g., PR NE PR 
or PR SD PR). However, only one (1) intervening time point will be allowed between PRs for 
confirmation. 
Verification of Progression: Progression of disease should be verified in cases where 
progression is equivocal.  If repeat scans confirm PD, then progression should be declared using 
the date of the initial scan.  If repeat scans do not confirm PD, then the patient is considered to 
not have PD. 

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Nektar Therapeutics 
 
STATISTICAL ANALYSIS PLAN 
 
A PHASE 3 RANDOMIZED OPEN-LABEL STUDY TO COMPARE NKTR-214 
COMBINED WITH NIVOLUMAB TO THE INVESTIGATOR’S CHOICE OF 
SUNITINIB OR CABOZANTINIB IN PATIENTS WITH PREVIOUSLY UNTREATED 
ADVANCED RENAL CELL CARCINOMA 
 
 
 
Protocol Number: 
17-214-09, Amendment 3.0 
SAP Version: 
Final 2.0 
Date: 
January 24, 2022 
 
 


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PREPARED BY: 
 
 
 
 


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TABLE OF CONTENTS 
PREPARED BY: ............................................................................................................................2 
LIST OF ABBREVIATIONS .......................................................................................................8 
1.0 
ADMINISTRATIVE STRUCTURE ..............................................................................10 
2.0 
INTRODUCTION............................................................................................................11 
3.0 
STUDY OBJECTIVES ....................................................................................................12 
3.1 
Primary Objectives .................................................................................................12 
3.2 
Secondary Objectives .............................................................................................12 
 
 
4.0 
STUDY ENDPOINTS ......................................................................................................14 
4.1 
Primary Efficacy Endpoints ...................................................................................14 
4.2 
Key Secondary Efficacy Endpoint .........................................................................14 
4.3 
Other Efficacy Endpoints .......................................................................................14 
5.0 
OVERALL STUDY DESIGN AND PLAN ...................................................................15 
5.1 
Study Design ..........................................................................................................15 
5.2 
Study Medications .................................................................................................15 
5.2.1 
Arm A: NKTR-214 Combined with Nivolumab ..................................16 
5.2.2 
Arm B: Treatment of Investigator’s Choice..........................................16 
5.3 
Pharmacokinetic, Pharmacodynamic,
 
Endpoints ...............................................................................................................16 
5.3.1 
Blood Sampling Times ..........................................................................16 
5.3.2 
Tumor Biopsy Times ............................................................................17 
5.3.3 
Pharmacokinetic Analysis Set (PKAS) .................................................17 
5.3.4 
Pharmacokinetic Measurements and Endpoints....................................17 
 
 
 
 
 
 
5.4 
Immunogenicity Measurements and Endpoints .....................................................19 
6.0 
STATISTICAL CONSIDERATIONS ...........................................................................20 
6.1 
General Considerations ..........................................................................................20 
6.2 
Determination of Sample Size ...............................................................................20 
6.2.1 
Sample Size Justification for ORR .......................................................21 
6.2.2 
Sample Size Justification for OS ..........................................................22 
6.3 
Analysis Populations ..............................................................................................23 
6.4 
Handling of Missing Data ......................................................................................24 
6.5 
Stratification and Pooling ......................................................................................27 


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6.6 
Definitions..............................................................................................................28 
6.7 
Study Drug Exposure .............................................................................................29 
7.0 
STATISTICAL ANALYSIS ...........................................................................................32 
7.1 
Patient Disposition .................................................................................................32 
7.2 
Important Protocol Deviations ...............................................................................32 
7.3 
Study Population ....................................................................................................33 
7.3.1 
Demographics and Other Baseline Disease Characteristics..................33 
7.3.2 
Medical and Cancer History .................................................................34 
7.3.3 
Prior Systemic Cancer/Oncology Therapies .........................................35 
7.3.4 
Surgical History and Prior Radiotherapy ..............................................35 
7.3.5 
Concomitant Radiotherapy and Procedures ..........................................35 
7.4 
Treatments and Medications ..................................................................................35 
7.4.1 
Prior and Concomitant Medications .....................................................35 
7.4.2 
Immune Modulating Medication...........................................................36 
7.4.3 
Subsequent Anti-Cancer Therapy .........................................................36 
7.4.4 
Study Drug Exposure ............................................................................37 
7.5 
Efficacy Analysis ...................................................................................................37 
7.5.1 
Efficacy Analysis of Primary Endpoints ...............................................37 
7.5.1.1 
Objective Response Rate ...............................................................38 
7.5.1.2 
Overall Survival .............................................................................38 
7.5.2 
Efficacy Analysis of Key Secondary Endpoint .....................................40 
7.5.2.1 
Progression-Free Survival ..............................................................40 
7.5.3 
Current Status of PFS and OS Follow-Up ............................................42 
7.5.4 
Efficacy Analysis of Other Endpoints...................................................43 
7.5.4.1 
Progression-Free Survival 2 ...........................................................43 
7.5.4.2 
Concordance Between BICR and Investigator Assessment of 
Progression ....................................................................................44 
7.5.4.3 
Duration of Response .....................................................................44 
7.5.4.4 
Time to Response ...........................................................................44 
7.5.4.5 
Clinical Benefit Rate ......................................................................45 
7.5.5 
Subgroup Analyses ...............................................................................45 
7.6 
Health-Related Quality of Life (HRQoL) ..............................................................46 
7.6.1 
FKSI-19 .................................................................................................46 
7.6.2 
EQ5D3L ................................................................................................47 
7.6.3 
PRO-CTCAE ........................................................................................48 
7.7 
Healthcare Resource Utilization ............................................................................48 


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7.8 
Immunogenicity .....................................................................................................49 
7.8.1 
Immunogenicity Measurements and Endpoints ....................................49 
7.8.2 
Evaluation of ADA ...............................................................................51 
7.8.3 
Definitions .............................................................................................51 
8.0 
SAFETY ANALYSIS.......................................................................................................53 
8.1 
Adverse Events ......................................................................................................53 
8.2 
Adverse Events of Special Interest for Checkpoint Inhibitors ...............................55 
8.2.1 
Select Adverse Events (to Support EU MAA) .......................................55 
8.2.1.1 
Incidence of Select AE ...................................................................56 
8.2.1.2 
Time-to Onset of Drug-Related Select AE ....................................57 
8.2.1.3 
Time-to Resolution of Drug-Related Select AE ............................57 
8.2.2 
Immune Mediated Adverse Events (IMAEs) (to Support US BLA) .....57 
8.2.3 
Other Events of Special Interest ............................................................59 
8.3 
Adverse Events for NKTR-214 .............................................................................59 
8.3.1 
Adverse Event of Special Interest for NKTR-214 ................................59 
8.3.2 
Other Safety Observations (OSO) for NKTR-214 ................................60 
8.4 
Deaths ....................................................................................................................62 
8.5 
Laboratory Parameters ...........................................................................................62 
8.5.1 
Hematology ...........................................................................................62 
8.5.2 
Serum Chemistry ...................................................................................63 
8.5.3 
Electrolytes ............................................................................................63 
8.5.4 
Additional Analyses ..............................................................................63 
8.6 
Additional Safety Analyses....................................................................................65 
8.6.1 
Vital Signs .............................................................................................65 
9.0 
COVID-19 RELATED ANALYSES ..............................................................................66 
9.1 
Study Conduct ........................................................................................................66 
9.1.1 
Patients Impacted ..................................................................................66 
9.1.2 
Multiple Incidences ...............................................................................66 
9.2 
Impacts on Efficacy Results ...................................................................................67 
9.3 
Impacts on Safety Results ......................................................................................67 
10.0 
EFFICACY INTERIM AND FINAL ANALYSES ......................................................68 
11.0 
DATA MONITORING COMMITTEE .........................................................................69 
12.0 
PHARMACOKINETIC, PHARMACODYNAMIC, 
 
ANALYSIS .......................................................................................................................70 
12.1 
Pharmacokinetic Analysis ......................................................................................70 
12.1.1 
Handling of Missing Values, BLQ, and Outliers ..................................71 


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13.0 
DOCUMENT HISTORY ................................................................................................75 
14.0 
REFERENCES .................................................................................................................77 
15.0 
APPENDIX .......................................................................................................................78 
15.1 
The Logrank Test for OS Analysis ........................................................................78 
15.2 
The Weighted Logrank Test for PFS Analysis ......................................................79 
15.3 
Proof of Strong Family-wise Error Rate Control for the Four Primary 
Hypotheses and Two Key Secondary Hypotheses .................................................80 
15.3.1 
Study Design .........................................................................................80 
15.3.2 
Notation and Test Statistics ...................................................................80 
15.3.3 
Strong Control of Family-wise Error Rate ............................................81 
15.4 
Time-to onset and time-to resolution definition and conventions for select 
adverse events, immune-mediated adverse events and other AEs of interest for 
NKTR-214 .............................................................................................................85 
15.4.1 
Time-to onset definition ........................................................................85 
15.4.2 
Time-to resolution definition ................................................................85 
 


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LIST OF TABLES 
Table 1: 
Tumor Tissue Collection Schedule ............................................................17 
Table 2: 
NKTR-214 and Nivolumab Pharmacokinetic Measurements ...................18 
Table 3: 
PFS Primary Analysis: Date of Progression or Censoring ........................42 
Table 4: 
ADA Status: Individual Samples ...............................................................52 
Table 5: 
ADA Response Categories:  Patient Level ................................................52 
Table 6: 
Planned Analyses for OSO for NKTR-214 ...............................................62 
Table 7: 
Criteria for Clinically Notable Vital Sign Abnormalities ..........................65 
Table 8: 
Derivation of Clustered AE .......................................................................86 
 
LIST OF FIGURES 
Figure 1: 
Testing Procedure for Primary Endpoints and Key Secondary 
Endpoints ...................................................................................................21 
Figure 2: 
Study Flow and Decision-Making Time Points .........................................23 
 


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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
AST 
aspartate aminotransferase 
ATC 
anthracycline, taxane, capecitabine 
ATCL 
Anatomical, Therapeutic Chemical Level classification 
BCBM 
breast cancer brain metastases 
BFI 
Brief Fatigue Inventory 
BICR 
blinded independent central review 
BMI 
body mass index 
BN-20 
quality of life assessment specific to brain neoplasms 
BSA 
body surface area 
CBR 
clinical benefit rate 
CMH 
Cochran-Mantel-Haenszel 
CNS 
central nervous system 
CR 
complete response 
DoR 
duration of response 
DMC 
data monitoring committee 
eCRF 
electronic case report form 
ECOG 
Eastern Cooperative Oncology Group 
EORTC 
European Organization for Research and Treatment of Cancer 
EQ-5D-3L™ 
EuroQol 5D 3 Level Version 
ESMO-MCBS 
European Society for Medical Oncology magnitude of clinical benefit scale 
GCP 
Good Clinical Practice 
GPA 
Graded Prognostic Assessment 
HER 
human epidermal growth factor receptor 
HR 
hazard ratio 
HRQoL 
health-related quality of life 
IPFI 
initial progression-free interval 
IRT 
interactive response technology 
ITT 
intent-to-treat 
IV 
intravenous 
KM 
Kaplan-Meier 
KPS 
Karnofsky Performance Status 
LBA 
Ligand binding assay 


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Abbreviation 
Definition 
LDH 
lactate dehydrogenase 
LR 
locally recurrent 
MBC 
metastatic breast cancer 
MedDRA 
Medical Dictionary for Regulatory Activities 
MID 
minimal important difference 
MMRM 
Repeated Measures Linear Mixed Effects Model 
NCI-CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NE 
not evaluable 
ORR 
objective response rate 
OS 
overall survival 
PD 
progressive disease 
PE 
physical examination 
PEG 
polyethylene glycol 
PFS 
progression-free survival 
PK 
pharmacokinetic(s) 
PR 
partial response 
Q21d 
once every 21 days 
QLQ-C30 
Quality of Life Core 30 
QoL 
quality of life 
RANO-BM 
Response Assessment in Neuro-Oncology—Brain Metastases 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RS 
raw score 
SAE 
serious adverse event 
SD 
stable disease 
SN38 
7-ethyl-10-hydroxy-camptothecin; the active metabolite of irinotecan 
SOC 
system organ class 
SRS 
stereotactic radiosurgery 
TEAE 
Treatment-emergent adverse event 
TNBC 
triple-negative breast cancer 
TPC 
Treatment of Physician’s Choice 
UGT1A1 
uridine diphosphate-glucoronosyl transferase 1A1 
WHO-DDE 
World Health Organization Drug Dictionary Enhanced 
 


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1.0 
ADMINISTRATIVE STRUCTURE 
This study will be managed via partnership between Nektar Therapeutics and a contract research 
organization (CRO). Central clinical laboratories will be used for processing of safety specimens, 
biomarkers, immunogenicity, pharmacokinetic (PK), and pharmacodynamics (PD) samples. An 
interactive response technology (IRT) service provider will manage the randomization system, 
study drug, and comparator distribution and inventory management. Data for this trial will be 
entered into an Electronic Data Capture (EDC) system, using a Medidata Rave platform. An 
independent data monitoring committee (DMC) is established to review the interim efficacy and 
safety data on a periodic basis. Response and progression will be determined by blinded 
independent central review (BICR) using modified Response Evaluation Criteria in Solid 
Tumors version 1.1 (RECIST 1.1; see modified RECIST 1.1 criteria in Appendix 8 of the clinical 
study protocol). 


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2.0 
INTRODUCTION 
This document describes the planned statistical analyses of the efficacy, safety, PK, PD,  
biomarker and immunogenicity data captured according to Nektar Therapeutics Protocol 
17-214-09 “A Phase 3 Randomized Open-Label Study to Compare NKTR-214 Combined with 
Nivolumab to the Investigator’s Choice of Sunitinib or Cabozantinib in Patients with Previously 
Untreated Advanced Renal Cell Carcinoma” version amendment 3.0 dated 19 October 2021. 
This Phase 3 study is conducted in accordance with the protocol, Good Clinical Practice (GCP), 
and all applicable regulatory requirements. 


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3.0 
STUDY OBJECTIVES 
3.1 
Primary Objectives 
• To compare the objective response rates (ORR) by blinded independent central review 
(BICR) assessment using modified Response Evaluation Criteria in Solid Tumors 
(mRECIST) 1.1 of NKTR-214 combined with nivolumab to that of tyrosine kinase inhibitor 
(TKI) monotherapy (sunitinib or cabozantinib) in International Metastatic Renal Cell 
Carcinoma Database Consortium (IMDC) intermediate- or poor-risk patients with previously 
untreated advanced renal cell carcinoma (RCC) 
• To compare the ORR by BICR using mRECIST 1.1 of NKTR-214 combined with nivolumab 
to that of TKI monotherapy (sunitinib or cabozantinib) in IMDC all-risk patients with 
previously untreated advanced RCC 
• To compare the overall survival (OS) of NKTR-214 combined with nivolumab to that of TKI 
monotherapy (sunitinib or cabozantinib) in IMDC intermediate- or poor- risk patients with 
previously untreated advanced RCC 
• To compare the OS of NKTR-214 combined with nivolumab to that of TKI monotherapy 
(sunitinib or cabozantinib) in IMDC all-risk patients with previously untreated advanced 
RCC 
 
3.2 
Secondary Objectives 
The key secondary objectives are: 
• To compare the progression-free survival (PFS) by BICR using mRECIST 1.1 of NKTR-214 
combined with nivolumab to TKI monotherapy (sunitinib or cabozantinib) in IMDC 
intermediate- or poor- patients with previously untreated advanced RCC 
• To compare the PFS by BICR using mRECIST 1.1 of NKTR-214 combined with nivolumab 
to TKI monotherapy (sunitinib or cabozantinib) in IMDC all-risk patients with previously 
untreated advanced RCC 
The other secondary objectives are: 
• To estimate the incidence of adverse events (AEs) of NKTR-214 combined with nivolumab 
versus TKI monotherapy (sunitinib or cabozantinib) in patients with previously untreated 
advanced RCC 
• To evaluate whether programmed cell death ligand 1 (PD-L1) expression (< 1% vs ≥ 1%) 
using the PD-L1 immunohistochemistry (IHC) 28-8 pharmDx assay is a predictive biomarker 
for ORR, PFS, and OS in patients with previously untreated advanced RCC 
• To characterize changes in cancer-related symptoms and quality-of-life in patients with 
previously untreated advanced RCC using the National Comprehensive Cancer 
Network/Functional Assessment of Cancer Therapy (NCCN/FACT) Symptom Index for 
Kidney Cancer (FKSI-19) 


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4.0 
STUDY ENDPOINTS 
4.1 
Primary Efficacy Endpoints 
• ORR, defined as the percentage of patients with a confirmed best overall response of 
complete response (CR) or partial response (PR) per mRECIST 1.1 by BICR. 
• OS, defined as time from randomization to the date of death from any cause. Patients who do 
not have a date of death will be censored at their last known alive date. 
 
4.2 
Key Secondary Efficacy Endpoint 
• PFS, defined as time from randomization to the first date of documented tumor progression 
per mRECIST 1.1 by BICR or death due to any cause, whichever comes first. 
 
4.3 
Other Efficacy Endpoints 
• PFS2 (PFS after the next line of treatment), defined as time from randomization to 
objectively documented progression, per investigator assessment, after the next line of 
therapy or to death from any cause, whichever occurs first. 
• Duration of response (DOR), defined as the time between the date of first confirmed 
documented response (CR or PR) to the date of the first documented tumor progression as 
determined per mRECIST 1.1 by the BICR, or death due to any cause, whichever occurs 
first. 
• Time to response (TTR), defined as the time from randomization to the date of the first 
confirmed documented response (CR or PR) per mRECIST 1.1 by BICR. 
• Clinical benefit rate (CBR), defined as defined as the number of patients with CR, PR, or SD 
per mRECIST 1.1 by BICR  
 


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5.0 
OVERALL STUDY DESIGN AND PLAN 
5.1 
Study Design 
This is a multicenter, randomized, open label, Phase 3 study that will evaluate the efficacy and 
safety of NKTR-214 combined with nivolumab compared with the Investigator’s choice of a 
TKI, either sunitinib or cabozantinib, in patients with previously untreated advanced RCC. 
The treatment period of the study is divided into multiple treatment cycles with associated 
evaluations and procedures. One cycle of treatment is defined as 6 weeks. Results of the 
assessments must be reviewed and documented before administering the scheduled dose of study 
drugs. In certain circumstances, patients with progressive disease (PD) per mRECIST 1.1 but 
with otherwise stable or improved performance and clinical status may continue to be treated in 
the event of a perceived benefit per Investigator. 
This study is divided into a Screening period, a Treatment period, and a Long-Term Follow-Up 
period, which will continue until withdrawal of consent, death, lost to follow-up, or study 
termination by the Sponsor. 
Approximately 600 patients (including at least 500 patients with IMDC intermediate- or 
poor-risk and approximately 100 patients with IMDC favorable risk) with previously untreated 
advanced RCC will be randomized in a 1:1 ratio to the two treatment arms below: 
• Arm A: NKTR-214 0.006 mg/kg IV Q3W combined with nivolumab 360 mg IV Q3W 
• Arm B: Investigator’s choice of either one of the following treatments 
- 
Sunitinib 50 mg po once daily for 4 weeks followed by 2 weeks off 
OR 
- 
Cabozantinib 60 mg po once daily 
Randomization will be stratified by: 
• IMDC prognostic score (0 [favorable risk] versus 1-2 [intermediate risk] versus 3-6 [poor 
risk]); laboratory data used to calculate IMDC score are based on central laboratory results) 
• TKI choice (sunitinib versus cabozantinib) 
 
5.2 
Study Medications 
Patients should begin study treatment within 5 calendar days of randomization. 
Treatment will continue until progression, unacceptable toxicity, withdrawal of consent, 
completion of 2 years (Arm A only) of treatment, the study ends, or other protocol specified 
reasons, whichever occurs first. 


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5.2.1 
Arm A: NKTR-214 Combined with Nivolumab 
Each patient’s NKTR-214 dose will be determined by the patient’s weight in kilograms, which 
will be determined on the day of each NKTR-214 dosing.  If the patient’s weight is within 10% 
of the Cycle 1 Day 1 weight, the study drug dose does not need to be recalculated depending on 
institutional guidelines/preference. Patients should receive NKTR-214 at a starting dose of 
0.006 mg/kg on Day 1 and Day 22 of each treatment cycle. 
NKTR-214 will be administered before nivolumab via IV infusion over 30 (± 5) minutes Q3W. 
Nivolumab administration should start at least 30 minutes after completion of the NKTR-214 
infusion.  Patients should receive nivolumab at a flat-dose of 360 mg as a 30-minute infusion on 
Day 1 and Day 22 of each treatment cycle. 
For patients randomized to Arm A, in the event that one of the study drugs is stopped due to 
toxicities, the other drug can be continued as a monotherapy if the toxicities are considered 
related to only one of the study drugs, once the criteria to resume are met. 
5.2.2 
Arm B: Treatment of Investigator’s Choice 
Patients randomized to TKI will receive a widely used standard-of-care agent: sunitinib or 
cabozantinib. Sunitinib is a vascular endothelial growth factor (VEGF) receptor TKI that is 
approved and recommended for the treatment of advanced RCC across prognostic groups. The 
starting dose of sunitinib is 50 mg, and it is administered po once daily for 4 weeks followed by 
2 weeks off (6-week cycle). Cabozantinib is a small molecule inhibitor of the tyrosine kinases 
c-Met, AXL, and VEGFR2, and has been shown to reduce tumor growth, metastasis, and 
angiogenesis. Cabozantinib has been evaluated in both first-line and second-line settings in 
advanced RCC. The starting dose of cabozantinib is 60 mg (40 mg for patients with moderate 
hepatic impairment [Child-Pugh score B]) and it is administered po once daily. 
5.3 
Pharmacokinetic, Pharmacodynamic,
 Study Measurements and 
Endpoints 
PK assessments are only performed for Arm A.  Blood samples for the assessment of NKTR-214 
and nivolumab concentrations will be collected and analyzed. 
 
