Conditions: Metastatic Urothelial Carcinoma Unresectable Urothelial Carcinoma
Keywords: Urothelial carcinoma fibroblast growth factor receptor (FGFR) inhibitor FGFR3 mutation FGFR3 rearrangement metastatic unresectable cisplatin-ineligible
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 7
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the safety and efficacy of pemigatinib plus pembrolizumab or pemigatinib alone versus the standard of care for participants with metastatic or unresectable urothelial carcinoma who are not eligible to receive cisplatin, are harboring FGFR3 mutation or rearrangement, and who have not received prior treatment.

Detailed description:

Arms:
arm 1: Combination of pemigatinib (13.5 milligrams \[mg\] once a day orally) plus pembrolizumab (200 mg every 3 weeks \[Q3W\] intravenously \[IV\]) arm 2: Pemigatinib (13.5 mg once a day orally) alone arm 3: Either gemcitabine plus carboplatin or pembrolizumab as standard of care. Gemcitabine 1000 mg/meters squared (m\^2) IV over 30 minutes on Days 1 and 8, followed by carboplatin (dosed to target area under the concentration-time curve \[AUC\] of 5 mg/milliliters \[mL\]/minute \[min\] or 4.5 mg/mL/min if required per local guidelines) on Day 1 or 2 of each 3-week cycle. Pembrolizumab 200 mg IV on Day 1 of each 21-day treatment cycle for up to 35 cycles or disease progression.

Interventions: intervention 1: Pemigatinib intervention 2: Pembrolizumab intervention 3: Gemcitabine intervention 4: Carboplatin
Intervention descriptions: intervention 1: 13.5 mg once a day orally intervention 2: 200 mg Q3W intravenously intervention 3: 1000 mg/m\^2 IV over 30 minutes on Days 1 and 8 of each 3-week cycle intervention 4: Dosed to target AUC of 5 mg/mL/min or 4.5 mg/mL/min if required per local guidelines on Day 1 or 2 of each 3-week cycle

Protocol document:
Prot_000.pdf: 
Official Title: 
NCT Number: 
NCT04003610
Document Date: 
Clinical Study Protocol Version 2: 17 April 2020 
A Phase 2, Open-Label, Randomized, Multicenter Study to Evaluate the Efficacy and 
Safety of Pemigatinib Plus Pembrolizumab Versus Pemigatinib Alone Versus 
Standard of Care as First-Line Treatment for Metastatic or Unresectable Urothelial 
Carcinoma in Cisplatin-Ineligible Participants Whose Tumors Express FGFR3 
Mutation or Rearrangement (FIGHT-205)


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Clinical Study Protocol 
INCB 54828-205 
A Phase 2, Open-Label, Randomized, Multicenter Study to Evaluate the 
Efficacy and Safety of Pemigatinib Plus Pembrolizumab Versus 
Pemigatinib Alone Versus Standard of Care as First-Line Treatment for 
Metastatic or Unresectable Urothelial Carcinoma in Cisplatin-Ineligible 
Participants Whose Tumors Express FGFR3 Mutation or Rearrangement 
(FIGHT-205) 
Product: 
INCB054828 (pemigatinib) 
IND Number: 
124,358 
EudraCT Number: 
2019‐000721‐50 
Phase of Study: 
2 
Sponsor: 
Incyte Corporation 
1801 Augustine Cut-Off 
Wilmington, DE 19803 
Original Protocol: 
11 JUN 2019 
Amendment 1: 
17 APR 2020 
This study will be performed in accordance with ethical principles that have their origin in the Declaration of 
Helsinki and conducted in adherence to the study Protocol, applicable Good Clinical Practices, and applicable laws 
and country-specific regulations in which the study is being conducted. 
The information in this document is confidential.  No part of this information may be duplicated, referenced, or 
transmitted in any form or by any means (electronic, mechanical, photocopy, recording, or otherwise) without prior 
written consent. 


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INVESTIGATOR'S AGREEMENT 
I have read the INCB 54828-205 Protocol Amendment 1 (dated 17 APR 2020) and agree to 
conduct the study as outlined.  I agree to maintain the confidentiality of all information received 
or developed in connection with this Protocol. 
 