5.3.1 
Blood Sampling Times 
Blood samples for PK, immunogenicity, and
/pharmacodynamic assessments of 
NKTR-214 and nivolumab will be collected as described in Protocol Amendment 2.0 Table 6. 


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5.3.2 
Tumor Biopsy Times 
Tumor biopsies or archival tissues will be collected as described in Table 1.  The samples for the 
formalin-fixed paraffin-embedded block or unstained slides sectioned from a block will be 
collected within 3 months prior to randomization (minimum of 8 slides, preferably 20 slides). 
Table 1: 
Tumor Tissue Collection Schedule 
Study Day of Sample Collection 
(1 cycle= every 6 weeks)a 
Archival or Fresh Tumor Tissue in FFPE 
Screening 
X 
Cycle 1 Days 14-21 
Xb 
Disease Progression 
Xb 
Source: Table 6 of Study protocol 
 
 
b. Optional but highly recommended 
 
5.3.3 
Pharmacokinetic Analysis Set (PKAS)  
The pharmacokinetic analysis set (PKAS) will consist of 4 different analyses. The PKAS 
includes all patients who received at least 1 dose of NKTR-214 and at least 1 measurable 
concentration of: 
• NKTR-214-RC (related cytokine) PKAS: NKTR-214-RC  
• NKTR-214-AC (active cytokine) PKAS: NKTR-214-AC 
• Total-PEG PKAS: Total-PEG 
• Nivolumab PKAS: Nivolumab 
 
5.3.4 
Pharmacokinetic Measurements and Endpoints 
NKTR-214-RC and Total-PEG will be analyzed using fully validated ligand binding assays 
(LBA). NKTR-214-AC will be analyzed using a qualified LBA. 
Nivolumab will be assayed using a fully validated LBA method. These assays are summarized in 
Table 2. 


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Table 2: 
NKTR-214 and Nivolumab Pharmacokinetic Measurements 
Assay 
Matrix 
Assay 
Format 
Assay Type 
Analytes Captured 
NKTR-214-RC 
Plasma 
LBA 
Validated 
Mixture of compounds containing IL-2 independent of 
PEG conjugation status 
NKTR-214-AC 
Plasma 
LBA 
Qualified 
Mixture of 2-PEG-IL-2, 1-PEG-IL-2 and free IL-2 
Total-PEG 
Plasma 
LBA 
Validated 
PEG, independent of conjugation status to IL-2 
Nivolumab 
Serum 
LBA 
Validated 
Nivolumab 
Abbreviations: LBA = ligand binding assay 
 
The analysis methods described in Section 12.1 will be used to estimate the Cycle 1 PK 
parameters for NKTR-214-RC, NKTR-214-AC, and Total-PEG for individual patients based on 
observed concentration values. Cycle 3 PK parameters will also be estimated if data allows. 
 
 
 
 


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5.4 
Immunogenicity Measurements and Endpoints 
Immunogenicity assessments are only performed for Arm A.  Blood samples for the assessment 
of the anti-drug antibodies of NKTR-214 and nivolumab will be collected and measured as 
described in Table 6 of the protocol. 
Validated methods to detect anti-NKTR-214/anti-PEG, anti-IL-2 and anti-nivolumab anti-drug 
antibodies (ADA) will be used to analyze immunogenicity samples.  Immunogenicity sample 
testing will be done in tiers as per the 2019 FDA guidance (FDA 2019).  Samples will be first 
tested with screening electrochemiluminescence assays (ECLAs).  Putative positive samples for 
anti-NKTR-214, anti-IL-2 and anti-nivolumab ADA will then be analyzed in competition 
ECLAs to confirm positivity. Confirmed anti-NKTR-214 ADA-positive samples will be tested 
further in a polyethylene glycol (PEG) immuno-competition assay to determine the antibody 
specificity of the reactivity to the PEG or non-PEG (IL-2, linker) moiety of NKTR-214.  
Confirmed positive samples from each assay (anti-nivolumab, anti-NKTR-214 and anti-IL-2) 
will then be tested to obtain a titer Samples confirmed to be positive for anti-NKTR-214/anti-
PEG, anti-IL-2 antibodies will be tested for neutralizing activity for IL-2 using a validated 
cell-based assay.  Anti-nivolumab antibodies positive samples will also be tested for neutralizing 
activity for nivolumab using a validated cell-based assay. 


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6.0 
STATISTICAL CONSIDERATIONS 
6.1 
General Considerations 
Although this is an open label study, analyses for treatment comparisons prior to final database 
lock will not be performed except for the pre-planned interim safety and efficacy analyses as 
described in Section 11.0 of this document and in the DMC charter. 
Blinding for aggregated treatment information during the trial and data unblinding for interim 
analysis and after final database lock are provided in the Aggregate Data Handling Plan. 
Summary statistics for continuous variables will include the mean, standard deviation, median, 
minimum, and maximum.  The mean and median will be presented to one decimal place beyond 
which the data were captured.  The standard deviation will be presented to two decimal places 
beyond which the data were captured.  The minimum and maximum will be presented to the 
precision with which the data were captured. 
Categorical variables will be presented as frequency counts and percentages.  A row or column 
denoted ‘Missing’ will be included in count tabulations where necessary to account for dropouts 
and missing values.  Percentages will be rounded to 1 decimal place and the percent will be 
suppressed when the count is zero.  The denominator will be the number of patients in the 
population of interest unless otherwise noted. 
Time-to-event variables will be analyzed using the Kaplan-Meier (KM) method. The KM 
estimates for 25th, 50th (median) and 75th percentiles with associated 2-sided 95% confidence 
interval using Greenwood’s formula (Greenwood, 1926), as well as the percentage of censored 
observations will be presented. All time-to-event variables will be plotted using the KM method. 
Data listings will be created to support each table and to present all data.  Data listings will be 
presented by treatment group and patient number. 
6.2 
Determination of Sample Size 
The sample size of the study accounts for the following primary efficacy endpoints: ORR in 
IMDC intermediate- or poor-risk and IMDC all-risk populations, and OS in IMDC intermediate- 
or poor-risk and IMDC all-risk populations.  The overall alpha for this study is 0.05, which is 
split with 0.001 to evaluate ORR and 0.049 to evaluate OS.  All alpha levels are two-sided.  
Statistical testing for the IMDC all-risk population will be gated by the corresponding tests in the 
IMDC intermediate- or poor- risk population for both ORR and OS. That is, ORR in the IMDC 
all-risk population will not be tested unless ORR in IMDC intermediate- or poor-risk population 
is statistically significant; and similarly, OS in the IMDC all-risk population will not be tested 
unless OS in IMDC intermediate- or poor- risk population is statistically significant. 
In addition, a fallback approach will be used to reallocate alpha from ORR to OS. If ORR is 
significant in the IMDC intermediate- or poor-risk population and the IMDC all-risk population, 


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the alpha of 0.001 will be passed to OS. OS in the IMDC intermediate- or poor-risk population 
can then be tested at the 0.05 (instead of 0.049) level. If it is significant, the alpha of 0.05 will be 
passed to OS in the IMDC all-risk population. The testing procedure of ORR and OS is 
described in Figure 1. The total sample size is 600 patients. It is estimated that at least 500 IMDC 
intermediate- or poor-risk and approximately 100 IMDC favorable-risk, previously untreated 
advanced RCC patients will be randomized into the two treatment arms (NKTR-214  combined 
with nivolumab vs. TKIs) in a 1:1 ratio. 
Abbreviations: All-risk = IMDC all-risk population; I/P risk = IMDC intermediate- or poor-risk population; 
ORR = objective response rate; OS = overall survival; PFS = progression-free survival. 
 
6.2.1 
Sample Size Justification for ORR 
Given a two-sided alpha of 0.001, 500 patients in the IMDC intermediate- or poor-risk 
population will provide approximately 82% power to detect an 18% difference in ORR between 
the 2 treatment arms using a Chi-square test, assuming an ORR of 27% for TKIs. If the observed 
ORR difference is greater than 13.9%, the result will be statistically significant. Six hundred 
patients in the IMDC all-risk population will provide approximately 89% power to detect an 18% 
difference in ORR between 2 treatment arms using a Chi-square test, assuming an ORR of 32% 
for TKIs. If the observed ORR difference is greater than 13.2%, the result will be statistically 
significant. If ORR is significant in IMDC intermediate- or poor-risk population, the alpha of 
0.001 will be passed to ORR in IMDC all-risk population. 
This ORR analysis will occur at the time of the interim analysis of OS. Based on the average 
accrual rate of 28 patients per month, at the time of OS interim analysis, it is estimated that 
600 patients in the IMDC all-risk population would have been enrolled and followed for 
6 months of which at least 500 patients will be IMDC intermediate- or poor-risk. 
Figure 1: 
Testing Procedure for Primary Endpoints and Key Secondary 
Endpoints 


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6.2.2 
Sample Size Justification for OS 
The study is powered to detect an improvement in OS for NKTR-214 combined with nivolumab 
as compared to TKIs.  Due to the long duration of OS and potential subsequent non-protocol 
therapies, there may be confounding issues for the OS endpoint. Thus, it is critically important to 
use interim OS results to efficiently power the OS endpoint and conduct the final analysis as 
early as possible using an adaptive approach. The interim analysis will be triggered when at least 
156 OS events in IMDC intermediate- or poor- risk population are observed. All primary 
endpoints will be tested at this interim analysis. Two parallel sequential tests will be conducted: 
(1) ORR in IMDC intermediate- or poor- risk and IMDC all-risk population at α = 0.001 and 
(2) OS in IMDC intermediate- or poor- risk and IMDC all-risk population at α = 0.01. Within 
(1), ORR in IMDC all-risk population will only be tested at 0.001 if ORR in IMDC intermediate 
or poor risk is statistically significant at 0.001. Within (2), OS in IMDC all-risk population will 
only be tested at 0.01 if OS in IMDC intermediate or poor risk is statistically significant at 0.01. 
If OS in IMDC intermediate- or poor-risk is not statistically significant, conditional power will 
be calculated based on this population. The adaptive method in Liu and Hu (2016), and 
Mehta and Pocock (2011) will be used to determine the number of OS events in IMDC 
intermediate- or poor-risk population to target approximately 85% to 90% conditional power for 
the final analysis. The final analysis will be triggered when this re-estimated number of OS 
events in IMDC intermediate- or poor- risk is reached. The test of OS in IMDC all-risk 
population will also be performed at the time of the final analysis regardless of number of events 
observed in this group. 
If OS in IMDC intermediate- or poor-risk is statistically significant, but not in the IMDC all-risk 
population, conditional power will be calculated for the IMDC all-risk population. The adaptive 
method in Liu and Hu (2016), and Mehta and Pocock (2011) will be used to determine the 
number of OS events in IMDC all-risk population to target approximately 85% to 90% 
conditional power for the final analysis. 
The minimum and maximum number of OS events in IMDC intermediate- or poor-risk 
population for the final analysis are 200 and 308, respectively.  The minimum event size is 
calculated to achieve 90% power with alpha=0.049 (two-sided) assuming an exponential 
distribution in each treatment arm and a HR = 0.63 with median OS for the TKI arm of 
26 months in IMDC intermediate- or poor- risk population. The maximum event size is 
determined based on the minimum clinically meaningful effect. When the minimum event size of 
200 is reached in the IMDC intermediate- or poor-risk population, approximately 211 events are 
expected to be observed in the IMDC all-risk population, which gives approximately 80% power 
with alpha=0.049 (two-sided) assuming an exponential distribution in each treatment arm and a 
HR = 0.68 with median OS for the TKI arm of 32.9 months in the IMDC all-risk population. 
The detailed sample size adaptation rules based on conditional power will be described in an 
appendix of the DMC Charter, which will not be accessible to the study team or sites to prevent 
introduction of any potential bias; however, the operational procedures will be described in the 


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DMC charter, which is accessible to the study team.  The key secondary endpoint of PFS in the 
IMDC intermediate- or poor-risk population and the IMDC all-risk population will be tested 
hierarchically given the statistical significance of OS. 
Figure 2 provides the study flow and decision-making time points. 
Figure 2: 
Study Flow and Decision-Making Time Points 
 
6.3 
Analysis Populations 
Intent-to-Treat (ITT) IMDC Intermediate- or Poor-risk Population:  All patients who are 
randomized and are classified as intermediate- or poor risk according to the IMDC prognostic 
score entered in the IRT system at randomization. Patients are grouped by the treatment to which 
they are randomized. It is abbreviated as ITT I/P-risk Population in the document. 
ITT IMDC All-risk Population: All patients who are randomized. Patients are grouped by the 
treatment to which they were randomized. It is abbreviated as ITT All-risk Population in the 
document. 
Safety IMDC Intermediate- or Poor-risk Population:  All patients who receive at least 1 dose 
(or partial dose) of any study drug and are classified as the intermediate- or poor-risk according 
to the IMDC prognostic score entered in the IRT system at randomization. Patients are grouped 
according to the treatment they actually received. It is abbreviated as Safety I/P-risk Population 
in the document. 
Safety IMDC All-risk Population: All patients who receive at least 1 dose (or partial dose) of 
study drug. Patients are grouped according to the treatment they actually received. It is 
abbreviated as Safety All-risk Population in the document. 


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Objective Response Rate (ORR) IMDC Intermediate- or Poor-risk Population: All 
randomized patients classified as the intermediate- or poor-risk according to the IMDC 
prognostic score who have at least 6 months of follow-up at the time point of the ORR analysis. 
A patient’s follow-up time is defined here as the time between randomization date and clinical 
data cutoff date regardless of patient disposition (i.e., ITT principle). Patients are grouped by the 
treatment to which they were randomized. This analysis population will be equivalent to the ITT 
IMDC Intermediate- or Poor-risk Population if the clinical data cutoff date is at least 6 months 
after the date that the last patient was randomized. It is abbreviated as ORR I/P-risk Population 
in the document. 
ORR IMDC All-risk Population: All randomized patients who have at least 6 months of 
follow-up at the time point of the ORR analysis. A patient’s follow-up time is defined here as the 
time between randomization date and clinical data cutoff date regardless of patient disposition 
(i.e., intent-to-treat principle). Patients are grouped by the treatment to which they were 
randomized. This analysis population will be equivalent to the ITT IMDC All-risk Population if 
the clinical data cutoff date is at least 6 months after the date that the last patient was 
randomized. It is abbreviated as ORR All-risk Population in the document. 
Pharmacokinetics (PK) Population: The PK Population is defined as all patients in the Safety 
IMDC All-risk Population who have at least one quantifiable PK concentration for either 
NKTR-214-RC, NKTR-214-AC, Total-PEG, or nivolumab. 
 
 
 
 
Immunogenicity Population: The Immunogenicity Population is defined as all patients in the 
Safety IMDC All-risk Population Arm A (i.e., treated with NKTR-214 and nivolumab) who have 
at least baseline and 1 post-baseline ADA assessment. 
6.4 
Handling of Missing Data 
• For the subsequent anti-cancer therapy start date: 
– If only the day is missing then: if the end date of the subsequent anti-cancer therapy is 
complete, impute to the minimum of (the last day of the month, end date of subsequent 
anti-cancer therapy); otherwise impute to the last day of the month. 
– If the month or year is missing, then leave missing. 
• For the time from initial diagnosis to randomization and the time from diagnosis of 
metastatic disease to randomization, partial dates for initial diagnosis and diagnosis of 
metastatic disease will be imputed as follows: 
– No imputation will be done if the year is missing 


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– If the year is before the randomization date, then missing days will be imputed as the first 
day of the month and missing months will be imputed as July 
– If the year is the current year of the randomization date, then missing days will be 
imputed as the first day of the month and missing months will be imputed as January 
• For the duration of AEs, partial dates for the start of the AE will be imputed as follows: 
– Missing day, month, and year should be queried.  In case of non-resolution of missing 
year, then the missing day will be imputed as Cycle 1 Day 1 (C1D1). 
– Start day of AE is missing and the year is same as Cycle 1 Day 1 (C1D1) 
o If the reported month of occurrence of the AE is after the month of the C1D1 dose, 
then missing day will be imputed as the first day of the month of occurrence of AE. 
o If the reported month of occurrence of AE is the month of C1D1 dose then the 
missing day will be imputed as the same day as C1D1. 
o If the reported month of the AE start date is before the month of C1D1, then the 
missing day will be imputed as day 15 of the month of the AE start date. 
o If the month of the AE start date is missing, the missing day will be imputed as the 
date of C1D1. 
– Start day of the AE is missing and the year is after the year of C1D1 
o Missing day will be imputed as the first day of the month of the occurrence of the AE 
o If the month of the AE start date is missing, the missing day will be imputed as 
01 January of the year of the AE start date. 
• For the duration of AEs, partially missing dates for the stop of the AE will be imputed as 
follows: 
– If the stop date is completely missing, it should be queried.  In case of non-resolution of 
missing year, no imputation will be performed. 
– If only the day is missing, the earlier of the following will be used as the stop date: 
o the last day of the month for stop of AE 
o the later of (last known alive date, AE start date if imputed) 
– If themonth and day are missing, the earlier of the following will be used as the stop date: 
o December 31st of the year for stop of AE 
o the later of (last known alive date, AE start date if imputed) 
• For the determination of prior medication, any medication with a start date prior to C1D1 
will be classified as prior medication regardless of the the stop date.  Missing or partial dates 
will be handled as follows: 


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– If missing day and/or month of the start date, the medication will be classified as prior 
unless the month and/or year of the start date is after C1D1 
• For determination of concommitant medication, the following will be classified as 
concomitant medication: 
– Any medication with a start date prior to or on C1D1 and continued after C1D1 (this will 
be considered as both prior and concomitant medication) 
– Any medication with a start date after C1D1, but prior to the last dose date + 100 days or  
(date of initiation of subsequent anti-cancer therapy – 1 day), whichever is earlier 
• Missing or partial dates for concomitant medication will be handled as follows: 
– If missing the day and/or month of the start date, the medication will not be considered as 
concomitant if the month and/or year of the start date is after the last dose date 
+ 100 days or (date of initiation of subsequent anti-cancer therapy – 1 day), whichever is 
earlier 
– If missing the day and/or month of the stop date, the medication will not be considered as 
concomitant if the month and/or year of the stop date is prior to C1D1 
– A medication with completely missing start and stop dates will be classified as 
concomitant 
• In order to calculate duration of immune modulating medication for management of 
drug-related select AEs or IMAEs (as defined in Section 8.2.2), missing or partial dates for 
these medications will be handled as follows: 
Missing or partial start date: 
– If the start date is completely missing, it will not be imputed. Only the number of days 
that the medication was taken on or after the AE start date will be counted toward the 
duration of IMM for management of certain AE. 
– If only the year is provided, impute the start date to January 1st of the year, 
– If only the day is missing, impute the start date to the first day of the month. 
Missing or partial stop date: 
– If the stop date is completely missing, impute stop date to the later of (last known alive 
date, AE start date if imputed) 
– If only the day is missing, the earlier of the following will be used as the stop date: 
o the last day of the month for stop of AE 
o the later of (last known alive date, AE start date if imputed) 
– If month and day are missing, the earlier of the following will be used as the stop date: 


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o December 31st of the year for stop of AE 
o the later of (last known alive date, AE start date if imputed) 
• For death date, the following conventions will be used: 
− If the death date is completely missing but reason for death is present, it will be imputed 
as the last known alive date 
− If the the death date is partially missing (missing day only, or missing both day and 
month), the death date and corresponding last known alive date will be imputed in 
2 steps: 
1. Imputed as the 1st of the month (missing day only) or January 1st of the year 
(missing both day and month) 
2. The imputed death date from the 1st step will be compared to the latest alive date 
captured from multiple sources (unimputed last known alive date), and the 
maximum of the two will be considered as the imputed death date and last known 
alive date 
Some laboratory analytes may be reported by range (e.g., gamma-glutamyl transferase [GGT] 
< 17 U/L) and will be imputed by the corresponding boundary (e.g., 17 U/L). 
Handling of missing data for efficacy analyses and HRQoL analyses are described in Section 7.5 
and Section 7.6, respectively. 
No imputation of other missing data is planned. 
6.5 
Stratification and Pooling 
For stratified analyses, the randomization stratification factors (IMDC prognostic score and TKI 
choice) entered into the IRT system at the time of randomization will be used, as follows: 
• IMDC prognostic score as entered in IRT (0 [favorable risk] vs 1-2 [intermediate risk] vs 3-6 
[poor risk]) 
• TKI choice as entered in IRT (sunitinib vs cabozantinib) 
The IMDC prognostic score will also be derived based on data entered in EDC. When deriving 
IMDC prognostic score, the latest assessment prior to or on the date of randomization will be 
used (if not available, then the latest assessment before the date and time of first dose of study 
drug will be used); if the site used local laboratory data for randomization, the local laboratory 
data collected in EDC cancer history form will be used. Discrepancies between IMDC prognostic 
score derived vs IMDC prognostic score as entered in IRT system will be summarized. 
If the discrepany between the IMDC prognostic score (0 vs 1-2 vs 3-6) derived versus as entered 
in IRT is ≥ 10%, a sensitivity stratified analyses using strata based upon derived IMDC 


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prognostic score per EDC and TKI choice will be performed for the primary and key secondary 
endpoints. 
To avoid unstable estimates, if any stratum (defined by the stratification factors for analysis) 
have fewer than 6 patients (1% of the estimated total number of patients) or there are no events, 
that stratum will be pooled with the smallest adjacent stratum for analyses. The smallest adjacent 
stratum is defined as the stratum with the fewest number of patients or events if the former is a 
tie, and the adjacent stratum is defined as the stratum with one of the two factors at the same 
level. 
6.6 
Definitions 
• Baseline: In general, baseline will be defined as the last assessment result on or before the 
randomization date (and time if available). 
For safety assessment data (laboratory, vital sign): for treated patients, baseline will be 
defined as the last assessment result on or before the date (and time if available) of the first 
dose of study treatment; for patients who are randomized but not treated, baseline will be 
defined as the last assessment result on or before the randomization date. 
If there are multiple valid safety assessments on or prior to the first dose of study treatment: 
− For laboratory tests, the latest non missing lab value on or before the first dose date 
(and time if collected) will be used as the baseline in the analyses. If multiple 
observations exist on the latest collection date (and time if collected), then the first 
observation is used as baseline. 
− For ADA, the record related to the most recent assessment among those records 
where date (and time if collected) of the ADA assessment being performed for a 
specific drug is on or before to the date (and time if collected) of the first dose date of 
that specific drug. 
Pre-treatment AEs will be defined as AEs with an onset date prior to, but not including, the 
day of the first dose of study treatment. 
• Study Day:  There is no study day zero. In general, Study Day 1 is the date of randomization. 
− For post-randomization days, study day is calculated as: 
assessment date – randomization date + 1 
− For pre-randomization days, study day is calculated as: 
assessment date – randomization date 
For safety analysis, study day is calculated and presented based on the first dose date as 
defined below. 