 
 
 
 
(Printed Name of Investigator) 
 
 
 
 
 
 
 
 
(Signature of Investigator) 
 
(Date) 


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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ..........................................................................................................9 
1. 
PROTOCOL SUMMARY ..........................................................................................13 
2. 
INTRODUCTION ......................................................................................................23 
2.1. 
Background .................................................................................................................23 
2.1.1. 
Fibroblast Growth Factor Receptor Inhibition in Oncology .......................................23 
2.1.2. 
Overview and Treatment of Urothelial Carcinoma ....................................................25 
2.2. 
Study Rationale ...........................................................................................................27 
2.2.1. 
Scientific Rationale for Study Design ........................................................................27 
2.2.2. 
Justification for Dose and Schedule ...........................................................................28 
2.2.2.1. 
Pemigatinib .................................................................................................................28 
2.2.2.2. 
Pembrolizumab ...........................................................................................................29 
2.2.2.3. 
Gemcitabine and Carboplatin .....................................................................................30 
2.2.2.4. 
Combination of Pemigatinib and Pembrolizumab ......................................................31 
2.3. 
Benefit/Risk Assessment ............................................................................................32 
2.3.1. 
Benefit/Risk of Pemigatinib .......................................................................................33 
2.3.2. 
Benefit/Risk of Pembrolizumab .................................................................................33 
2.3.3. 
Benefit/Risk of Combination of Pemigatinib and Pembrolizumab ............................33 
3. 
OBJECTIVES AND ENDPOINTS ............................................................................34 
4. 
STUDY DESIGN .......................................................................................................35 
4.1. 
Overall Design ............................................................................................................35 
4.2. 
Overall Study Duration ...............................................................................................36 
4.3. 
Study Termination ......................................................................................................36 
5. 
STUDY POPULATION .............................................................................................37 
5.1. 
Inclusion Criteria ........................................................................................................37 
5.2. 
Exclusion Criteria .......................................................................................................40 
5.3. 
Lifestyle Considerations .............................................................................................44 
5.3.1. 
Meals and Dietary Restrictions ...................................................................................44 
5.4. 
Screen Failures ............................................................................................................44 
5.5. 
Replacement of Participants .......................................................................................44 
6. 
STUDY TREATMENT ..............................................................................................45 
6.1. 
Study Treatments Administered .................................................................................45 


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6.2. 
Phosphate Binders in Japan ........................................................................................46 
6.3. 
Preparation, Handling, and Accountability ................................................................46 
6.4. 
Measures to Minimize Bias:  Randomization and Blinding .......................................47 
6.4.1. 
Stratification ...............................................................................................................48 
6.4.1.1. 
PD-L1 CPS Results.....................................................................................................48 
6.5. 
Study Treatment Compliance .....................................................................................48 
6.6. 
Dose Modifications .....................................................................................................49 
6.6.1. 
Criteria and Procedures for Dose Interruptions and Adjustments of 
Pemigatinib .................................................................................................................49 
6.6.2. 
Management of Hyperphosphatemia ..........................................................................50 
6.6.2.1. 
Up-Titration ................................................................................................................51 
6.6.3. 
Criteria for Permanent Discontinuation of Pemigatinib .............................................52 
6.6.4. 
Criteria for Procedures for Doses Interruptions or Adjustments of 
Pembrolizumab, Gemcitabine, and Carboplatin .........................................................52 
6.7. 
Concomitant Medications and Procedures .................................................................52 
6.7.1. 
Restricted Medications and Procedures ......................................................................52 
6.7.2. 
Prohibited Medications and Procedures .....................................................................53 
6.7.2.1. 
Prohibited Medications and Procedures for Pemigatinib ...........................................53 
6.7.2.2. 
Prohibited Medications and Procedures for Pembrolizumab, Gemcitabine, 
and Carboplatin ...........................................................................................................53 
6.7.3. 
Permitted Medications and Procedures ......................................................................54 
6.7.3.1. 
Rescue Medications and Supportive Care for Pembrolizumab ..................................54 
6.8. 
Treatment After the End of the Study .........................................................................55 
7. 
DISCONTINUATION OF STUDY TREATMENT AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ..................................................................55 
7.1. 
Discontinuation of Study Treatment ...........................................................................55 
7.1.1. 
Reasons for Discontinuation .......................................................................................55 
7.1.2. 
Discontinuation Procedures ........................................................................................56 
7.2. 
Participant Withdrawal From the Study .....................................................................57 
7.3. 
Lost to Follow-Up.......................................................................................................57 
8. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................58 
8.1. 
Administrative and General Procedures .....................................................................58 
8.1.1. 
Informed Consent Process ..........................................................................................58 
8.1.2. 
Prescreening and Screening Procedures .....................................................................59 