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• First Dose Date:  First dose date will be defined as the date of first dose of study treatment, 
Cycle 1 Day 1 (C1D1).  Note, per protocol, the first dose date may be ≤ 5 days after the date 
of randomization. If the randomization date and the first dose date is not on the same day, 
then the date of randomization will be different from C1D1.  Safety data will be calculated 
and presented based on First Dose Date. 
• Treatment-emergent/Extended Treatment-emergent Period: 
For patients on treatment, both the treatment-emergent period and the extended 
treatment-emergent period will be defined as the period of time on or after the day (and time, 
if collected and not missing) of the first dose of study treatment. 
For patients off treatment, the treatment-emergent period is defined as the period of time on 
or after the day (and time, if collected and not missing) of the first dose of study treatment, 
until: the date of (initiation of new anticancer therapy – 1 day) or (30 days after the date of 
the last dose of any study treatment), whichever is earlier. 
The extended treatment-emergent period will be defined as the period of time on or after the 
day (and time, if collected and not missing) of the first dose of study treatment until earlier 
date of (initiation of new anticancer therapy – 1 day) and (100 days after the date of the last 
dose of any study treatment). 
• Treatment-Emergent Adverse Event (TEAE): 
TEAEs are AEs with an onset date (and time, if collected and not missing) within the 
treatment-emergent period, or extended treatment-emergent period depending on the analysis 
Incomplete start and end dates for TEAEs will be imputed. Any AE will be considered as a 
TEAE if its status cannot be fully determined because of incomplete data. 
• Last Known Alive Date: Last known alive date will be defined as the latest alive date on or 
before data cutoff date, captured from multiple sources. Note that if there is an event date 
(either an assessment or death) beyond the data cutoff date, the last known alive date will be 
the data cutoff date. If a patient died before or on the data cutoff date, the last known alive 
date will be set as the death date. The last known alive date will not be imputed, except in the 
case that the death date is partially missing (see details in Section 6.4) 
 
6.7 
Study Drug Exposure 
For NKTR-214 and nivolumab in Arm A, the following parameters will be calculated: 
• Exposure duration (days) for each drug: Date of last dose – date of first dose (C1D1) + 1 
For NKTR-214 in Arm A, the following parameters will be calculated: 
• Total number of infusions: Total number of infusions for which the patient received a 
non-zero dose across all cycles 


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• Cumulative dose (mg/kg): Total actual dose (mg/kg) the patient received across all cycles, 
defined as the sum of actual doses (mg/kg) received across all cycles 
• Average dose per infusion (mg/kg): Cumulative dose (mg/kg) / Total number of infusions 
• Average duration of infusion (min): Total infusion time (min) / Total number of infusions; 
where total infusion time = summation of (completion time of infusion – start time of 
infusion) for all infusions of a patient 
• Actual dose intensity (mg/kg/week): [Cumulative dose (mg/kg) / (Exposure duration (in 
days) + 20 days)] × 7 
• Expected dose intensity (mg/kg/week) = (0.006 mg/kg) / (3 weeks) = 0.002 mg/kg/week 
• Relative dose intensity (%): (Actual dose intensity / Expected dose intensity) × 100 
For Nivolumab in Arm A, the following parameters will be calculated: 
• Total number of infusions: Total number of infusions for which the patient received a 
non-zero dose across all cycles 
• Cumulative dose (mg): Total actual dose (mg) the patient received across all cycles, defined 
as the sum of actual doses (mg) received across all cycles 
• Average dose per infusion (mg): Cumulative dose (mg) / Total number of infusions 
• Average duration of infusion (min): Total infusion time (min) / Total number of infusions; 
where total infusion time = summation of (completion time of infusion – start time of 
infusion) for all infusions of a patient 
• Actual dose intensity (mg/week): [Cumulative dose (mg) / (Exposure duration (in days) 
+ 20 days)] × 7 
• Expected dose intensity (mg/week) = (360 mg) / (3 weeks) = 120 mg/week 
• Relative dose intensity (%): (Actual dose intensity / Expected dose intensity) × 100 
For Sunitinib in Arm B, the following parameters will be calculated: 
• Exposure duration (days): Date of last dose – date of first dose (C1D1) + 1 
• Total number of doses: Total number of doses the patient received 
• Average daily dose (mg/day): Sum of all sunitinib doses in mg actually received / Exposure 
of duration (in days) 
• Expected daily dose (mg/day): 33.33 mg/day (= 50 mg × 28 days / 42 days) 
(Note that sunitinib treatment consists of 50 mg PO daily dose for 4 weeks followed by 2 
weeks of a washout period) 
• Relative dose intensity (%): (Average daily dose / Expected daily dose) × 100 


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For Cabozantinib in Arm B, the following parameters will be calculated: 
• Exposure duration (days): Date of last dose – date of first dose (C1D1) + 1 
• Total number of doses: Total number of doses the patient received 
• Average daily dose (mg/day): Sum of all cabozantinib doses in mg actually received / 
Exposure of duration (in days) 
• Expected daily dose (mg/day): 60 mg/day or 40 mg/day (40 mg for patients with mild to 
moderate hepatic impairment [Child-Pugh score A or B]) 
• Relative dose intensity (%): (Average daily dose / Expected daily dose) × 100 


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7.0 
STATISTICAL ANALYSIS 
7.1 
Patient Disposition 
A summary of patient disposition will display the number of patients who were randomized and 
the number that comprised each analysis population by treatment arm for the ITT I/P-risk 
population and ITT all-risk population.  In addition, the number of patients who discontinued 
study drug and the number of patients who exited the study, both overall and by reason, will be 
presented by treatment arm for the ITT I/P-risk population and the ITT all-risk population. 
Descriptive statistics for time to NKTR-214 discontinuation (mean, median, min, max) will be 
summarized for the patients who discontinued NKTR-214. 
All disposition data will be presented in a data listing. 
7.2 
Important Protocol Deviations 
Important protocol deviations are defined as protocol deviations that fall into the following 
categories: 
• Violated key inclusion/exclusion criteria 
o Patient did not have advanced or metastatic RCC with a clear-cell component 
o Patient received prior systemic therapy 
o Patient had active brain metastases 
o Patient did not meet inclusion/exclusion criteria for lab values (e.g., absolute 
neutrophil count [ANC], platelet count, hemoglobin, serum creatinine, alanine 
aminotransferase [ALT], aspartate aminotransferase [AST], total bilirubin, urine 
protein creatinine ratio [UPCR]) 
o Patient had a Karnofsky Performance Status of less than 70% 
o Patient required more than 2 anti-hypertensive medications for managing 
hypertension 
o Patient received prior palliative radiotherapy within 2 weeks prior to randomization 
• Received wrong treatment or significant incorrect dose 
o Treated differently from the randomized assignment 
o Relative dose intensity >125% for study drug (programmatically derived). Received 
important prohibited medication during study participation 
o Any antineoplastic therapy (i.e., chemotherapy, hormonal therapy, immunotherapy, 
extensive non-palliative radiation therapy, or investigational agent) 
• Missing critical primary/key secondary efficacy assessment 
o The baseline disease assessment is missing in BICR data (programmatically derived) 


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• Stratification error 
• Issues that affect patient rights 
o Patient did not sign the informed consent for the study before randomization 
(programmatically derived) 
o Patient developed withdraw criteria during the study but were not withdrawn (manual 
review) 
• Other issues that may significantly impact the completeness, accuracy, and/or reliability of 
key study data or that may significantly affect a patient’s rights, safety, or well-being 
Final determination of important protocol deviations will be reviewed by the study team 
(including Clinical Trial Lead (CTL), the Medical Monitor, and the statistician). 
The number and percentage of patients in each important protocol deviations category and sub-
category will be summarized by treatment arm for the ITT I/P-risk population and ITT all-risk 
population. All protocol deviations will be listed. 
7.3 
Study Population 
7.3.1 
Demographics and Other Baseline Disease Characteristics 
The following baseline data will be summarized and listed by treatment arms for ITT I/P-risk 
population and ITT all-risk population: 
• Age 
• Age categorization I (< 65, ≥ 65 years) 
• Age categorization II (<65, ≥ 65 and < 75, ≥ 75 years) 
• Age categorization III (<65, ≥ 65 and < 75, ≥ 75 and <85, ≥ 85 years) 
• Sex (male, female) 
• Ethnicity 
• Race (White, Black, Asian, Other) 
• Height 
• Weight 
• Geographic region (US, Rest of the world) 
• Karnofsky performance status (<80,  ≥80) 
• IMDC prognostic score as per IRT (0, 1-2, 3-6) 
• IMDC prognostic score as per EDC (0, 1-2, 3-6) 
• TKI choice as per IRT (Sunitinib, Cabozatinib) 


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• Prior nephrectomy (Yes, No) 
• Prior radiotherapy (Yes, No) 
• Baseline liver mets as per BICR (Yes, No) 
• LDH level (≤ 1.5 × ULN, > 1.5 × ULN) 
• Hemoglobin (< LLN, ≥ LLN) 
• Corrected Calcium (≤ ULN, > ULN) 
• Absolute neutrophil count (ANC)  
• Platelet (≤ ULN, > ULN) 
• Alanine aminotransferase (ALT) 
• Aspartate aminotransferase (AST) 
• Alkaline phosphatase (≤ ULN, > ULN) 
• PD-L1 status (≥ 1%, <1%, indeterminate or non-evaluable) 
• All lesions (Investigator and BICR Assessments at Baseline): sites of disease, number of 
disease sites per patient 
• Target lesions (Investigator and BICR Assessments at Baseline): presence of target lesions, 
site of target lesions, sum of reference diameter of target lesions, number of disease sites per 
patient 
• Hepatic impairment (No [total bilirubin ≤ ULN and AST ≤ ULN], Yes [total bilirubin > ULN 
or AST > ULN]) 
• Renal impairment (No [creatinine clearance ≥ 60 mL/min], Yes [creatinine clearance < 60 
mL/min]) 
 
7.3.2 
Medical and Cancer History 
Cancer history will be summarized and listed for the ITT I/P-risk population and the ITT all-risk 
population, and will include the time since initial RCC cancer diagnosis, time since 
metastatic/advanced RCC cancer diagnosis, history of brain metastases, histology and 
sarcomatoid component. 
Medical history collected at screening will be mapped by the Medical Dictionary for Regulatory 
Activities (MedDRA) and will be summarized by system organ class (SOC) and preferred term 
for the ITT I/P-risk population and the ITT all-risk population.  For summary tables, a patient 
will be counted only once per SOC and preferred term. 


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7.3.3 
Prior Systemic Cancer/Oncology Therapies 
An eligible patient should not receive any prior systemic cancer/oncology therapies for RCC.  
All patients who received prior systemic cancer/oncology therapies for RCC are considered to 
have important protocol violations. 
All prior systemic cancer/oncology therapies will be listed, if applicable. 
7.3.4 
Surgical History and Prior Radiotherapy 
The number and percent of patients who had prior cancer-related surgery will be summarized by 
type of surgery for each treatment arm using the ITT I/P-risk population and ITT all-risk 
population.  Patients who have undergone prior nephrectomy will be summarized. 
The number and percent of patients who had prior radiotherapy will be summarized by type of 
radiotherapy for each treatment arm using the ITT I/P-risk population and ITT all-risk 
population. 
All prior radiotherapy and surgical procedures will be listed. 
7.3.5 
Concomitant Radiotherapy and Procedures 
The number and percent of patients who had concomitant radiotherapy will be summarized by 
site and type of radiotherapy for each treatment arm using the ITT I/P-risk population and ITT 
all-risk population. 
The number and percent of patients who had concomitant procedures will be summarized by 
each coded procedure preferred term for each treatment arm using the ITT I/P-risk population 
and ITT all-risk population. 
All concomitant radiotherapy and procedures will be listed. 
7.4 
Treatments and Medications 
7.4.1 
Prior and Concomitant Medications 
Prior and concomitant medications will be coded according to Anatomical, Therapeutic 
Chemical Level (ATCL) classification and preferred drug name using the World Health 
Organization Drug Dictionary Enhanced (WHO-DDE). 
Concomitant medications are defined as medications taken on or after the date of first dose of 
study drug, including medications initiated prior to the date of first dose of study drug and 
continued during treatment, and medications initiated on or after the date of first dose of study 
drug and within 100 days after last dose of study drug or initiation of new anticancer therapy 
– 1 day, whichever is earlier. 


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Concomitant medications will be tabulated for the Safety I/P-risk population and the Safety 
all-risk population by WHO-DDE ATCL-2 classifications and preferred term.  If the ATCL-2 
classification is missing, the next non-missing higher level of classification will be used 
(Level 1).  If a patient reports the same medication multiple times, then the frequency reported 
for that medication will be incremented by only one.  As with the medication, if a patient reports 
multiple medications within the same ATCL-2 classification then the frequency for that ATCL-2 
classification will be incremented by only one.  Percentages will be calculated using the total 
number of patients in the Safety I/P-risk population and the Safety all-risk population. 
Prior medications are defined as medications taken starting prior to the first dose of study drug.  
Prior medications will be summarized for the ITT I/P-risk population and ITT all-risk population 
using the same analytical procedures as concomitant medications. For the medications initiated 
prior to the date of first dose of study drug and continued during treatment, they are considered 
as both prior medications and concomitant medications. 
Number of patients that received narrow-range CYP substrates as concomitant medication will 
also be summarized. 
Prior and concomitant medications will be presented in a data listing. 
7.4.2 
Immune Modulating Medication 
The list of anatomic class, therapeutic class and generic name used for the selection of 
immune-modulating medication (IMM) will be provided at the time of the database lock. 
The percentage of patients who received immune-modulating concomitant mediations for 
• Management of drug-related select adverse events (any Grade, Grade 3-5) by select AE 
category/subcategory (see Section 8.2 for select AEs) 
• Management of IMAEs (any grade, grade 3-5) by IMAE category (see Section 8.2.2 for 
IMAEs) will be reported by medication class and generic term. 
For each category/subcategory of drug-related select AEs (any grade, grade 3-5) and IMAEs 
(any grade, grade 3-5), the following will be reported: 
• Total duration of IMM use (excluding overlaps), duration of high dose of corticosteroid, 
initial dose of corticosteroid, and tapering duration (summary statistics) 
7.4.3 
Subsequent Anti-Cancer Therapy 
Subsequent anti-cancer systemic therapy will be summarized based on the ITT I/P-risk 
population and the ITT all-risk population, and tabulated using the WHO-DDE and ATCL-2 
classifications and preferred term.  The number and percent of patients who took at least one 
subsequent anti-cancer therapy will be calculated and presented by treatment group, ATCL-2 
classifications, and preferred term. 


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7.4.4 
Study Drug Exposure 
Overall exposure to each study drug will be summarized for the Safety I/P-risk population and 
the Safety all-risk population.  Overall exposure to each study drug will be summarized in terms 
of exposure duration, number of infusions/doses, and relative dose intensity.  The following 
summaries will also be performed: 
• Time from randomization to first dose of study therapy (0 to 5 days, > 5 to 7, > 7 to 14, 
> 14 to 21, > 21 to 28, > 28) 
• Relative dose intensity (%) using the following categories: < 50%; 50 - < 70%; 70 - < 90%; 
90 - < 110%; ≥ 110% 
• For Arm A, the number of patients with at least one dose infusion interruption, the reason for 
interruption, and the number of infusion interruptions per patient 
• For Arm A, the number of patients with at least one dose delay (either study drug) or dose 
reduction (for NKTR-214 only) and their reason(s) 
• For Arm B, the number of patients with dose reduction and dose missed will be tabulated 
along with their reason(s) 
• For NKTR-214, the time to first dose reduction and time to first dose infusion interruption 
will be summarized using descriptive statistics (mean, median, minimum, maximum) 
All study exposure data will be presented in a data listing. 
7.5 
Efficacy Analysis 
7.5.1 
Efficacy Analysis of Primary Endpoints 
The primary endpoints are ORR by BICR in the ITT I/P-risk population and the ITT all-risk 
population, and OS in the ITT I/P-risk population and the ITT all-risk population. The overall 
alpha for this study is 0.05, which is split with 0.001 to evaluate ORR in the ITT I/P-risk 
population and the ITT all-risk population, and 0.049 to evaluate OS in the ITT I/P-risk 
population and the ITT all-risk population. All alpha levels are two-sided. The test in the ITT 
all-risk population is gated by the one in ITT I/P-risk population for both ORR and OS. That is, 
ORR in the ITT all-risk population will not be tested unless ORR in the ITT I/P-risk population 
is statistically significant; and similarly, OS in the ITT all-risk population will not be tested 
unless OS in the ITT I/P-risk population is statistically significant. 
In addition, a fallback approach will be used to reallocate alpha from ORR to OS. If ORR is 
significant in the ITT I/P-risk population and the ITT all-risk population, the alpha of 0.001 will 
be passed to OS. OS in the ITT I/P-risk population can then be tested at 0.05 (instead of 0.049) 
level. If it is significant, the alpha of 0.05 will be passed to OS in the ITT all-risk population. 


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7.5.1.1 
Objective Response Rate 
Objective response rate (ORR) is defined as the number of randomized patients who achieve a 
best overall response of confirmed complete response (CR) or confirmed partial response (PR) 
based on BICR assessments (using mRECIST 1.1 criteria) divided by the number of all 
randomized patients. Best Overall Response (BOR) is defined as the best response, as 
determined by the BICR, recorded between the date of randomization and the date of objectively 
documented progression per mRECIST 1.1 criteria or the date of subsequent anti-cancer therapy 
(including tumor-directed radiotherapy and tumor-directed surgery), whichever occurs first. For 
patients without documented progression or subsequent anti-cancer therapy, all available 
response designations will contribute to the BOR determination. Confirmation of response is 
required at least 4 weeks after the initial response. A Best Overall Response of SD requires a 
minimum of 56 days on study from randomization to the date of the first imaging assessment. 
The primary analysis is based on the ORR I/P-risk Population and the ORR All-risk Population. 
The ORR will be compared between treatment arms using a Cochran-Mantel Haenszel (CMH) 
test stratified by the stratification factors for analysis (IMDC prognostic score and TKI choice) at 
a 0.001 alpha level. The ORR difference between the two treatment arms with its 95% and 
99.9% confidence interval (CI) will be calculated using CMH methodology and adjusted by the 
same stratification factors. The ORR and its corresponding 95% exact CI will also be calculated 
by Clopper-Pearson method (Clopper and Pearson, 1934) for each arm. The number and 
percentage of patients in each category of BOR per BICR (complete response [CR], partial 
response [PR], stable disease [SD], progressive disease [PD], or not evaluable [NE]) will be 
presented, by treatment arm. 
The ORR per investigator assessment will also be analyzed as a sensitivity analysis, following 
the same approach as above. The ORR concordance rate will be computed as the frequency with 
which the investigator’s assessment and BICR’s assessment agree on classification of a patient 
as responder versus non responder. 
The ORR for patients who received sunitinib and the ORR for patients who received NKTR-214 
and nivolumab will be summarized and compared using the CMH test stratified by the 
stratification factor IMDC prognostic score.   
7.5.1.2 
Overall Survival 
Overall Survival (OS) is defined as the time from the date of randomization to death from any 
cause. Patients will be followed until their date of death, loss to follow-up, or withdrawal of 
consent for further follow-up for survival. Patients who are lost to follow-up will be censored at 
their last known alive date.  Patients who do not have date of death at final database lock will be 
censored at their last known alive date. Patients who do not have any follow-up since 
randomization will be censored on the date of randomization. 


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The primary analysis for OS will use the ITT I/P-risk Population and the ITT All-risk 
Population. 
Two-sided alpha levels of 0.01 and 0.0472 are allocated to the interim and final analyses, 
respectively, to control the overall type I error rate at 0.05 level for the primary OS analysis in 
the IMDC Intermediate- or Poor-risk and the IMDC All-risk Populations assuming ORR is 
significant in both the IMDC Intermediate- or Poor-risk and the IMDC All-risk Populations. If 
ORR is not statistically significant in either population, an overall alpha of 0.049 will be used for 
OS where 0.01 will be spent at the interim analysis and 0.0462 will be spent at the final analysis. 
Within each analysis, OS in the IMDC Intermediate- or Poor-risk Population will be tested first, 
and only when it is statistically significant, can OS in the IMDC All-risk Population be tested at 
the same level. 
Overall survival will be compared between the treatment groups at the interim and final analyses, 
using the stratified logrank test. The stratification factors will be the same as those used in the 
analysis of ORR (IMDC prognostic score and TKI choice) as defined in Section 6.5. At the final 
analysis, the primary analysis of OS to claim statistical significance will be based on the 
weighted combination test of the stratified logrank test statistic with pre-specified weights of 
ඥ2/3 and ඥ1/3 (Lehmacher and Wassmer, 1999). The details are included in Appendix 15.1. 
The conventional stratified logrank test with equal weights for every patient will be conducted as 
a sensitivity analysis at the final analysis. 
A stratified Cox proportional hazards model with treatment as the single covariate will be used to 
estimate the hazard ratio and corresponding 95% CI. The stratification factors will be the same as 
those used in the analysis of ORR (IMDC prognostic score and TKI choice) as defined in 
Section 6.5. The Kaplan-Meier method will be used to further summarize OS, including Kaplan-
Meier curves, and medians with corresponding 95% CIs. The OS rates at fixed timepoints (e.g. 
12 months, 24 months, depending on minimum follow-up) will also be estimated along with their 
corresponding 95% CIs. 
A sensitivity analysis for OS using an unstratified logrank test will also be performed. The 
hazard ratio associated with treatment will be presented along with the corresponding 95% CI. 
The status of patients who are censored in the OS Kaplan-Meier (KM) analysis will be tabulated 
for each treatment group using the following categories: 
• On-study (on-treatment, in follow-up) 
• Off-study (lost to follow-up, withdraw consent, never treated) 
The OS for patients who received sunitinib and the OS for patients who received NKTR-214 and 
nivolumab will be summarized and compared using the Kaplan-Meier method. The median and 
95% CI will be presented for each treatment group, and the stratified logrank test will be 
performed. The stratification factor IMDC prognostic score will be used.  


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7.5.2 
Efficacy Analysis of Key Secondary Endpoint 
The key secondary endpoint of PFS by BICR will be tested hierarchically given the statistical 
significance of OS. Statistical test will be two-sided with a type I error rate of 0.05 if both ORR 
by BICR and OS are significant in both the IMDC Intermediate- or Poor-risk and the IMDC 
All-risk Populations; the type I error rate will be 0.049 if OS (but not ORR by BICR) is 
significant in both the IMDC Intermediate- or Poor-risk and the IMDC All-risk Populations. 
The PFS interim and final analysis will be conducted at the same time as the OS interim and final 
analyses. Two-sided alpha levels of 0.03 and 0.0335 are allocated to the PFS in the interim and 
final analyses, respectively, to control the overall type I error rate at two-sided 0.05. If the overall 
type I error rate is to be controlled at two-sided 0.049, two-sided alpha levels of 0.03 and 0.0323 
will be allocated to the PFS interim and final analyses. Details are provided in Appendix 15.2. 
7.5.2.1 
Progression-Free Survival 
The definition for PFS accounts for subsequent anti-cancer therapy by censoring at the last 
evaluable tumor assessment on or prior to the date of subsequent anti-cancer therapy. Clinical 
deterioration in the absence of unequivocal evidence of progression per mRECIST 1.1 is not 
considered progression for purposes of determining PFS by BICR. PFS rates by BICR at fixed 
time points (e.g. 6 months, depending on the minimum follow-up) are defined as the probability 
that a patient has not progressed and is alive at time T following randomization. 
The definition of PFS (PFS truncated at subsequent anti-cancer therapy) is defined as the time 
between the date of randomization and the date of first documented tumor progression based on 
BICR assessments per mRECIST v1.1, or death due to any cause, whichever occurs first, prior to 
subsequent anti-cancer therapy. 
Patients who die without a reported progression will be considered to have progressed on the 
date of their death. The following censoring rules will be applied for the primary definition of 
PFS: 
• Patients who did not have any on study tumor assessments and did not die will be censored 
on their date of randomization. 
• Patients who did not receive subsequent anti-cancer therapy, did not progress and did not die 
will be censored on the date of their last evaluable tumor assessment. 
• Patients who received subsequent anti-cancer therapy prior to documented progression or 
death will be censored at the date of the last evaluable tumor assessment conducted on or 
prior to the date of initiation of the subsequent anti-cancer therapy. 
• Patients who received subsequent anti-cancer therapy without documented progression or 
death will be censored at the date of the last evaluable tumor assessment conducted on or 
prior to the initiation of the subsequent anti-cancer therapy. 


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The potential of a delayed effect in immunotherapy interventions may cause a late separation in 
the PFS Kaplan-Meier curves and non-proportional hazards may be observed, as was seen for 
PFS in the Checkmate-214 study (Motzer 2018b). Thus, the primary analysis of PFS will account 
for the expected delayed effect and compare the two treatment arms via a stratified weighted 
logrank test (Harrington and Fleming 1982). The two-sided stratified weighted logrank p-value 
will be reported using 𝐺 (𝜌= 0, 𝛾= 1) weights. The stratification factors will be the same as 
those used in the analysis of ORR (IMDC prognostic score and TKI choice) as defined in 
Section 6.5. At the final analysis, the primary analysis of PFS to claim statistical significance 
will be based on the weighted combination test of the stratified weighted logrank test statistic 
with pre-specified weights of ඥ2/3 and ඥ1/3 (Lehmacher and Wassmer, 1999). The details are 
presented in the Appendix. 
The estimate of the PFS hazard ratio between treatment groups will be calculated using a 
stratified Cox proportional hazards model, with treatment as the sole covariate. The stratification 
factors will be the same as those used in the analysis of ORR (IMDC prognostic score and TKI 
choice) as defined in Section 6.5. Ties will be handled using the exact method. A two-sided 95% 
CI for the hazard ratio will also be presented. The Kaplan-Meier method will be used to further 
summarize PFS, including Kaplan-Meier curves, and medians with corresponding 95% CIs. 
For the primary analysis of PFS, the censoring methods described in Table 3 will be used. 
The conventional stratified logrank test with equal weights for every patient will be conducted as 
a sensitivity analysis. 
The source of PFS event (progression or death) will be summarized by treatment group. 
The status of patients who are censored in the PFS KM analysis will be tabulated for each 
treatment group using the following categories: 
• On-study (on-treatment, in follow-up) 
• Off-study (lost to follow-up, withdraw consent, never treated) 
• No baseline tumor assessment 
• No on-study tumor assessment and no death 
• Received subsequent anticancer therapy 
PFS per investigator assessment will also be analyzed as a sensitivity analysis. The PFS by 
investigator will be defined as in Table 3, and it will be analyzed in the same approach following 
the primary definition of PFS by BICR. 


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Table 3: 
PFS Primary Analysis: Date of Progression or Censoring 
Situation 
Date of Disease Progression or Censoring 
Outcome 
No baseline tumor assessments* 
Date of randomization 
Censored 
No on study tumor assessments and no 
death* 
Date of randomization 
Censored 
Subsequent anti-cancer therapy started 
without death or progression per mRECIST 
v1.1 reported prior or on the same day 
Date of last evaluable tumor assessment per 
mRECIST v1.1 showing no evidence of disease 
progression prior to or on the date of initiation 
of the subsequent anti-cancer therapy 
Censored 
No progression and no death, and no 
subsequent anti-cancer therapy started 
Date of last evaluable tumor assessment per 
mRECIST v1.1 showing no evidence of disease 
progression 
Censored 
Documented progression per mRECIST 
v1.1 and no subsequent anti-cancer started 
before 
Date of the first documented progression per 
mRECIST v1.1 (excludes clinical progression) 
Progressed
Death without progression per mRECIST 
v1.1 and no subsequent anti-cancer therapy 
started before 
Date of death 
Progressed
* Tumor assessments and death if any, occurring after start of subsequent anti-cancer therapy are not considered. 
 
A sensitivity analysis of PFS accounting for two or more missing tumor assessments prior to PFS 
event (death or documented progression) will be conducted. A patient is considered to have two 
or more missing tumor assessments if the elapsed time between the PFS event and the last 
assessment prior to the event is greater than the time interval of two scheduled scans + 14 days 
(e.g., 18 weeks + 14 days if two missing tumor assessments happened before Week 54). Patients 
who had PFS events immediately after two or more missed tumor assessments will be censored 
at the date of last tumor assessment prior to the missed visits. 
7.5.3 
Current Status of PFS and OS Follow-Up 
The extent of follow-up for survival, defined as the time between randomization date and last 
known date alive (for patients who are alive) or death date (for patients who died), will be 
summarized descriptively (median, minimum, maximum) in months for all randomized patients. 
The currentness of follow-up for survival, defined as the time between last OS contact (i.e., last 
known alive date or death date) and clinical data cutoff date, will be summarized in months for 


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all randomized patients. Patients who died and patients with last known alive date on or after 
data cutoff date will have zero value for currentness of follow-up. 
The currentness of follow-up for PFS, defined as time from last evaluable tumor assessment to 
cutoff date will be summarized by treatment group and overall for all randomized patients. 
Patients who have a PFS event will be considered as current for this analysis. 
The currentness of follow-up will be categorized into the following categories: 0 month, 
0-3 months, 3-6 months, 6-9 months, 9-12 months, and 12 or more months. 
In addition, time to treatment discontinuation will be summarized and presented by treatment 
group using a Kaplan-Meier curve whereby the last dose date will be the event date for those 
patients who are off study therapy. Median duration of study therapy and associated 95% CI will 
be provided. Patients who are still on study therapy will be censored on their last dose date. Time 
to NKTR-214 discontinuation will be summarized in the same way as well. 
7.5.4 
Efficacy Analysis of Other Endpoints 
7.5.4.1 
Progression-Free Survival 2 
PFS on next-line therapy (PFS2) is defined as the time from randomization to documented 
progression, per investigator assessment, after the next line of therapy or to death from any 
cause, whichever occurs first. Patients who were alive and without progression after the next line 
of therapy will be censored at last known alive date. The following censoring rules will be 
applied for PFS2: 
For a patient who did not receive subsequent anti-cancer therapy: 
• If the patient died, the patient is considered as an event on the date of death 
• Else, the patient is censored at his/her last known alive date 
For a patient who received subsequent anti-cancer therapy: 
• If the patient had disease progression after the start of subsequent anti-cancer therapy, the 
patient is considered as an event on the date of PD 
• Else if the patient died or started a second subsequent anti-cancer therapy, the patient is 
considered as an event  at the death date or at the start date of second subsequent therapy 
whichever is the earliest. 
• Else, the patient is censored at his/her last known alive date 


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PFS2 will be analyzed as follows: 
• The PFS2 will be compared between treatment arms using a two-sided logrank test, stratified 
by the stratification factors for analysis (IMDC prognostic score and TKI choice) as defined 
in Section 6.5. The HR for PFS2 with its corresponding two-sided 95% CI will also be 
provided, estimated via a stratified Cox model with the stratifications factors specified above 
and treatment arm as the only covariate in the model. 
• The Kaplan-Meier method will be used to further summarize PFS2, including Kaplan-Meier 
curves, and medians with corresponding 95% CIs. 
7.5.4.2 
Concordance Between BICR and Investigator Assessment of Progression 
For the purpose of assessing concordance between the BICR and investigator tumor assessments, 
progression status will be categorized as documented progression, death or censored. A cross 
tabulation between the BICR and the investigator progression status will be presented, by 
treatment group. The primary analysis of PFS (ITT I/P-risk population and ITT all-risk 
population) will be used for this assessment. 
A by patient lising of BICR and investigator PFS status and the time between progression dates 
according to the BICR and the investigator will be provided. 
7.5.4.3 
Duration of Response 
Analysis of duration of response (DOR) will be performed for responders (confirmed CR or PR) 
only. Duration of Response (DOR) is defined as the time between the date of first confirmed 
documented response (CR or PR) to the date of the first documented tumor progression as 
determined by the BICR per mRECIST 1.1, or death due to any cause, whichever occurs first. 
Patients who start subsequent anti-cancer therapy without a prior reported progression will be 
censored at the last evaluable tumor assessments prior to initiation of the subsequent anticancer 
therapy. Patients who die without a reported prior progression will be considered to have 
progressed on the date of their death. For patients who neither progress nor die, DOR will be 
censored on the date of their last evaluable tumor assessment. The DOR for each treatment group 
will be estimated using the Kaplan-Meier method. Median values of DOR with corresponding 
95% CI for each treatment group will be computed based on a log-log transformation method. 
7.5.4.4 
Time to Response 
A descriptive analysis of time to response (TTR) will be performed for responders (confirmed 
CR or PR) only. Time to response is defined as the time from the date of randomization to date 
of first documented CR or PR per mRECIST 1.1 as assessed by BICR. TTR will be summarized 
using descriptive statistics only (median, min, max). TTR per investigator’s assessment will be 
summarized similarly. 


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7.5.4.5 
Clinical Benefit Rate 
The CBR per both BICR and investigator’s assessment, and its corresponding 95% exact CI will 
be calculated by the Clopper and Pearson method for each treatment arm.  
7.5.5 
Subgroup Analyses 
The following subgroup analyses will be performed for ORR by BICR, OS, and PFS by BICR. 
The benefit of NKTR-214 in combination with nivolumab compared to TKI will be evaluated by 
a unstratified rate difference for ORR by BICR or unstratified hazard ratio for OS and PFS by 
BICR with its 95% CI based on a Cox regression model for each subgroup. The hazard ratios and 
their 95% CI will be displayed in a forest plot. Subgroup analyses may not be performed if the 
sample size is too small to provide accurate estimates.  The following subgroup analyses (except 
age, race, region, and sex) will be conducted if the number of patients in each subgroup is > 10 
for each treatment group. 
• IMDC prognostic score (0 [favorable risk], 1-2 [intermediate risk], 3-6 [poor risk]) 
• Baseline PD-L1 status (≥ 1%, <1%, indeterminant or non-evaluable) 
• Age categorization (< 65, ≥ 65 years) 
• Sex (male, female) 
• Race (White, Black, Asian, Other) 
• Geographic region (US, Rest of the world) 
• Baseline Karnofsky performance status (<80, ≥80) 
• Sarcomatoid histology (Yes vs No) 
• Prior nephrectomy (Yes, No) 
• Baseline bone mets as per BICR (Yes, No) 
The following subgroups may be explored: 
• TKI choice (sunitinib, cabozantinib) 
• Baseline PD-L1 status (≥ 5%, <5%, indeterminant or non-evaluable; ≥ 10%, < 10%, 
indeterminant or non-evaluable) 
• Time from initial RCC diagnosis to randomization (≤ 1 year, > 1 year) 
• Patients with history of brain metastases (Yes, No) 
• Prior radiotherapy (Yes, No) 
• Baseline LDH level (≤ 1.5 x ULN, > 1.5 x ULN) 
• Baseline Hemoglobin (<LLN, ≥LLN) 


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• Baseline Corrected Calcium (≤ ULN, > ULN) 
• Baseline Absolute Neutrophil Count (≤ ULN, > ULN) 
• Baseline Platelet Count (≤ ULN, > ULN) 
• Baseline Alkaline phosphatase (≤  ULN, > ULN) 
• Tumor burden at baseline per BICR and per investigator (≤ 1st Tertile, > 1st Tertile to ≤ 2nd 
Tertile, > 2nd Tertile).  
• Baseline liver mets as per BICR (Yes, No) 
• Baseline lung mets as per BICR (Yes, No) 
• Baseline lymph node mets as per BICR (Yes, No) 
7.6 
Health-Related Quality of Life (HRQoL) 
Patients will be asked to complete the NCCN/FACT Symptom Index for Kidney Cancer 
(FKSI-19), 3-level version of the EuroQol Group’s EQ-5D (EQ-5D-3L), and selected items from 
the Patient-Reported Outcomes version of the Common Term Criteria for Adverse Events 
(PRO-CTCAE). 
Patients will complete the patient-reported outcome measures prior to any assessments at each 
clinic visit before randomization, prior to the first dose on Day 1 and 22 of every cycle through 
Cycle 4, and then on Day 1 of all subsequent cycles. In addition, the patient-reported outcome 
measures will be completed at designated time points during the follow-up period. The primary 
time points of interest will be Week 12, Week 24, and Week 48. 
7.6.1 
FKSI-19 
The National Comprehensive Cancer Network/Functional Assessment of Cancer Therapy–
Kidney Symptom Index-19 (FKSI-19) is a 19-item self-reported questionnaire with a total score 
and four subscales that assess disease-related symptoms (DRS), treatment side effects (TSE), and 
function/well-being associated with advanced kidney cancer.  It captures symptom severity and 
interference in activity and general health perceptions.  The FKSI-19 comprises four subscales 
(DRS-Physical, DRS-Emotional, TSE, and Function/Well-Being).  Each of the items is scored on 
a five-point scale from zero (not at all) to four (very much).  The FKSI-19 uses a recall period of 
“the past 7 days”, and higher FKSI-19 scores indicate improvement (Rothrock, 2013). 
If there are missing items, subscale scores can be prorated. This can be done using the following 
formula: 
Prorated subscale score = [Sum of item scores] x [N of items in subscale] / [N of items 
answered] 
When there are missing data, prorating by subscale in this way is acceptable as long as more than 
50% of the items were answered in that subscale; otherwise the subscale is considered as not 


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having a valid score. The total score is then calculated as the sum of the prorated subscale scores. 
The total score should only be calculated if ALL of the component subscales have valid scores. 
The following descriptive analyses will be conducted by treatment group in the ITT I/P-risk 
population and the ITT all-risk population: 
• FKSI-19 questionnaire completion rate, defined as the proportion of questionnaires actually 
received out of the expected number (ie, number of patients on treatment or in follow up), 
will be calculated and summarized for each assessment time point. 
• For the total score and subscales, separately: 
− Mean score and mean change from baseline at each assessment time point will be 
summarized using descriptive statistics (N, mean, SD, median, 25th and 75th percentiles, 
minimum, maximum). 
− A plot summarizing the mean change from baseline will be presented. 
− Changes from baseline will be compared between treatment groups using a linear mixed 
model with repeated measures (MMRM) with treatment, time, treatment and time 
interaction, baseline score, and stratification variables as covariates. An unstructured 
covariance matrix will be used unless the model fails to converge. Treatment effect on 
the change from baseline will be compared by the difference in the least-square means 
and corresponding 95% CI. The MMRM assumes that the missing data mechanism is 
ignorable (i.e., missing at random). 
7.6.2 
EQ5D3L 
The EQ-5D-3L is a standardized instrument used to measure self-reports of health status and 
functioning. The instrument’s descriptive system consists of 5 dimensions: mobility, self-care, 
usual activities, pain/discomfort, and anxiety/depression.  Each dimension has 3 levels, reflecting 
“no health problems,” “moderate health problems,” and “extreme health problems.”  A 
dimension for which there are no problems is said to be at level 1, while a dimension for which 
there are extreme problems is said to be at level 3.  Thus, the vectors 11111 and 33333 represent 
the best health state and the worst health state, respectively, as described by the EQ-5D-3L. 
Altogether, the instrument describes 35 = 243 health states (EuroQol, 1990). 
Empirically-derived weights can be applied to an individual’s responses to the EQ-5D-3L 
descriptive system to generate an index measuring the value to society of his or her current 
health.  Such preference-weighting systems have been developed for the UK, US, Spain, 
Germany, and numerous other populations.  Utility index values range from a 1 (full health) to 
0 (dead) with negative values indicating a state considered worse than being dead. In addition, 
the EQ-5D-3L includes a visual analog scale (VAS) that allows respondents to rate their own 
current health on a 101-point scale ranging from “best imaginable” to “worst imaginable” health. 
The EQ-5D-3L uses a recall period of “today.” 


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EQ-5D Index values will be computed using a scoring algorithm based on the US TTO (Time 
Trade-off) value set. The following descriptive analyses will be conducted: 
• EQ-5D questionnaire completion rate, defined as the proportion of questionnaires actually 
received out of the expected number (ie, number of patients on treatment or in follow up), 
will be calculated and summarized for each assessment time point. 
• A by-patient listing of EQ-5D with the problem level for each of the 5 dimensions (mobility, 
selfcare, usual activities, pain/discomfort and anxiety/depression), health state (5 dimensions 
digits combined in a 5-digit number), EQ-5D Index, and EQ-VAS will be provided. 
• Proportion of patients for each level of problem for the 5 EQ-5D dimensions will be 
summarized at each assessment timepoint. Percentages will be based on number patients 
assessed at assessment time point. 
• For the EQ-5D Index and visual analog scale (VAS), separately: 
− Mean score and mean change from baseline at each assessment time point will be 
summarized using descriptive statistics (N, mean, SD, median, 25th and 75th percentiles, 
minimum, maximum). 
− A plot summarizing the mean change from baseline will be presented. 
7.6.3 
PRO-CTCAE 
The PRO-CTCAE is a patient-reported outcome measure developed to evaluate symptomatic 
toxicity in patients participating in oncology clinical trials.  It was designed to be used as a 
companion to the Common Terminology Criteria for Adverse Events (CTCAE), the standard 
lexicon for adverse event reporting in cancer trials.  PRO-CTCAE includes an item library of 
124 items representing 78 symptomatic toxicities drawn from the CTCAE. PRO-CTCAE 
provides a systematic yet flexible tool for descriptive reporting of symptomatic treatment side 
effects in cancer clinical trials.  Selected items from the PRO-CTCAE will be administered. The 
PRO-CTCAE uses a recall period of “the last 7 days.” 
To report the PRO-CTCAE data, the tabulation of the maximum score post-baseline per patient 
per item will be used, and it will be presented by treatment group. A by-patient listing of 
PRO-CTCAE will also be provided. 
7.7 
Healthcare Resource Utilization 
Healthcare resource utilization (HCRU) information is collected up to safety follow up visit 1 
(100 days after last dose of study treatment), and will be summarized by treatment group. The 
HCRU summary includes: 
• Number of hospitalizations per patient (0, 1, 2, > 2) for overall and by hospitalization ward 
(general ward, intensive care ward, rehabitation ward, hospice ward, other ward) 


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• Number of hospitalizations per person-year 
o Numerator is number of hospitalizations from all patients in the analysis population. 
o Denominator is the sum of {min[(last dose date + 100 days), last known alive date] – 
first dose date +1} across all patients in the analysis population /365.25. 
• Number of days in each specific hospitalization ward per person-year. Specific 
hospitalization ward includes general ward, intensive care ward, rehabitation ward, hospice 
ward, other ward, and overall. 
o Numerator is sum of number of days in each specific hospitalization ward from all 
patients in the analysis population. 
o Denominator is the sum of {min[(last dose date + 100 days), last known alive date] – 
first dose date +1} across all patients in the analysis population /365.25. 
A by-patient listing of HCRU data will also be provided. 
7.8 
Immunogenicity 
7.8.1 
Immunogenicity Measurements and Endpoints 
The immunogenicity analysis will be performed separately for anti-NKTR-214/anti-PEG, 
anti-IL-2 and anti-nivolumab antibodies. The data will be summarized for 
anti-NKTR-214/anti-PEG, anti-IL-2 and anti-nivolumab antibodies and will be reported by both 
sample and patient status. 
For sample status, baseline samples will be classified as:  
• baseline ADA-positive, if ADA is detected in the immunogenicity sample collected before 
initiation of the treatment and  
• baseline ADA-negative, if ADA is not detected in the immunogenicity sample collected 
before initiation of the treatment.  
ADA samples will be classified as positive if after initiation of the treatment, the ADA is 
detected (positive seroconversion) in a sample from a patient who was baseline ADA-negative, 
or if there is at least 4-fold or greater (≥) increase in ADA titer in comparison to the baseline 
positive titer. Samples confirmed to be positive for anti-NKTR-214/anti-PEG, anti-IL-2 
antibodies will be tested for neutralizing activity for IL-2 using a validated cell-based assay.  
Anti-nivolumab antibodies positive samples will also be tested for neutralizing activity for   
nivolumab using a validated cell-based assay. ADA-positive samples with neutralizing activity 
will be classified as neutralizing positive. 
For patient status, immunogenicity will be reported by summarizing the number and percentage 
of ADA-positive patients and ADA-negative patients at baseline and after drug administration 
with positive status of anti-NKTR-214, anti-PEG, anti-IL-2, and anti-nivolumab ADA.  In the 


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immunogenicity evaluable population, the patients will be classified as treatment-induced 
ADA-positive if they were ADA-negative at baseline and became ADA-positive at any time 
after starting the treatment, or if they were ADA-positive at baseline and had a post-baseline 
ADA-positive titer that was at least 4-fold or greater (≥) than baseline positive titer (also known 
as Treatment-boosted).  The patients with an ADA-positive sample at 2 or more consecutive time 
points, where the first and last ADA-positive samples are at least 16 weeks apart will be 
classified as persistent positive.  Patients that are not persistent positive but have an 
ADA-positive sample at the last sampling time point will be classified as not persistent last-
sample positive.  Non persistent positive patients with an ADA-negative sample at the last 
sampling time point will be classified as transiently positive or other positive.  Patients with at 
least 1 ADA-positive sample with neutralizing activity will be classified as neutralizing positive.  
All other ADA-evaluable patients are considered as treatment-emergent ADA negative. 
All ADA-positive patients will be included in the ADA titer kinetics analysis. Summary statistics 
of patient-level ADA titers using the maximum titer value within an ADA-positive patient will 
be presented for baseline ADA-negative patients and baseline ADA-positive patients. The 
median, interquartile range, and range of the maximum titers will be reported. For ADA-positive 
patients with baseline ADA-positive sample, the median and interquartile range of the fold 
increase from baseline in titer (ratio of maximum post-baseline titer to baseline titer) will also be 
reported. For sample-level ADA titers, boxplots of ADA titers at each assessment timepoint will 
be provided, as appropriate, to demonstrate whether the ADA levels tend to change over time 
during the treatment, along with ADA incidence at each assessment timepoint. 
Analyses of ADA kinetics, including the onset and duration of ADA, will include only those 
ADA-positive patients that were ADA-negative at baseline. ADA-positive patients with baseline 
ADA-positive sample and an increased titer post-baseline will be excluded since this type of 
immune response differs mechanistically. 
Onset of ADA refers to the time period between the first dose of the treatment and the first 
instance of ADA detection. The median, interquartile range, and range of time to ADA 
development will be provided. The median and range of the number of treatment doses to before 
and after the first detection of ADA as well as the total number of doses received will also be 
provided. 
Duration of ADA refers to the longevity of ADA and is defined as the time from the first 
on-study ADA-positive date to the first ADA-negative date after the last on-study ADA-positive 
date. Duration of ADA will be estimated by the Kaplan-Meier method. Patients who do not have 
an ADA-negative date after the last on-study ADA-positive date will be censored on the date of 
their last ADA-evaluable assessment. The median together with the corresponding 
95% confidence interval (using log-log transformation method) and range (minimum, maximum) 
will be provided. 


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7.8.2 
Evaluation of ADA 
The following analyses will be conducted for anti-NKTR-214/anti-PEG, anti-IL-2 and anti-
nivolumab, separately. 
• Safety: All patients with ADA as mentioned above will be assessed for potential infusion 
related reactions under NKTR 214 safety events and will be compared against ADA negative 
patients, where infusion related reaction events that start after study drug administration on 
the same day or next day will be included. 
• Efficacy: Objective response rate will be presented by ADA status. 
• Concentration: Pre-dose NKTR-214 RC and pre-dose NKTR-214 AC concentrations will be 
summarized by ADA status. 
7.8.3 
Definitions 
There are two sets of definitions: one for categorizing individual samples (Table 4) and another 
for categorizing patient responses (Table 5). 


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Table 4: 
ADA Status: Individual Samples 
ADA Status 
Definition 
Baseline negative 
ADA is not detected in the last sample before initiation of treatment 
Baseline positive 
ADA is detected in the last sample before initiation of treatment 
Anti-NKTR-214 
ADA-positive sample 
After initiation of treatment,  
(1) an ADA detected (positive seroconversion) sample in a patient for whom anti-
NKTR-214 ADA is not detected at baseline, or 
(2) an ADA detected sample with anti-NKTR-214 titer to be at least 4-fold or greater 
(≥) than baseline positive titer
Anti-PEG ADA-positive 
sample 
Sample with a positive result in PEG-immunocompetition assay. 
Anti-IL-2 ADA-positive 
sample 
After initiation of treatment,  
(1) an ADA detected (positive seroconversion) sample in a patient for whom anti-IL-2 
ADA is not detected at baseline, or 
(2) an ADA detected sample with anti-IL-2 titer to be at least 4-fold or greater (≥) 
than baseline positive titer
Anti-nivolumab 
ADA-positive sample 
After initiation of treatment,  
(1) an ADA detected (positive seroconversion) sample in a patient for whom anti-
Nivolumab ADA is not detected at baseline, or 
(2) an ADA detected sample with anti-nivolumab titer to be at least 4-fold or greater 
(≥) than baseline positive titer
ADA-negative 
After initiation of treatment, assay result is not a positive sample relative to baseline, 
i.e., increase from baseline is <4-fold
 
Table 5: 
ADA Response Categories:  Patient Level 
ADA status 
Description 
Baseline ADA-positive 
A patient with baseline ADA-positive sample 
ADA-negative patient 
Patient with no ADA-positive sample after the initiation of treatment. 
Note: due to the definition of an ADA positive sample for a patient testing positive at 
baseline (see sample status table, above), it is possible (but highly unlikely) for 
a patient with a stable anti-drug titer throughout the study to be classified as 
‘ADA-negative’
ADA-positive patient 
(Treatment-emergent 
positive) 
Patient with at least 1 ADA positive-sample (relative to baseline) at any time after 
initiation of treatment 
Persistent positive 
ADA-positive sample at 2 or more consecutive time points, where the first and last 
ADA-positive samples are at least 16 weeks apart (endogenous human IgG1, IgG2, 
and IgG4 have approximate half-lives in the range of 21-25 days, and 5 half-lives are 
approximately equal to 16 weeks)
Not PP-last sample positive Not persistent positive with ADA-positive sample at the last sampling time point 
Transiently positive or 
other positive 
Patient not persistently positive but has 1 or more ADA positive samples with the last 
sample being ADA-negative. 
Neutralizing positive 
At least 1 ADA-positive sample with neutralizing antibodies detected 
Abbreviation: PP =  persistent positive 


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8.0 
SAFETY ANALYSIS 
The safety data will include AEs, SAEs, clinical laboratory tests, and vital signs. Summaries will 
use the Safety all-risk population and will be presented separately for patients who received 
NKTR-214 and nivolumab or who received TKI (sunitinib or cabozantinib). Summaries using 
the Safety I/P-risk population may be presented. All safety data will be presented in data listings. 
Summaries for patients who received sunitinib and patients who received cabozantinib may be 
performed separately on some key safety analyses.  
8.1 
Adverse Events 
Adverse events will be coded by system organ class (SOC) and preferred term (PT) using 
MedDRA. Adverse event severity will be based on NCI CTCAE Grade (version 5.0). 
All AEs will be coded by MedDRA version 21.1. The severity of AE will be determined based 
on the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI 
CTCAE) Grade (version 5.0). An AE is considered as related to treatment if it is related to any 
study drug; an AE with a missing relationship will be counted as related to study drug. An AE is 
considered as leading to treatment discontinuation if it is leading to discontinuation of any study 
drug. An AE is considered as leading to treatment delay, reduction or interruption if reported as 
leading to the dose delay, reduction or interruption of any study drug. An AE is considered as 
leading to death if the severity grade is 5 or the outcome is fatal. A patient reporting the same AE 
multiple times will be counted only once within each SOC and PT under the highest severity and 
closest relationship. 
The following adverse events summaries will be provided by treatment arm: 
• Overall summary of TEAEs 
• TEAEs presented by worst grade (any grade, grade 3-4, grade 5) by SOC and PT 
• Serious TEAEs presented by worst grade (any grade, grade 3-4, grade 5) by SOC and PT 
• Drug-related TEAEs presented by worst grade (any grade, grade 3-4, grade 5) by SOC and 
PT 
• NKTR-214-related TEAEs presented by worst grade (any grade, grade 3-4, grade 5) by SOC 
and PT 
• TEAEs leading to any study drug discontinuation presented by worst grade (any grade, grade 
3-4, grade 5) by SOC and PT 
• TEAEs leading to infusion interruption of any study drug presented by worst grade (any 
grade, grade 3-4, grade 5) by SOC and PT 
• TEAEs leading to dose reduction of any study drug presented by worst grade (any grade, 
grade 3-4, grade 5) by SOC and PT 


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• TEAEs leading to discontinuation of NKTR-214 presented by worst grade (any grade, grade 
3-4, grade 5) by SOC and PT 
• TEAEs leading to infusion interruption of NKTR-214 presented by worst grade (any grade, 
grade 3-4, grade 5) by SOC and PT 
• TEAEs leading to dose reduction of NKTR-214  presented by worst grade (any grade, grade 
3-4, grade 5) by SOC and PT 
• Overall summary of TEAEs that required immune modulating medication by worst grade 
(any grade, grade 3-4, grade 5) by SOC and PT 
Additionally, TEAEs will also be summarized in tables as follows: 
• Grade 3 or above TEAE by PT 
• Grade 3 or above drug-related TEAE by PT 
• Grade 3 or above NKTR-214-related TEAE by PT 
• Serious drug-related TEAE by PT 
• Serious NKTR-214-related TEAE by PT 
• Drug-related TEAE leading to discontinuation of any study drug 
• NKTR-214-related TEAE leading to discontinuation of NKTR-214 
• Drug-related TEAE leading to dose reduction of any study drug 
• NKTR-214-related TEAE leading to dose reduction of NKTR-214 
• Drug-related TEAE leading to death by PT 
• NKTR-214-related TEAE leading to death by PT 
The following analysis will be repeated using an extended treatment-emergent period. 
• Drug-related TEAE presented by worst grade (any grade, grade 3-4, grade 5) by SOC and PT 
• NKTR-214-related TEAE presented by worst grade (any grade, grade 3-4, grade 5) by SOC 
and PT 
All AEs will be presented in listing as follows: 
• SAEs 
• Grade 3 or above TEAEs 
• TEAE leading to any study drug dose delay 
•  TEAE leading to any study drug dose reduction 
• TEAE leading to any study drug infusion interruption 


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• TEAE leading to any study drug discontinuation 
• TEAEs leading to death 
Overall summary of TEAEs and TEAEs by worst grade (any grade, grade 3-4, grade 5) 
presented by SOC/PT and treatment group will be provided for the following subgroups: 
• Gender (Male, Female) 
• Race (White, Black, Asian, Other) 
• Age categorization (< 65, ≥ 65 years) 
• Region (US, Rest of the world) 
• Hepatic impairment at baseline (No [total bilirubin ≤ ULN and AST ≤ ULN], Yes [total 
bilirubin > ULN or AST > ULN]) 
• Renal impairment at baseline (No [creatinine clearance ≥ 60 mL/min], Yes [creatinine 
clearance < 60 mL/min])   
• TKI Choice (sunitinib, cabozantinib) 
• IMDC score (0 [favorable risk], 1-2 [intermediate risk], 3-6 [poor risk]) 
The subgroup analysis will be conducted using treatment-emergent period only. 
8.2 
Adverse Events of Special Interest for Checkpoint Inhibitors 
8.2.1 
Select Adverse Events (to Support EU MAA) 
The select Adverse Events (select AEs, also known as select immune-related AEs) consist of a 
list of preferred terms grouped by specific category (e.g., pulmonary events, gastrointestinal 
events categories, etc.). Select AEs are identified based on the following 4 guiding principles: 
• AEs that may differ in type, frequency, or severity from AEs caused by 
non-immunotherapies 
• AEs that may require immunosuppression (e.g., corticosteroids) as part of their management 
• AEs whose early recognition and management may mitigate severe toxicity 
• AEs for which multiple event terms may be used to describe a single type of AE, thereby 
necessitating the pooling of terms for full characterization. 
Based on these guiding principles and taking into account the types of AEs already observed 
across studies of nivolumab monotherapy, endocrinopathies, diarrhea/colitis, hepatitis, 
pneumonitis, interstitial nephritis, and rash are currently considered to be select AEs. Multiple 
event terms that may describe each of these are grouped into endocrine, gastrointestinal (GI), 
hepatic, pulmonary, renal, and skin select AE categories, respectively. 


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Hypersensitivity/infusion reactions are analyzed along with the select AE categories because 
multiple event terms may be used to describe such events and pooling of terms was therefore 
necessary for full characterization. Hypersensitivity/infusion reactions do not otherwise meet 
criteria to be considered select AEs. 
The list of MedDRA preferred terms used to identify select adverse events is revisited quarterly 
and updated accordingly. The preferred terms used for the selection at the time of the database 
lock will be provided by categories/subcategories. 
In addition to the frequency and worst severity of select AEs, time-to onset, time-to resolution, 
and time-to resolution where immune modulating medication was initiated will be analyzed for 
each specific category/subcategory of drug-related select AEs when applicable. 
Further details on the definitions of select adverse event, time-to onset and time-to resolution are 
described in Appendix 15.4. 
Unless otherwise specified, analyses will be performed by select AE category. Analyses will also 
be repeated by subcategory of endocrine events. 
8.2.1.1 
Incidence of Select AE 
Select AEs (also known as select immune related AEs) will be summarized using the treatment-
emergent period by treatment arm for each category/subcategory. 
• Overall summaries of any select AEs by worst CTC grade (any grade, grade 3-4, grade 5) 
presented by category or subcategory/PT 
• Overall summaries of any drug-related select AEs by worst CTC grade (any grade, grade 3-4, 
grade 5) presented by category or subcategory/PT 
• Overall summaries of any serious select AEs by worst CTC grade (any grade, grade 3-4, 
grade 5) presented by category or subcategory/PT 
• Overall summaries of drug-related serious select AEs by worst CTC grade (any grade, grade 
3-4, grade 5) presented by category or subcategory/PT 
• Overall summaries of any select AEs leading to any study drug discontinuation by worst 
CTC grade (any grade, grade 3-4, grade 5) presented by category or subcategory/PT 
• Overall summaries of drug-related select AEs leading to any study drug discontinuation by 
worst CTC grade (any grade, grade 3-4, grade 5) presented by category or subcategory /PT 
• Summary of frequency of unique select AEs by category 
A by-patient listing of select AE will be provided. 


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8.2.1.2 
Time-to Onset of Drug-Related Select AE 
Time-to onset of drug-related select AEs (any grade, grade 3-5) will be summarized for each 
category/subcategory by treatment arm. The summary is descriptive with median, min and max. 
Time-to onset analyses are restricted to treated patients who experienced at least one drug-related 
select AE in the category/subcategory. 
Additional details regarding the time-to onset definition are described in Appendix 
Section 15.4.1. 
8.2.1.3 
Time-to Resolution of Drug-Related Select AE 
Time-to resolution of the following specific events will be summarized separately for each 
category/subcategory by treatment arm. 
• Time-to resolution of drug-related select AE (any grade, grade 3-5) 
• Time-to resolution of drug-related select AE (any grade, grade 3-5) where immune 
modulating medication was initiated 
Time-to resolution analyses are restricted to treated patients who experienced the specific events. 
Time-to resolution where immune-modulating medication was initiated analyses are restricted to 
treated patients who experienced the specific events and who received immune-modulating 
medication during the longest select AE. 
The following summary statistics will be reported: percentage of patients with resolution of the 
longest select AE, median time-to resolution along with 95% CI (derived from Kaplan-Meier 
estimation) and ranges. 
Additional details regarding the time-to resolution definition are described in Appendix 
Section 15.4.2. 
8.2.2 
Immune Mediated Adverse Events (IMAEs) (to Support US BLA) 
Immune-mediated AEs (IMAE) are AEs consistent with an immune-mediated mechanism or 
immune-mediated component for which non-inflammatory etiologies (eg, infection or tumor 
progression) have been ruled out. IMAEs can include events with an alternate etiology which 
were exacerbated by the induction of autoimmunity. To be specific, IMAEs are events (or groups 
of PTs describing specific events) that include pneumonitis, diarrhea/colitis, hepatitis, 
nephritis/renal dysfunction, rash, endocrine (adrenal insufficiency, hypothyroidism/thyroiditis, 
hypothyroidism, thyroiditis, hyperthyroidism, diabetes mellitus and hypophysitis), and other 
specific events, considered as potential immune-mediated events by investigator that meet the 
definition summarized below: 
• those occurring within extended treatment-emergent period, 


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• regardless of causality, 
• treated with immune-modulating medication (of note, endocrine AEs such as adrenal 
insufficiency, hypothyroidism/thyroiditis, hypothyroidism, thyroiditis, hyperthyroidism, 
diabetes mellitus, and hypophysitis are considered IMAEs regardless of immune-modulating 
medication use, since endocrine drug reactions are often managed without immune-
modulating medication), 
• with no clear alternate etiology based on investigator assessment, or with an 
immune-mediated component 
The list of MedDRA preferred terms used to identify IMAEs is revisited quarterly and updated 
accordingly. The preferred terms used for the selection at the time of the database lock by 
categories will be provided. 
IMAEs will be summarized using the extended treatment-emergent period for each immune-
mediated category for Arm A only: 
• Overall summary of non-endocrine IMAEs by worst CTC grade (any grade, grade 3-4, 
grade 5) where immune-modulating medication was initiated presented by category / PT. 
• Overall summary of endocrine IMAEs by worst CTC grade (any grade, grade 3-4, grade 5) 
presented by category / PT 
• Overall summary of non-endocrine IMAEs leading to study drug discontinuation by worst 
CTC grade (any grade, grade 3-4, grade 5) where immune modulating medication was 
initiated presented by category / PT 
• Overall summary of endocrine IMAEs leading to study drug discontinuation by worst CTC 
grade (any grade, grade 3-4, grade 5) presented by category / PT 
• Overall summary of non-endocrine IMAEs leading to study drug dose delay or reduction by 
worst CTC grade (any grade, grade 3-4, grade 5) where immune modulating medication was 
initiated presented by category / PT 
• Overall summary of non-endocrine IMAEs leading to study drug dose delay by worst CTC 
grade (any grade, grade 3-4, grade 5) where immune modulating medication was initiated 
presented by category / PT 
• Overall summary of non-endocrine IMAEs leading to study drug dose reduction by worst 
CTC grade (any grade, grade 3-4, grade 5) where immune modulating medication was 
initiated presented by category / PT 
• Overall summary of endocrine IMAEs leading to study drug dose delay or reduction by worst 
CTC grade (any grade, grade 3-4, grade 5) presented by category / PT 
• Overall summary of endocrine IMAEs leading to study drug dose delay by worst CTC grade 
(any grade, grade 3-4, grade 5) presented by category / PT 


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• Overall summary of endocrine IMAEs leading to study drug dose reduction by worst CTC 
grade (any grade, grade 3-4, grade 5) presented by category / PT 
• Summaries of time-to onset and time-to resolution of non-endocrine IMAEs where immune 
modulating medication was initiated presented by category 
• Summaries of time-to onset and time-to resolution of endocrine IMAEs presented by 
category. 
A by-patient listing of IMAEs will be provided. By-patient listings of time-to resolution for 
longest IMAEs cluster (any grade and grade 3-5 in separate summaries) will also be provided. 
8.2.3 
Other Events of Special Interest 
Other events of special interest (OEOSI, also known as other immue-related adverse events of 
special interest) consist of a list of preferred terms grouped by specific category (e.g. Myositis 
Event, Myocarditis Event, Demyelination Event, Guillain-Barre Syndrome, Pancreatitis Event, 
Uveitis Event, Encephalitis Event, Myasthenic Syndrome, Rhabdomyolysis Event, Graft Versus 
Host Disease). 
The list of MedDRA preferred terms used to identify OEOSI is revisited quarterly and updated 
accordingly. The preferred terms used for the selection at the time of the database lock by 
categories will be provided. 
OEOSI will be summarized by treatment arm for each category. 
The following analyses will be conducted using the extended treatment-emergent period: 
• Overall summary of OEOSI by worst CTC grade (any grade, grade 3-4, grade 5) presented 
by category / PT 
• Overall summary of drug-related OEOSI by worst CTC grade (any grade, grade 3-4, grade 5) 
presented by category / PT 
A by-patient listing of OEOSI will be provided. 
8.3 
Adverse Events for NKTR-214 
8.3.1 
Adverse Event of Special Interest for NKTR-214 
Adverse events of special interest for NKTR-214 consists of ischemic cerebrovascular events 
(ICE). All analyses will be conducted in the Safety I/P-risk population and the Safety all-risk 
population by treatment arm using the treatment-emergent period. Search list used to identify 
ICE will be provided. 
The following analyses will be conducted for ICE: 


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• Overall summary of ICE by worst CTC grade (any grade, grade 3-4, grade 5) presented by 
PT 
• Overall summary of any serious ICE by worst CTC grade (any grade, grade 3-4, grade 5) 
presented by PT 
• Overall summary of any ICE leading to discontinuation of study therapy by worst CTC grade 
(any grade, grade 3-4, grade 5) presented by PT 
• Overall summary of any ICE leading to discontinuation of NKTR-214 by worst CTC grade 
(any grade, grade 3-4, grade 5) presented by PT. This summary will be conducted for Arm A 
patients only. 
• Time-to onset of ICE (any grade, grade 3-5) 
Time-to onset analyses are restricted to treated patients who experienced at least one ICEs. 
A by-patient listing of ICE will be provided. 
8.3.2 
Other Safety Observations (OSO) for NKTR-214 
Other safety observations (OSO) for NKTR-214 consists of the following: 
• IL-2 mediated AEs 
o Flu-like symptoms 
o Rash and pruritus 
o Fatigue/asthenia 
o Arthralgia 
o Elevated hepatic transaminases 
o Elevated serum creatinine 
o Eosinophilic disorders 
o Hypotension 
o Syncope 
• Infusion-related reaction (IRR, same day or next day post study drug administration) 
• Cytokine release syndrome/cytokine storm (CRS) 
• Capillary leak syndrome (CLS) 
• Tachyarrhythmias (including supraventricular and ventricular) 
All analyses will be conducted in the Safety I/P-risk population and the Safety all-risk population 
by treatment arm using the treatment-emergent period. 


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Table 6 lists the planned analyses for each category of OSO for NKTR-214. 
1) Overall summary of OSO by worst CTC grade presented by category/PT (any grade, 
grade 3-4, grade 5). 
2) Overall summary of serious OSO by worst CTC grade presented by category/PT (any grade, 
grade 3-4, grade 5). 
3) Overall summary of OSO leading to discontinuation of any study drug by worst CTC grade 
presented by category/PT (any grade, grade 3-4). 
4) Overall summary of OSO leading to discontinuation of NKTR-214 by worst grade presented 
by category/PT (any grade, grade 3-4). This summary will be conducted for Arm A patients. 
5) Time-to onset of OSO (any grade, grade 3-5) by category 
6) Overall summary of OSO by Cycle by Worst Grade by category (any grade, grade 3-5) (for 
Arm A only, and cycle is every 3 weeks in this analysis) 
Time-to onset analyses are restricted to treated patients who experienced at least one OSO in the 
specific category. 
For IRR, events that start after study drug administration on the same day or next day will be 
included. If AE onset time is available, the time information will be used to exclude events that 
start before study drug administration; otherwise, AEs that start on the same day as study drug 
administration will be included. Analysis on IRR will only be performed for Arm A. 
A by-patient listing of OSO will be provided. 


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Table 6: 
Planned Analyses for OSO for NKTR-214 
Table 
Numbersa 
Tachyarrhythmias 
Syncope 
CRS 
CLS 
Infusion-related 
reaction 
(same day or next 
day post study 
drug 
administration) 
(For Arm A only) 
Flu-like symptoms; 
Rash and pruritus; 
Fatigue/asthenia; 
Arthralgia; 
Elevated hepatic 
transaminases; 
Elevated serum creatinine; 
Eosinophilic disorders; 
Hypotension 
1), 2) 
Yes 
No 
No 
Yes 
Yes 
3), 4) 
Yes 
No 
No 
Yes 
Yes 
5) 
Yes 
Yes 
Yes 
Yes 
Yes 
6) 
No 
Yes 
No 
Yes 
Yes 
Abbreviations: CLS = capillary leak syndrome; CRS = cytokine release syndrome/cytokine storm 
a. 
Table descriptions provided in Section 8.3.2. 
 
8.4 
Deaths 
Deaths will be summarized by treatment group: 
• All deaths, reasons for death 
• Deaths within treatment-emergent period, and reasons for death 
• Deaths within extended treatment-emergent period, and reasons for death 
A by-patient listing of deaths will be provided for all randomized patients (ITT I/P-risk 
population and ITT all-risk population). 
8.5 
Laboratory Parameters 
The analysis population for each laboratory test is restricted to patients in the Safety I/P-risk 
population and the Safety all-risk population who had both a baseline and at least one 
treatment-emergent measurement of that laboratory test. 
8.5.1 
Hematology 
The following will be summarized by treatment group as baseline CTC grade and worst CTC 
grade on-treatment per patient: hemoglobin, platelet, white blood counts (WBC), absolute 
neutrophils count (ANC) and lymphocyte count (LYMP). A table presenting number and 
percentage of patients with post-baseline CTC grade increased from baseline (any grade, grade 
3-4) by treatment group will be provided. 
The analyses will be conducted using the treatment-emergent period. 


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A by-patient listing of these laboratory parameters will be provided. 
Eosinophil (EOS) 
• Summary of baseline and highest post-baseline EOS will be provided by treatment group: 
− Mean (standard deviation [SD] and standard error [SE]), median, min and max 
− Percent exceeding thresholds: ≥ 10 x 109/L, ≥ 5 x 109/L, ≥ 1.5 x 109/L 
− Time to highest post-baseline EOS: mean (standard deviation [SD]), median, min, max 
− Duration (Weeks) of Sustained Eosinophils ≥ 1.5 x 109/L: % of patients with eosinophils 
returned, % patients with duration longer than 6 months, median and 95% CI will be 
estimated using the KM method 
Plot of mean eosinophil (± SE) by treatment arm and time. 
8.5.2 
Serum Chemistry 
The following will be summarized by treatment group as baseline CTC grade and worst CTC 
grade on-treatment per patient: ALT, AST, alkaline phosphatase (ALP), total bilirubin, 
creatinine, amylase and lipase. A table presenting number and percentage of patients with 
post-baseline abnormalities increased from baseline (any grade, grade 3-4) by treatment group 
will be provided. 
The analyses will be conducted using the treatment-emergent period. 
A by-patient listing of these laboratory parameters will be provided. 
8.5.3 
Electrolytes 
The following will be summarized by treatment group as baseline CTC grade and worst CTC 
grade on-treatment per patient: sodium (high and low), potassium (high and low), calcium (high 
and low), and glucose. A table presenting number and percentage of patients with post-baseline 
abnormalities increased from baseline (any grade, grade 3-4) by treatment group will be 
provided. 
The analyses will be conducted using the treatment-emergent period. 
A by-patient listing of these laboratory parameters will be provided. 
8.5.4 
Additional Analyses 
In addition, further analyses on specific laboratory parameters will be performed by treatment 
group: 


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Abnormal Hepatic Function Test 
The number of patients with the following laboratory abnormalities from on-treatment 
evaluations will be summarized by treatment group: 
• ALT or AST > 3 x ULN, > 5 x ULN, > 10 x ULN and > 20 x ULN 
• Total bilirubin > 2 x ULN 
• alkaline phosphatase (ALP) > 1.5 x ULN 
• Concurrent (within 30 days) ALT or AST > 3 x ULN and total bilirubin > 1.5 x ULN 
• Concurrent (within 30 days) ALT or AST > 3 x ULN and total bilirubin > 2 x ULN 
• Concurrent (within 30 days) ALT or AST > 3 x ULN and total bilirubin > 2 x ULN and all 
ALP measurements normal or < 2 x ULN 
For identification of concurrent elevations, window for identification of total bilirubin elevation 
applies to on or after ALT/AST elevation. Window for ALP applies to both before and after 
ALT/AST elevation. 
The analyses will be conducted using the extended treatment-emergent period. 
A by-patient listing of these specific abnormalities will be provided. 
Abnormal Thyroid Function Test 
The number of patients with the following laboratory abnormalities from on-treatment 
evaluations will be summarized by treatment group: 
• TSH value > ULN and 
− with baseline TSH value ≤ ULN 
− with at least one FT3/FT4 test value < LLN within 2-week window after the abnormal 
TSH test 
− with all FT3/FT4 test values ≥  LLN within 2-week window after the abnormal TSH test 
− with FT3/FT4 missing within 2-week window after the abnormal TSH test. 
• TSH < LLN and 
− with baseline TSH value ≥ LLN 
− with at least one FT3/FT4 test value > ULN within 2-week window after the abnormal 
TSH test 
− with all FT3/FT4 test values ≤  ULN within 2-week window after the abnormal TSH test 
− with FT3/FT4 missing within 2-week window after the abnormal TSH test 
The analyses will be conducted using the treatment-emergent period. 


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A by-patient listing of these specific abnormalities will be provided. 
8.6 
Additional Safety Analyses 
8.6.1 
Vital Signs 
Values at each scheduled visit, change, and percent change from baseline for vital signs, 
including systolic blood pressure, diastolic blood pressure, pulse, respiration rate, and body 
temperature will be summarized descriptively. 
Criteria for clinically notable vital sign abnormalities are defined in Table 7 below. Abnormal 
values for patients exhibiting clinically notable vital sign abnormalities will be listed along with 
their assigned treatment group.  Alert vital signs are defined as an absolute value outside the 
defined range and percentage change > 25%.  The abnormal values for patients exhibiting alert 
vital sign abnormalities will be listed. 
Table 7: 
Criteria for Clinically Notable Vital Sign Abnormalities 
Parameter 
High Threshold 
Low Threshold 
Systolic blood pressure 
> 160 mmHg 
< 90 mmHg 
Diastolic blood pressure 
> 100 mmHg 
< 60 mmHg 
Pulse 
> 100 bpm 
< 60 bpm 
Temperature 
> 38ºC 
< 35ºC 
Respiratory rate 
> 24/min 
< 12/min 
 


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9.0 
COVID-19 RELATED ANALYSES 
9.1 
Study Conduct 
9.1.1 
Patients Impacted 
A brief high-level summary of patients impacted by coronavirus disease 2019 (COVID-19) will 
be provided by treatment group for the Safety IMDC I/P-risk Analysis Set and Safety IMDC 
All-risk Analysis Set. This summary will present the number and percentage of patients with any 
incidence in each of the categories listed below due to COVID-19 and any reason, where total 
number of patients in corresponding treatment group will be used as denominator for percentage 
calculation: 
• Any positive test of COVID-19 
• Received COVID-19 vaccine (type/manufacturer of vaccine, e.g., RNA vaccine from Pfizer) 
during treatment 
• Missed study visit 
• Missed at least 9 weeks of doses (For Arm A, missing 2 consecutive doses for NKTR-214 
and nivolumab means no infusion in 9 weeks, which is comparable to missing 9 weeks of 
doses for Arm B).Delayed scan 
• Missed scan (any missed scan, 2 scans missed, ≥ 3 scans missed) 
• Study treatment discontinuation 
• Study discontinuation 
• Death 
• Study treatment discontinuation 
 
9.1.2 
Multiple Incidences 
Number of unique incidences per person in each of the categories listed below due to COVID-19 
will be summarized by country and by treatment group using descriptive statistics: 
• Missed study visit 
• Missed at least 9 weeks of doses Delayed scan 
• Missed scan 
A table showing total number of occurrences (unique incidences) in each category by treatment 
group will be provided. 
A listing of all COVID-19 impact data collected will be created. 


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9.2 
Impacts on Efficacy Results 
Supplementary analyses for ORR and OS may be performed to estimate the treatment effects 
without the COVID-19 impact if needed.  
9.3 
Impacts on Safety Results 
By-patient listing for COVID-19 related adverse events will be provided for the Safety Analysis 
Set. If sample size allows (e.g., > 10 per treatment group), COVID-19 related TEAEs can be 
summarized by worst CTC grade and treatment group for COVID-19 infected patients. Impact of 
COVID-19 vaccines on study drug dosing and adverse events may be further explored. 
If central clinical laboratory data was missing for some patients in some visits due to COVID-19, 
local laboratory data may be collected in place of missed central laboratory data. In such a case, 
central laboratory and local laboratory data may be combined for the lab related analysis. 
Specifical considerations are described as follows: 
1. For summary of post-baseline laboratory toxicity worsening from baseline 
All (scheduled and unscheduled) central and local laboratory data will be included. 
The central and local laboratory data will be graded according to their corresponding 
laboratory normal ranges (central laboratory normal range for central laboratory data, 
local laboratory normal range for local laboratory data). If the baseline value is 
involved in the derivation of toxicity grade based on CTCAE 5.0, the corresponding 
baseline value for central and local laboratory will be used as reference (central 
laboratory toxicity grade based on central laboratory baseline value, local laboratory 
toxicity grade based on local laboratory baseline value). If a corresponding baseline 
value is not available, for that particular laboratory value, the toxicity grade will be 
derived assuming the baseline value is normal, thus the grade will be derived based 
on corresponding normal range only. 
In summary table, the baseline toxicity grade will be based on central laboratory data 
if the central laboratory data is available; otherwise (central laboratory data is not 
available), then the baseline grade will be based on local laboratory if available. The 
post-baseline worst toxicity grade will be based on the worst grade of both central and 
local laboratory data. 
2. For summary of abnormal hepatic fuction and summary of abnormal thyroid function 
All (scheduled and unscheduled) central and local laboratory data will be included. 
The central and local laboratory data (AST, ALT, total bilirubin, TSH, FT3, FT4) will 
be summarized according to their corresponding laboratory normal ranges (central 
laboratory normal range for central laboratory data, local laboratory normal range for 
local laboratory data). 


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10.0 
EFFICACY INTERIM AND FINAL ANALYSES 
This study will have 1 planned efficacy interim analysis and 1 final analysis: 
• Interim Analysis (IA – ORR & OS interim and OS events re‑estimation): when at least 
156 OS events in IMDC Intermediate- or Poor-risk Population have been observed. 
• Final Analysis (FA – OS final): timing will be determined at the time of IA using the 
promising zone adaptive method (Mehta and Pocock 2011) to estimate the OS events needed. 
 


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11.0 
DATA MONITORING COMMITTEE 
An external multidisciplinary Data Monitoring Committee (DMC) will be convened for this 
study.  The DMC will be comprised of qualified clinicians and a biostatistician, all independent 
from the Sponsor and (for the clinicians) independent of investigational sites, selected to avoid 
conflict(s) of interest.  The DMC’s specific activities will be detailed in a mutually agreed upon 
charter, which will define the relevant processes, including meeting proceedings and structure, 
data assessments, documentation and recordkeeping, process for DMC recommendations, and 
regulatory reporting, as applicable. The charter will contain procedures to ensure the 
minimization of bias, such as maintaining confidentiality of any interim data. 
The DMC will review the results of the interim analyses as well as assess accumulating safety 
data and emerging risk/benefit balance at regular intervals and on an ad-hoc basis as detailed in 
the DMC charter.  The DMC will also conduct the OS events re-estimation; details will be 
provided in the DMC charter. 
 


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12.0 
PHARMACOKINETIC, PHARMACODYNAMIC, 
 
ANALYSIS 
In addition to the objectives described in this section, PK data obtained in this study may also be 
combined with data from other studies to develop population PK models.  These models may be 
used to evaluate the effects of intrinsic and extrinsic covariates on the PK of NKTR-214 related 
molecules and/or nivolumab and to determine measures of individual exposure for nivolumab 
(such as single dose and steady state peak, trough and time averaged concentration, CL volume, 
half-life) and for NKTR-214 (such as AUC, clearance, volume, half-life, Cmax, Cmin, and 
Cavg).  Model predicted exposures may be used for exposure-response analyses of selected 
efficacy and safety endpoints.  Results of any population PK or exposure-response analyses will 
be reported separately.  
 
12.1 
Pharmacokinetic Analysis 
Listings for blood collection dates, times and concentrations will be generated by patient for each 
analyte.  Sampling time deviations will be computed as differences between scheduled (nominal) 
and actual sampling times and expressed in hours and as a percentage of the nominal time. 
Observed plasma NKTR-214-RC, NKTR-214-AC, and Total-PEG, and serum nivolumab 
concentrations at each nominal PK sampling time will be listed by patient and tabulated for each 
analyte using descriptive statistics, including but not limited to n (observed), n (non-zero), 
arithmetic mean, standard deviation (SD), standard error of the mean (SE), arithmetic coefficient 
of variation (CV%), geometric mean, geometric CV%, median, minimum, and maximum. 
Mean (+ standard deviation) observed plasma NKTR-214-RC, NKTR-214-AC, and Total-PEG 
concentrations versus nominal time plots will be generated on linear and semi-logarithmic scales 
for each analyte for Cycle 1  based on nominal sampling times.  For serum nivolumab, mean (+ 
standard deviation)  serum concentrations versus nominal time will be generated on linear scale 
by nominal sampling time.  Nivolumab concentrations should not be connected by a line as all 
the samples are pre-dose concentrations from different cycles. 
PK samples that were collected outside the protocol accepted time windows will be excluded 
from summary tables and summary figures. 
Rounding for the reporting of descriptive statistics will be to three significant digits, except for n, 
which will be rounded to the whole value. Percentages such as CV% presented in tables will be 
rounded to one decimal place.   
Descriptive statistics will not be performed if n < 3 and summary tables will only include 
median, minimum, and maximum. 


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12.1.1 
Handling of Missing Values, BLQ, and Outliers 
• NKTR-214-RC, NKTR-214-AC, and Total-PEG 
When summarizing concentration values, below the limit of quatification (BLQ) values will be 
considered as zero, and zero values will be excluded from the calculation of geometric means 
and CV% geometric mean, however, zero values will be included for all other summary statistics 
and the number of non-zero concentrations will be reported. Listings for concentrations values 
(except for pre-dose C1D1) will list these concentrations as < lower limit of quantification 
(LLOQ). 
Samples with concentrations 5 x higher than mean + standard deviations (SD) for all samples at 
that time will be considered outliers and not included in  analyses and summary statistics and 
plots.  The reason for not using selected data will be presented and discussed in the clinical study 
report (CSR). 
• Nivolumab 
When summarizing concentration values, BLQ values (except for pre-dose C1D1) will be 
imputed as LLOQ/2.  Listings for concentrations values (except for pre-dose C1D1) will list 
these concentrations as <LLOQ. Pre-dose C1D1 BLQ values will be set to zero, and zero values 
will be excluded from the calculation of geometric means and CV% geometric mean, however, 
zero values will be included for all other summary statistics and the number of non-zero 
concentrations will be reported for pre-dose C1D1. 
12.2 
/Pharmacodynamic Analysis 
Observed plasma sCD25 and cytokine concentrations, and fold change from baseline at each 
nominal PK sampling time and maximum fold change and time of maximum fold change will be 
listed by patient and tabulated for each analyte using descriptive statistics, including but not 
limited to n (number of non-missing data), arithmetic mean, standard deviation, SE, arithmetic 
CV%, geometric mean, geometric CV%, median, 25th and 75th percentiles, minimum, and 
maximum.  
For sCD25, all Cycle 1 pre-dose concentrations that are BLQ will be set to 0, all other 
concentrations that are BLQ will considered missing. Zero values will be excluded from the 
calculation of geometric means and CV% geometric mean.Missing concentration values will not 
be included in the descriptive statistics.  
For each cytokine, all BLQ values will be set to the lower limit of quantification (LLOQ).  
Plot of mean (+SE) plasma sCD25 and cytokine concentrations versus nominal time will be 
generated for each analyte for baseline and Cycle 1. Fold change from baseline plots will also be 
generated. Baseline is the last observation prior first  dose of study drug within 2 weeks (or 
14 days). 


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Plot of mean (+SE) cytokine concentrations and its fold change from baseline will be generated 
for baseline and all cycles.  
Absolute eosinophil count, absolute lymphocyte count, and their ratios of C1D8 / baseline will 
be summarized with descriptive statistics: n (number of non-missing data),  arithmetic mean, 
standard deviation, SE, CV%, median, 25th and 75th percentiles, minimum, and maximum.  
Plot of mean (+SE) absolute lymphocyte counts and absolute eosinophil counts versus nominal 
time will be generated for baseline and Cycle 1.  Fold change from baseline plots will also be 
generated. Baseline is the last observation prior to first dose within 2 weeks (or 14 days). 
Plot of mean (+SE) eosinohpil trough count and its change from baseline will be generated for 
baseline and all cycles.  
Rounding for the reporting of parameters will be to 3 significant digits. Percentages presented in 
tables such as CV%  will be rounded to one decimal place. The same convention will be 
followed for descriptive statistics, except for n, which will be rounded to the whole value. 
Descriptive statistics will not be performed if n < 3 and summary tables will only include 
median, minimum, and maximum. 


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13.0 
DOCUMENT HISTORY 
Version Number 
Author(s) 
Description 
1.0 
 
Initial version 
2.0 
 
• Section 6.2: Added PFS to testing procedures in Figure 1 
• Section 7.2: removed “Only when the overdose is 
affiliated with adverse events, will this be considered an 
important protocol deviaton” from the important protocol 
deviation criterion “Relative dose intensity >125% for 
study drug (programmatically derived). “ 
• Section 7.1: added “Baseline liver mets as per BICR (Yes, 
No)” and “number of disease sites per patient for target 
lesions’. 
• Section 7.4.3: removed “The number and percent of 
patients who took at least one subsequent post-study 
immune-oncology therapy, and post-study TKI therapy 
will be calculated and presented.” 
• Section 7.5.2: added sensitivity analysis of PFS 
accounting for two or more missing tumor assessments 
prior to PFS event (death or documented progression). 
• Section 7.5.4.3: Removed the sensitivity analysis of 
restricted mean of duration of response (this analysis will 
be done for DMC only).  
• Section 7.8.1: Removed sample level ADA analysis by 
analyte and by visit. Clarified that samples confirmed to 
be positive for anti-NKTR-214/anti-PEG, anti-IL-2 
antibodies will be tested for neutralizing activity for IL-2 
using a validated cell-based assay.  Anti-nivolumab 
antibodies positive samples will also be tested for 
neutralizing activity for   nivolumab using a validated 
cell-based assay. 
• Section 7.8.2: Clarified that infusion related reaction 
events that start after study drug administration on the 
same day or next day will be included. Clarified that 
pre-dose NKTR-214 RC and pre-dose NKTR-214 AC 
concentrations will be summarized by ADA status. 


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• Section 8.1: add the following NKTR-214-related TEAE 
summaries: 
o NKTR-214-related TEAEs presented by worst 
grade (any grade, grade 3-4, grade 5) by SOC and 
PT 
o Grade 3 or above NKTR-214-related TEAE by PT 
o Serious NKTR-214-related TEAE by PT 
o NKTR-214-related TEAE leading to death by PT 
o NKTR-214-related TEAE presented by worst 
grade (any grade, grade 3-4, grade 5) by SOC and 
PT (using an extended treatment-emergent period) 
• Section 8.2: Clarified that IMAEs will be summarized 
using the extended treatment-emergent period for each 
immune-mediated category for Arm A only. Re-challenge 
analysis is removed. 
• Section 8.3: Time to resolution analysis is removed.  
• Section 8.3.1: exposure adjusted analysis for ICE is 
removed. 
• Section 8.6.1: Table 7 (Criteria for Clinically Notable 
Vital Sign Abnormalities) is updated. 
• Section 9.2: The analysis on COVID 19 impacts on 
efficacy results may be performed if needed, and sections 
9.2.1 (supplemental analysis on objective response rate) 
and 9.2.2 (supplemental analysis on overall survival) are 
removed. 
• Section 13: Document History section is added.  
 


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14.0 
REFERENCES 
Clopper, C.; Pearson, E. S. The use of confidence or fiducial limits illustrated in the case of the 
binomial. Biometrika. 1934; 26: 404–413. 
Greenwood, M. The errors of sampling of the survivorship tables, Reports on Public Health and 
Statistical Participants, 33, Appendix 1, HMSO, London, 1926 
Harrington B, Fleming T. A Class of Rank Test Procedures for Censored Survival Data. 
Biometrika, Volume 69, Issue 3, 1982. 
Huang B, Tian L, et al. Analysis of Response Data for Assessing Treatment Effects in 
Comparative Clinical Studies. Annals of Internal Medicine 2020;173:368-374. 
W. Lehmacher, G. Wassmer, Adaptive sample size calculations in group sequential trials, 
Biometrics. 1999, 55:1286–1290. 
Liu Y, and Hu M. Testing multiple primary endpoints in clinical trials with sample size 
adaptation. Pharmaceut. Statist. 2016, 15: 37–45. doi: 10.1002/pst.1724. 
Mehta C, Pocock SJ. Adaptive increase in sample size when interim results are promising: A 
practical guide with examples. Statistics in Medicine 2011; 30: 3267-3284. 
Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus Ipilimumab versus Sunitinib in 
Advanced Renal-Cell Carcinoma. N Engl J Med. 2018b; 378(14):1277-90. 
Rothrock E. Development and Initial Validation of the NCCN/FACT Symptom Index for 
Advanced Kidney Cancer. Value Health 2013 Jul-Aug; 16(5): 789-796. 
The EuroQol Group: EuroQol: A new facility for the measurement of health-related quality 
of life - The EuroQol Group. Health Policy 16:199-208, 1990. 
Wassmer G. Planning and analyzing adaptive group sequential survival trials. Biometrical 
Journal. 2006; 48: 714-729. 


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15.0 
APPENDIX 
15.1 
The Logrank Test for OS Analysis 
Let 𝑇ଵ denote the interim logrank test statistic with d1 number of events and 𝑇ଶ denote the 
logrank test statistic based on the cumulative data at final analysis with adapted 𝑑ଶ
∗ number of 
events. Then we calculate the incremental test statistic as following: 
𝑇෨ଶ
∗=
ඥௗమ∗்మିඥௗభ்భ
ඥௗమ∗ିௗభ
. 
The final combination test statistic (Lehmacher and Wassmer, 1999) with weight ට
ଶ
ଷ and ට
ଵ
ଷ can 
be written as  𝑇ଶ
∗= ට
ଶ
ଷ𝑇ଵ+ ට
ଵ
ଷ𝑇෨ଶ
∗. The overall Type I error rate is the probability of rejecting 
OS at either interim or final analysis under the null that there is no difference in survival between 
the treatment and control group (denoted as H0).  The critical value for the interim analysis is 
denoted as 𝑧బ.బభ
మ= Фିଵ(1 −
଴.଴ଵ
ଶ) (where Ф denotes the CDF for standard normal distribution) as 
two-sided 0.01 level of alpha is spent at this time. The critical value c for the final analysis is 
calculated so that the overall type I error rate is maintained at 0.049 (two-sided) or 0.0245 (one-
sided). The probability can be calculated as follows: 
0.0245 = 𝑃ுబ(𝑇ଵ> 𝑧଴.଴ଵ/ଶ or 𝑇ଶ
∗> 𝑐) = 𝑃ுబ(𝑇ଵ> 𝑧଴.଴ଵ/ଶ) + 𝑃ுబ(𝑇ଵ≤𝑧଴.଴ଵ/ଶ and 𝑇ଶ
∗> 𝑐) 
Therefore, we need to find c such that 𝑃ுబ൬𝑇ଵ≤𝑧బ.బభ
మ and 𝑇ଶ
∗> 𝑐൰= 0.0195. Because 𝑇ଵ and 𝑇ଶ
∗ 
asymptotically follows standard normal distribution with correlation ට
ଶ
ଷ (Wassmer, 2006), the 
critical value c can be found to be 𝑧଴.଴ଶଷଵ. This implies that the significant p-value will be 0.0231 
(one-sided) or approximately 0.0462 (two-sided). 
With similar arguments, if the overall type I error rate is to be maintained at 0.05 (two-sided) or 
0.025 (one-sided), the nominal alpha for OS final analysis with weighted combination test will 
be 0.0236 (one-sided) or approximately 0.0472 (two-sided). 
 
 


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15.2 
The Weighted Logrank Test for PFS Analysis 
Let Z denote the weighted logrank test statistic with 𝑑௜ number of events and 𝑌௜ number at risk. 
The test statistic Z can be written as 
𝑍=
∑
𝑊(𝑡௜) ൤𝑑௜ଵ−𝑌௜ଵቀ𝑑௜
𝑌௜ቁ൨
஽
௜ୀଵ
ඥ𝑉𝑎𝑟
෢(𝑍)
 
where 𝑉𝑎𝑟
෢(𝑍) = ∑
𝑊(𝑡௜)ଶ௒೔భ
௒೔ቀ1 −
௒೔భ
௒೔ቁቀ
௒೔ିௗ೔
௒೔ିଵቁ𝑑௜
஽
௜ୀଵ
  and 𝑊(𝑡௜) = ൛𝑆መ(𝑡௜ିଵ)ൟ
ఘ൛1 −𝑆መ(𝑡௜ିଵ)ൟ
ఊ. 
Considering the expected delayed effect on PFS, we select 𝜌= 0 and 𝛾= 1 for the Fleming-
Harrington test. Therefore, the weight 𝑊(𝑡௜) = 1 −𝑆መ(𝑡௜ିଵ). 
The PFS will be tested hierarchically given statistical significance of OS in both IMDC 
intermediate- or poor-risk (I/P-risk) population and all-risk population. The PFS interim and final 
analysis will be performed at the same time of OS interim or final analysis. The combination test 
statistic with weight ට
ଶ
ଷ and ට
ଵ
ଷ will be used in the final PFS analysis. For PFS, a 0.03 (two-
sided) level of alpha will be spent at interim analysis. Following the same arguments as in 
Section 15.1, if the overall type I error is 0.049 (two-sided), the nominal alpha for the PFS final 
analysis will be 0.0323 (two-sided); if the overall type I error is 0.05 (two-sided), the nominal 
alpha for the PFS final analysis will be 0.0335 (two-sided). 
 
 


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15.3 
Proof of Strong Family-wise Error Rate Control for the Four Primary Hypotheses 
and Two Key Secondary Hypotheses 
15.3.1 
Study Design 
Figure 2 gives study design flow charts for ORR, OS, and Figure 1 shows the overall testing 
procedure for ORR, OS and PFS where PFS will be tested in IMDC I/P-risk and all-risk 
populations sequentially after statistical significance of OS in both populations. All p-values and 
testing levels are two-sided in this section and one-sided in Section 15.3.3. At interim analysis, if 
OS in IMDC I/P-risk population is not statistically significant at 0.01 level, then number of 
events in this population for the final analysis will be re-estimated based on the pre-specified 
adaptation rule. The final analysis will be triggered by the required number of events in the 
IMDC I/P risk population. At final analysis, if OS in IMDC I/P risk population is statistically 
significant (at 0.0462 level if ORR is not significant at IA and at 0.0472 level if ORR is 
significant at IA), then OS in IMDC all-risk population will also be tested at the same level as 
the IMDC I/P risk population. Given the ststistical significance of OS in the IMDC all-risk 
population at FA, the key secondary endpoint of PFS by BICR in the IMDC I/P-risk population 
and the IMDC all-risk population will be test sequentially at level 0.0323 if ORR is not 
significant at IA and at level 0.0335 if ORR is significant at IA.   
On the other hand, if OS in IMDC I/P risk population is statistically significant at 0.01 level at 
interim, then formal efficacy claim can be obtained, and no further testing will be performed for 
this population. At the same time, OS in the IMDC all-risk population can also tested at 0.01 
level. If statistically significant, the key secondary endpoint of PFS by BICR in both populations 
will be tested sequentially at 0.03 level. Otherwise, if OS in all-risk population is not significant, 
number of events in this population for the final analysis will be re-estimated based on the pre-
specified adaptation rule. The final analysis occurs when the adapted number of events in the 
IMDC all-risk population is achieved. The OS in IMDC all-risk population will be tested at 
0.0462 level if ORR is not significant at IA and at 0.0472 level if ORR is significant at IA. And 
the key secondary endpoint of PFS by BICR in the two populations will be tested sequentially at 
level 0.0323 if ORR is not significant at IA and at level 0.0335 if ORR is significant at IA, given 
the statistical significance of OS in all-risk population at final analysis. 
15.3.2 
Notation and Test Statistics 
For OS in the IMDC I/P-risk populatio,  let 𝑇ଵ denote the interim logrank test statistic with d1 
number of events and 𝑇ଶ denote the regular logrank test statistic based on the cumulative data at 
final analysis with adapted 𝑑ଶ
∗ number of events. Then we calculate the incremental test statistic 
following Wassmer (2006): 
𝑇෨ଶ
∗=
ඥௗమ∗்మିඥௗభ்భ
ඥௗమ∗ିௗభ
. 
The final weighted test statistic with weight ඥ2 3
⁄  and ඥ1 3
⁄  can be written as 
𝑇ଶ
∗= ඥ2 3
⁄ 𝑇ଵ+ ඥ1 3
⁄ 𝑇෨ଶ
∗. 


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Similarly for OS in the IMDC all-risk population,  let 𝑇ଵ
௔ denote the interim logrank test statistic 
with 𝑑ଵ
௔ number of events, let 𝑇ଶ
௔∗ denote the logrank test statistic based on the cumulative data 
at final analysis with 𝑑ଶ
௔∗ number of events resulting from adaption in the IMDC I/P population 
and 𝑇ଶ
௔∗∗ denote the logrank test statistic based on the cumulative data at final analysis with  
𝑑ଶ
௔∗∗ number of events resulting from adaption in the IMDC all-risk population. Then the 
corresponding incremental test statistics could be calculated as follows: 
𝑇෨ଶ
௔∗=
ඥௗమ
ೌ∗்మೌ∗ିඥௗభೌ்భೌ
ඥௗమ
ೌ∗ିௗభೌ
  or  𝑇෨ଶ
௔∗∗=
ඥௗమ
ೌ∗∗்మೌ∗∗ିඥௗభೌ்భೌ
ඥௗమ
ೌ∗∗ିௗభೌ
. 
The final test statistics can be written as 
𝑇ଶ
௔∗= ඥ2/3𝑇ଵ
௔+ ඥ1/3𝑇෨ଶ
௔∗ or  𝑇ଶ
௔∗∗= ඥ2/3𝑇ଵ
௔+ ඥ1/3𝑇෨ଶ
௔∗∗. 
Following a similar logic, we denote the interim test statistics for PFS in I/P and all-risk 
populations as 𝑍ଵ and 𝑍ଵ
௔, denote the final test statistics for PFS in both populations as 𝑍ଶ
∗, 𝑍ଶ
௔∗ 
based on adaption in the IMDC I/P population with event size 𝑑ଶ
௔∗, and 𝑍ଶ
∗∗ and 𝑍ଶ
௔∗∗ based on 
adaption in the IMDC all-risk population with event size 𝑑ଶ
௔∗∗. 
Further, let 𝐻଴ଵ
ைௌand 𝐻଴ଶ
ைௌ denote the null hypotheses regarding the OS in IMDC I/P-risk and 
IMDC all-risk population, 𝐻଴ଵ
ைோோ and 𝐻଴ଶ
ைோோ denote the null hypotheses regarding the ORR in 
IMDC I/P-risk and IMDC all-risk population, and 𝐻଴ଵ
௉ிௌ and 𝐻଴ଶ
௉ிௌ denote the null hypotheses 
regarding the PFS in IMDC I/P-risk and IMDC all-risk population. 
15.3.3 
Strong Control of Family-wise Error Rate 
By the partition principle, the family-wise error rate is strongly controlled at one-sided level 
0.025 if the probability of false rejection in each of the following partitioned parameter space 
could be controlled at the same one-sided 0.025 level. Although there are six individual 
hypotheses: 𝐻଴ଵ
ைௌ, 𝐻଴ଶ
ைௌ, 𝐻଴ଵ
ைோோ, 𝐻଴ଶ
ைோோ, 𝐻଴ଵ
௉ிௌ, and 𝐻଴ଶ
௉ிௌ, due to the decision path between 
𝐻଴ଵ
ைௌ, 𝐻଴ଶ
ைௌ, 𝐻଴ଵ
௉ிௌ, 𝐻଴ଶ
௉ிௌ and the decision path between 𝐻଴ଵ
ைோோ and 𝐻଴ଶ
ைோோ, there are only a total of 
3*5-1=14 partitioned parameter spaces (Liu and Hsu 2009). 


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Partitioned parameter space (where ∙𝑪 denotes the 
complement of the null space) 
False rejection 
𝟏. 𝑯𝟎𝟏
𝑶𝑹𝑹∩𝑯𝟎𝟏
𝑶𝑺 
Reject 𝐻଴ଵ
ைோோ or 𝐻଴ଵ
ைௌ
2. (𝑯𝟎𝟏
𝑶𝑹𝑹)𝑪∩𝑯𝟎𝟐
𝑶𝑹𝑹∩𝑯𝟎𝟏
𝑶𝑺 
Reject 𝐻଴ଶ
ைோோ or 𝐻଴ଵ
ைௌ
𝟑. 𝑯𝟎𝟏
𝑶𝑹𝑹∩(𝑯𝟎𝟏
𝑶𝑺)𝑪∩𝑯𝟎𝟐
𝑶𝑺 
Reject 𝐻଴ଵ
ைோோ or 𝐻଴ଶ
ைௌ
𝟒. (𝑯𝟎𝟏
𝑶𝑹𝑹)𝑪∩𝑯𝟎𝟐
𝑶𝑹𝑹∩(𝑯𝟎𝟏
𝑶𝑺)𝑪∩𝑯𝟎𝟐
𝑶𝑺
Reject 𝐻଴ଶ
ைோோ or 𝐻଴ଶ
ைௌ
𝟓. (𝑯𝟎𝟏
𝑶𝑹𝑹)𝑪∩(𝑯𝟎𝟐
𝑶𝑹𝑹)𝑪∩𝑯𝟎𝟏
𝑶𝑺 
Reject 𝐻଴ଵ
ைௌ 
𝟔. (𝑯𝟎𝟏
𝑶𝑹𝑹)𝑪∩(𝑯𝟎𝟐
𝑶𝑹𝑹)𝑪∩(𝑯𝟎𝟏
𝑶𝑺)𝑪∩𝑯𝟎𝟐
𝑶𝑺
Reject 𝐻଴ଶ
ைௌ 
7. 𝑯𝟎𝟏
𝑶𝑹𝑹∩(𝑯𝟎𝟏
𝑶𝑺)𝑪∩(𝑯𝟎𝟐
𝑶𝑺)𝑪∩𝑯𝟎𝟏
𝑷𝑭𝑺
Reject 𝐻଴ଵ
ைோோ or 𝐻଴ଵ
௉ிௌ
8. (𝑯𝟎𝟏
𝑶𝑹𝑹)𝑪∩𝑯𝟎𝟐
𝑶𝑹𝑹∩(𝑯𝟎𝟏
𝑶𝑺)𝑪∩(𝑯𝟎𝟐
𝑶𝑺)𝑪∩𝑯𝟎𝟏
𝑷𝑭𝑺
Reject 𝐻଴ଶ
ைோோ or 𝐻଴ଵ
௉ிௌ
9. (𝑯𝟎𝟏
𝑶𝑹𝑹)𝑪∩(𝑯𝟎𝟐
𝑶𝑹𝑹)𝑪∩(𝑯𝟎𝟏
𝑶𝑺)𝑪∩(𝑯𝟎𝟐
𝑶𝑺)𝑪∩𝑯𝟎𝟏
𝑷𝑭𝑺
Reject 𝐻଴ଵ
௉ிௌ 
10. 𝑯𝟎𝟏
𝑶𝑹𝑹∩(𝑯𝟎𝟏
𝑶𝑺)𝑪∩(𝑯𝟎𝟐
𝑶𝑺)𝑪∩(𝑯𝟎𝟏
𝑷𝑭𝑺)𝑪∩𝑯𝟎𝟐
𝑷𝑭𝑺
Reject 𝐻଴ଵ
ைோோ or 𝐻଴ଶ
௉ிௌ
11. (𝑯𝟎𝟏
𝑶𝑹𝑹)𝑪∩𝑯𝟎𝟐
𝑶𝑹𝑹∩(𝑯𝟎𝟏
𝑶𝑺)𝑪∩(𝑯𝟎𝟐
𝑶𝑺)𝑪∩(𝑯𝟎𝟏
𝑷𝑭𝑺)𝑪∩𝑯𝟎𝟐
𝑷𝑭𝑺
Reject 𝐻଴ଶ
ைோோ or 𝐻଴ଶ
௉ிௌ
12. (𝑯𝟎𝟏
𝑶𝑹𝑹)𝑪∩(𝑯𝟎𝟐
𝑶𝑹𝑹)𝑪∩(𝑯𝟎𝟏
𝑶𝑺)𝑪∩(𝑯𝟎𝟐
𝑶𝑺)𝑪∩(𝑯𝟎𝟏
𝑷𝑭𝑺)𝑪∩𝑯𝟎𝟐
𝑷𝑭𝑺
Reject 𝐻଴ଶ
௉ிௌ 
13. 𝑯𝟎𝟏
𝑶𝑹𝑹∩(𝑯𝟎𝟏
𝑶𝑺)𝑪∩(𝑯𝟎𝟐
𝑶𝑺)𝑪∩(𝑯𝟎𝟏
𝑷𝑭𝑺)𝑪∩(𝑯𝟎𝟐
𝑷𝑭𝑺)𝑪
Reject 𝐻଴ଵ
ைோோ 
14. (𝑯𝟎𝟏
𝑶𝑹𝑹)𝑪∩𝑯𝟎𝟐
𝑶𝑹𝑹∩(𝑯𝟎𝟏
𝑶𝑺)𝑪∩(𝑯𝟎𝟐
𝑶𝑺)𝑪∩(𝑯𝟎𝟏
𝑷𝑭𝑺)𝑪∩(𝑯𝟎𝟐
𝑷𝑭𝑺)𝑪
Reject 𝐻଴ଶ
ைோோ 
 
• Under partitioned parameter spaces 1 or 2 (with j=1 or 2), 
P (false rejection) = P (Reject 𝐻଴௝
ைோோ or 𝐻଴ଵ
ைௌ) 
= P (Reject 𝐻଴௝
ைோோ) + P (Reject 𝐻଴ଵ
ைௌ but do not reject 𝐻଴௝
ைோோ) 
≤ 0.0005 + 𝑃൫𝑇ଵ> 𝑧଴.଴଴ହ or 𝑇ଶ
∗> 𝑧଴.଴ସ଺ଶ/ଶ൯ 
= 0.0005 + 𝑃(𝑇ଵ> 𝑧଴.଴଴ହ) + 𝑃൫𝑇ଵ≤𝑧଴.଴଴ହ and 𝑇ଶ
∗> 𝑧଴.଴ସ଺ଶ/ଶ൯ 
=0.0005+0.005+0.0195 = 0.025 
since 𝑇ଵ and 𝑇ଶ
∗ asymptotically follows standard bivariate normal distribution with 
correlation ඥ2 3
⁄ . (Wassmer, 2006) 
• Under partitioned parameter space 3 or 4 (with j=1 or 2), 
P (false rejection) = P (Reject 𝐻଴௝
ைோோ or 𝐻଴ଶ
ைௌ) 
= P (Reject 𝐻଴௝
ைோோ) + P (Reject 𝐻଴ଶ
ைௌ but do not reject 𝐻଴௝
ைோோ) 
≤ 0.0005 + 𝑃(𝑇ଵ> 𝑧଴.଴଴ହ, 𝑇ଵ
௔> 𝑧଴.଴଴ହ) 
+ 𝑃(𝑇ଵ> 𝑧଴.଴଴ହ, 𝑇ଵ
௔≤𝑧଴.଴଴ହ, 𝑇ଶ
௔∗∗> 𝑧0.0462/2) 
+ 𝑃(𝑇ଵ≤𝑧଴.଴଴ହ, 𝑇ଶ
∗> 𝑧0.0462/2, 𝑇ଶ
௔∗> 𝑧0.0462/2) 
≤ 0.0005 + 𝑃(𝑇ଵ> 𝑧଴.଴଴ହ, 𝑇ଵ
௔> 𝑧଴.଴଴ହ) 
+ 𝑃(𝑇ଵ> 𝑧଴.଴଴ହ, 𝑇ଵ
௔≤𝑧଴.଴଴ହ, 𝑇ଶ
௔∗∗> 𝑧0.0462/2) 
+ 𝑃(𝑇ଵ≤𝑧଴.଴଴ହ, 𝑇ଶ
௔∗> 𝑧0.0462/2) 


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≤ 0.0005 + 𝑃(𝑇ଵ> 𝑧଴.଴଴ହ, 𝑇ଵ
௔> 𝑧଴.଴଴ହ) 
+ 𝑃(𝑇ଵ> 𝑧଴.଴଴ହ, 𝑇ଵ
௔≤𝑧଴.଴଴ହ, 𝑇ଶ
௔∗∗> 𝑧0.0462/2) 
+ 𝑃(𝑇ଵ≤𝑧଴.଴଴ହ, 𝑇ଵ
௔> 𝑧଴.଴଴ହ) + 𝑃(𝑇ଵ≤𝑧଴.଴଴ହ, 𝑇ଵ
௔≤𝑧଴.଴଴ହ, 𝑇ଶ
௔∗> 𝑧0.0462/2) 
= 0.0005 + 𝑃(𝑇ଵ
௔> 𝑧଴.଴଴ହ) + 𝑃(𝑇ଵ> 𝑧଴.଴଴ହ, 𝑇ଵ
௔≤𝑧଴.଴଴ହ, 𝑇ଶ
௔∗∗> 𝑧0.0462/2) 
+ 𝑃(𝑇ଵ≤𝑧଴.଴଴ହ, 𝑇ଵ
௔≤𝑧଴.଴଴ହ, 𝑇ଶ
௔∗> 𝑧0.0462/2) 
= 0.0005 + 0.005 +𝑃(𝑇ଵ> 𝑧଴.଴଴ହ, 𝑇ଵ
௔≤𝑧଴.଴଴ହ, ඥ2/3𝑇ଵ
௔+ ඥ1/3𝑇෨ଶ
௔∗∗> 𝑧0.0462/2) 
+ 𝑃(𝑇ଵ≤𝑧଴.଴଴ହ, 𝑇ଵ
௔≤𝑧଴.଴଴ହ, ඥ2/3𝑇ଵ
௔+ ඥ1/3𝑇෨ଶ
௔∗> 𝑧0.0462/2) 
By Wassmer (2006), the conditional null distribution of 𝑇෨ଶ
௔∗and 𝑇෨ଶ
௔∗∗ given the interim data 
(𝑇ଵ and 𝑇ଵ
௔) approximately equals standard normal distribution, denoted as 𝑇෨ଶ
௔∗|(𝑇ଵ, 𝑇ଵ
௔)
ௗ⇔𝑇෨ଶ
௔∗∗|(𝑇ଵ, 𝑇ଵ
௔)
ௗ⇔ 𝑇 ~ 𝑁(0, 1). Therefore, the following joint distributions are the same: 
(𝑇ଵ, 𝑇ଵ
௔, 𝑇෨ଶ
௔∗)
ௗ⇔(𝑇ଵ, 𝑇ଵ
௔, 𝑇෨ଶ
௔∗∗)
ௗ⇔(𝑇ଵ, 𝑇ଵ
௔, T). Subsequently, the following joint distributions 
are also the same:  
(𝑇ଵ, 𝑇ଵ
௔, ඥ2/3𝑇ଵ
௔+ ඥ1/3𝑇෨ଶ
௔∗)
ௗ⇔(𝑇ଵ, 𝑇ଵ
௔, ඥ2/3𝑇ଵ
௔+ ඥ1/3𝑇෨ଶ
௔∗∗)  
ௗ⇔(𝑇ଵ, 𝑇ଵ
௔, ඥ2/3𝑇ଵ
௔+ ඥ1/3 T)( 1 ) 
Hence, above= 0.0055 + 𝑃(𝑇ଵ> 𝑧଴.଴଴ହ, 𝑇ଵ
௔≤𝑧଴.଴଴ହ, ඥ2/3𝑇ଵ
௔+ ඥ1/3𝑇> 𝑧଴.଴ସ଺ଶ/ଶ) 
+ 𝑃(𝑇ଵ≤𝑧଴.଴଴ହ, 𝑇ଵ
௔≤𝑧଴.଴଴ହ, ඥ2/3𝑇ଵ
௔+ ඥ1/3𝑇> 𝑧0.0462/2). 
= 0.0055 +𝑃(𝑇ଵ
௔≤𝑧଴.଴଴ହ , ඥ2/3𝑇ଵ
௔+ ඥ1/3𝑇> 𝑧0.0462/2) 
= 0.025. 
• Under partitioned parameter space 5, 
P (false rejection) = P (Reject 𝐻଴ଵ
ைௌ) ≤ 𝑃൫𝑇ଵ> 𝑧଴.଴଴ହ or 𝑇ଶ
∗> 𝑧଴.଴ସ଻ଶ/ଶ൯= 0.025 
• Under partitioned parameter space 6,  
P (false rejection) = P (Reject 𝐻଴ଶ
ைௌ) ≤ 𝑃(𝑇ଵ> 𝑧଴.଴଴ହ, 𝑇ଵ
௔> 𝑧଴.଴଴ହ) 
       + 𝑃(𝑇ଵ> 𝑧଴.଴଴ହ, 𝑇ଵ
௔≤𝑧଴.଴଴ହ, 𝑇ଶ
௔∗∗> 𝑧଴.଴ସ଻ଶ/ଶ) 
       + 𝑃(𝑇ଵ≤𝑧଴.଴଴ହ, 𝑇ଶ
∗> 𝑧଴.଴ସ଻ଶ/ଶ, 𝑇ଶ
௔∗> 𝑧଴.଴ସ଻ଶ/ଶ) 
≤𝑃(𝑇ଵ> 𝑧଴.଴଴ହ, 𝑇ଵ
௔> 𝑧଴.଴଴ହ)+ 𝑃(𝑇ଵ> 𝑧଴.଴଴ହ, 𝑇ଵ
௔≤𝑧଴.଴଴ହ, 𝑇ଶ
௔∗∗> 𝑧଴.଴ସ଻ଶ/ଶ) 
       + 𝑃(𝑇ଵ≤𝑧଴.଴଴ହ, 𝑇ଶ
௔∗> 𝑧଴.଴ସ଻ଶ/ଶ) 
= 𝑃(𝑇ଵ> 𝑧଴.଴଴ହ, 𝑇ଵ
௔> 𝑧଴.଴଴ହ)+ 𝑃(𝑇ଵ> 𝑧଴.଴଴ହ, 𝑇ଵ
௔≤𝑧଴.଴଴ହ, 𝑇ଶ
௔∗∗> 𝑧଴.଴ସ଻ଶ/ଶ) 
       + 𝑃(𝑇ଵ≤𝑧଴.଴଴ହ, 𝑇ଵ
௔> 𝑧଴.଴଴ହ, 𝑇ଶ
௔∗> 𝑧଴.଴ସ଻ଶ/ଶ) + 𝑃(𝑇ଵ≤𝑧଴.଴଴ହ, 𝑇ଵ
௔≤𝑧଴.଴଴ହ, 𝑇ଶ
௔∗> 𝑧଴.଴ସ଻ଶ/ଶ) 
≤𝑃(𝑇ଵ> 𝑧଴.଴଴ହ, 𝑇ଵ
௔> 𝑧଴.଴଴ହ)+ 𝑃(𝑇ଵ> 𝑧଴.଴଴ହ, 𝑇ଵ
௔≤𝑧଴.଴଴ହ, 𝑇ଶ
௔∗∗> 𝑧଴.଴ସ଻ଶ/ଶ) 


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       + 𝑃(𝑇ଵ≤𝑧଴.଴଴ହ, 𝑇ଵ
௔> 𝑧଴.଴଴ହ) + 𝑃(𝑇ଵ≤𝑧଴.଴଴ହ, 𝑇ଵ
௔≤𝑧଴.଴଴ହ, 𝑇ଶ
௔∗> 𝑧଴.଴ସ଻ଶ/ଶ) 
= 𝑃(𝑇ଵ
௔> 𝑧଴.଴଴ହ)+ 𝑃(𝑇ଵ> 𝑧଴.଴଴ହ, 𝑇ଵ
௔≤𝑧଴.଴଴ହ, 𝑇ଶ
௔∗∗> 𝑧଴.଴ସ଻ଶ/ଶ) 
       + 𝑃(𝑇ଵ≤𝑧଴.଴଴ହ, 𝑇ଵ
௔≤𝑧଴.଴଴ହ, 𝑇ଶ
௔∗> 𝑧଴.଴ସ଻ଶ/ଶ) 
       (following similar logic in (1)) = 0.005 + 𝑃(𝑇ଵ
௔≤𝑧଴.଴଴ହ , ඥ2/3𝑇ଵ
௔+ ඥ1/3𝑇> 𝑧଴.଴ସ଻ଶ/ଶ)  
       =0.025 
• Under partitioned parameter spaces 7 or 8 (with j=1 or 2),  
P (false rejection) = P (Reject 𝐻଴௝
ைோோ or 𝐻଴ଵ
௉ிௌ) 
= P (Reject 𝐻଴௝
ைோோ) + P (Reject 𝐻଴ଵ
௉ிௌ but do not reject 𝐻଴௝
ைோோ) 
≤ 0.0005 + 𝑃(𝑇ଵ> 𝑧଴.଴଴ହ, 𝑇ଵ
௔> 𝑧଴.଴଴ହ, 𝑍ଵ> 𝑧଴.଴ଵହ  ) 
+ 𝑃(𝑇ଵ> 𝑧଴.଴଴ହ, 𝑇ଵ
௔≤𝑧଴.଴଴ହ, 𝑇ଶ
௔∗∗> 𝑧0.0462/2, 𝑍ଶ
∗∗> 𝑧0.0323/2) 
+ 𝑃(𝑇ଵ≤𝑧଴.଴଴ହ, 𝑇ଶ
∗> 𝑧0.0462/2, 𝑇ଶ
௔∗> 𝑧0.0462/2, 𝑍ଶ
∗> 𝑧0.0323/2) 
≤ 0.0005 + 𝑃(𝑇ଵ> 𝑧଴.଴଴ହ, 𝑇ଵ
௔> 𝑧଴.଴଴ହ, 𝑍ଵ> 𝑧଴.଴ଵହ  ) 
+ 𝑃(𝑇ଵ> 𝑧଴.଴଴ହ, 𝑇ଵ
௔≤𝑧଴.଴଴ହ, 𝑇ଶ
௔∗∗> 𝑧0.0462/2, 𝑍ଶ
∗∗> 𝑧0.0323/2) 
+ 𝑃(𝑇ଵ≤𝑧଴.଴଴ହ,  𝑇ଶ
௔∗> 𝑧0.0462/2, 𝑍ଶ
∗> 𝑧0.0323/2) 
= 0.0005 + 𝑃(𝑇ଵ> 𝑧଴.଴଴ହ, 𝑇ଵ
௔> 𝑧଴.଴଴ହ, 𝑍ଵ> 𝑧଴.଴ଵହ  ) 
+ 𝑃(𝑇ଵ> 𝑧଴.଴଴ହ, 𝑇ଵ
௔≤𝑧଴.଴଴ହ, 𝑇ଶ
௔∗∗> 𝑧0.0462/2, 𝑍ଶ
∗∗> 𝑧0.0323/2) 
+ 𝑃(𝑇ଵ≤𝑧଴.଴଴ହ, 𝑇ଵ
௔> 𝑧଴.଴଴ହ, 𝑇ଶ
௔∗> 𝑧0.0462/2, 𝑍ଶ
∗> 𝑧0.0323/2) 
+ 𝑃(𝑇ଵ≤𝑧଴.଴଴ହ, 𝑇ଵ
௔≤𝑧଴.଴଴ହ, , 𝑇ଶ
௔∗> 𝑧0.0462/2, 𝑍ଶ
∗> 𝑧0.0323/2) 
≤ 0.0005 + 𝑃(𝑇ଵ> 𝑧଴.଴଴ହ, 𝑇ଵ
௔> 𝑧଴.଴଴ହ, 𝑍ଵ> 𝑧଴.଴ଵହ  ) 
+ 𝑃(𝑇ଵ> 𝑧଴.଴଴ହ, 𝑇ଵ
௔≤𝑧଴.଴଴ହ, 𝑍ଶ
∗∗> 𝑧0.0323/2) 
+ 𝑃(𝑇ଵ≤𝑧଴.଴଴ହ, 𝑇ଵ
௔> 𝑧଴.଴଴ହ, 𝑍ଶ
∗> 𝑧0.0323/2) 
+ 𝑃(𝑇ଵ≤𝑧଴.଴଴ହ, 𝑇ଵ
௔≤𝑧଴.଴଴ହ, 𝑍ଶ
∗> 𝑧0.0323/2) 
< 0.0005 + 𝑃൫𝑇ଵ> 𝑧଴.଴଴ହ, 𝑇ଵ
௔> 𝑧଴.଴଴ହ, (𝑍ଵ> 𝑧଴.଴ଵହ 𝑜𝑟 𝑍ଶ
∗∗> 𝑧0.0323/2)൯ 
+ 𝑃(𝑇ଵ> 𝑧଴.଴଴ହ, 𝑇ଵ
௔≤𝑧଴.଴଴ହ, (𝑍ଵ> 𝑧଴.଴ଵହ 𝑜𝑟 𝑍ଶ
∗∗> 𝑧0.0323/2)) 
+ 𝑃(𝑇ଵ≤𝑧଴.଴଴ହ, 𝑇ଵ
௔> 𝑧଴.଴଴ହ, (𝑍ଵ> 𝑧଴.଴ଵହ 𝑜𝑟 𝑍ଶ
∗> 𝑧0.0323/2)) 
+ 𝑃(𝑇ଵ≤𝑧଴.଴଴ହ, 𝑇ଵ
௔≤𝑧଴.଴଴ହ, (𝑍ଵ> 𝑧଴.଴ଵହ 𝑜𝑟 𝑍ଶ
∗> 𝑧0.0323/2)) 
= 0.0005+ 𝑃൫𝑇ଵ> 𝑧଴.଴଴ହ, (𝑍ଵ> 𝑧଴.଴ଵହ 𝑜𝑟 𝑍ଶ
∗∗> 𝑧0.0323/2)൯ 
+ 𝑃(𝑇ଵ≤𝑧଴.଴଴ହ, (𝑍ଵ> 𝑧଴.଴ଵହ 𝑜𝑟 𝑍ଶ
∗> 𝑧0.0323/2)) 


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(following similar logic in (1)) = 0.0005+ 𝑃൫𝑍ଵ> 𝑧଴.଴ଵହ 𝑜𝑟ඥ2/3𝑍ଵ+ ඥ1/3𝑇> 𝑧0.0323/2൯ 
=0.025 
• Under partitioned parameter spaces 9, 10, 11, or 12 the false rejection rate is controlled by 
similar arguments as shown for partitioned parameter space 7 or 8. 
• Under partitioned parameter spaces 13 or 14 (with j=1 or 2), 
P (False rejection) = P (Reject 𝐻଴௝
ைோோ) = 0.0005 < 0.025 
15.4 
Time-to onset and time-to resolution definition and conventions for select adverse 
events, immune-mediated adverse events and other AEs of interest for NKTR-214 
15.4.1 
Time-to onset definition 
Time-to onset of AE (any grade) for a specific category is defined as the time between the day of 
the first dose of study treatment and the onset date of the earliest AE (of any grade) in this 
category. 
The time-to onset of AE (grade 3-5) for a specific category is defined similarly with an onset 
date corresponding to a grade 3-5 AE. 
Time-to onset of drug-related AE (any grade or grade 3-5) for a specific category is defined 
similarly but restricted to drug-related AE. 
Time-to onset for a specific subcategory is defined similarly but restricted to event of this 
subcategory. 
15.4.2 
Time-to resolution definition 
In order to derive the time-to resolution, overlapping or contiguous AEs within a specific 
category or subcategory will be collapsed into what will be termed “clustered” AEs. For 
example, if a patient (without pre-treatment AE) experienced an AE from 1st to 5th January, 
another AE (with different PT but within same category) from 6th to 11th January and same AE 
from 10th to 12th January, these will be collapsed into one clustered AE from 1st to 12th January. 
Table 8 is summarizing key derivation steps for each type of clustered AEs. 
Time-to resolution of AE (any grade) for a specific category is defined as the longest time from 
onset to complete resolution or improvement to the grade at baseline among all clustered AEs 
experienced by the patient in this category per adverse event criteria category. Events which 
worsened into grade 5 events (death) or have a resolution date equal to the date of death are 
considered unresolved. If a clustered AE is considered as unresolved, the resolution date will be 
censored to the last known alive date. Improvement to the grade at baseline implies that all 
different events in the clustered adverse event should at least have improved to the corresponding 


Protocol 17-214-09 Statistical Analysis Plan 
 
bempegaldeskeukin (NKTR-214) and nivolumab 
Nektar Therapeutics 
 
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Confidential and Proprietary 
 
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(i.e. with same preferred term) baseline grade. This measure is defined only for patients who 
experienced at least one AE in the specific category. 
The time-to resolution of AE (grade 3-5) for a specific category is defined similarly with an 
onset date corresponding to a grade 3-5 AE. 
Time-to resolution of drug-related AE (any grade or grade 3-5) for a specific category is defined 
similarly but restricted to drug-related AE. 
The time-to resolution of AE (any grade or grade 3-5, drug-related or all) where immune 
modulating medication was initiated is defined similarly. For data presentation not restricted to 
IMAE, the additional condition that the patient started an immune modulating medication during 
the longest AE resolution period will be applied. 
Time-to resolution for a specific subcategory is defined similarly but restricted to event of this 
subcategory. 
Table 8: 
Derivation of Clustered AE 
Type of clustered AE 
Derivation 
Any grade 
Collapse any on-treatment AE from the same category 
Drug-related of any grade 
Collapse any on-treatment drug-related 
AE from the same category 
Grade 3-5 
Collapse any on-treatment AE from the same category. 
Resolution will be based on the onset date of the earliest grade 
3-5 records (if no grade 3-5 record, clustered AE is excluded) 
Drug-related of Grade 3-5 
Collapse any on-treatment drug-related AE from the same 
category 
Resolution will be based on the onset date of  the earliest grade 
3-5 record (if no Grade 3-5 record, clustered AE is excluded) 
 
The algorithm for collapsing adverse event records is using the following conventions: 
For each patient and specified category, the corresponding adverse event records will be 
collapsed when: 
1) Multiple adverse event records have the same onset date. 
2) The onset date of an event record is either the same day or 1 day later than the resolution date 
of a preceding event record (contiguous events). 
3) The onset date of an event record is after the onset date and prior to or on the resolution date 
of a preceding event record (overlapping events).