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8.1.3. 
Interactive Response Technology Procedure ..............................................................59 
8.1.4. 
Distribution of Reminder Cards ..................................................................................60 
8.1.5. 
Demography and Medical History ..............................................................................60 
8.1.5.1. 
Demographics and General Medical History .............................................................60 
8.1.5.2. 
Disease Characteristics and Treatment History ..........................................................60 
8.2. 
Efficacy Assessments .................................................................................................60 
8.2.1. 
Tumor Imaging ...........................................................................................................60 
8.2.1.1. 
Initial Tumor Imaging .................................................................................................61 
8.2.2. 
Tumor Imaging During the Study...............................................................................61 
8.2.2.1. 
End of Treatment and Follow-Up Tumor Imaging .....................................................62 
8.2.3. 
ECOG Performance Status .........................................................................................62 
8.3. 
Quality of Life Assessments .......................................................................................63 
8.3.1. 
EORTC QLQ-C30 ......................................................................................................63 
8.3.2. 
EQ-5D-5L ...................................................................................................................63 
 
63 
8.5. 
Safety Assessments .....................................................................................................64 
8.5.1. 
Adverse Events ...........................................................................................................64 
8.5.2. 
Physical Examinations ................................................................................................64 
8.5.3. 
Vital Signs ..................................................................................................................65 
8.5.4. 
Electrocardiograms .....................................................................................................65 
8.5.5. 
Comprehensive Eye Examination...............................................................................65 
8.5.6. 
Laboratory Assessments .............................................................................................65 
8.5.6.1. 
Pregnancy Testing ......................................................................................................68 
8.5.6.2. 
Serology ......................................................................................................................68 
 
68 
 
69 
8.7.1. 
Tumor Tissue Collection and Requirements ..............................................................69 
8.7.1.1. 
Tumor For Genomics Testing for FGFR Genetic Alterations and Gene 
Expression ...................................................................................................................69 
8.7.1.2. 
Tumor Tissue Collection for Testing PD-L1 Expression ...........................................69 
 
70 
 
71 
 
71 


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71 
 
71 
8.8. 
Unscheduled Visits .....................................................................................................71 
8.9. 
End of Treatment and/or Early Termination ..............................................................71 
8.10. 
Follow-Up ...................................................................................................................72 
8.10.1. 
Safety Follow-Up ........................................................................................................72 
8.10.2. 
Post-Treatment Disease Follow-Up ............................................................................72 
8.10.3. 
Survival Follow-Up ....................................................................................................72 
9. 
ADVERSE EVENTS:  DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING ......................73 
9.1. 
Definition of Adverse Event .......................................................................................73 
9.2. 
Definition of Serious Adverse Event ..........................................................................74 
9.3. 
Recording and Follow-Up of Adverse Events and/or Serious Adverse Events .........75 
9.4. 
Reporting of Serious Adverse Events .........................................................................77 
9.5. 
Adverse Events of Special Interest .............................................................................79 
9.6. 
Emergency Unblinding of Treatment Assignment .....................................................79 
9.7. 
Pregnancy ...................................................................................................................79 
9.8. 
Warnings and Precautions ..........................................................................................79 
9.9. 
Product Complaints ....................................................................................................80 
9.10. 
Treatment of Overdose ...............................................................................................80 
10. 
STATISTICS ..............................................................................................................81 
10.1. 
Sample Size Determination ........................................................................................81 
10.2. 
Populations for Analysis .............................................................................................82 
10.3. 
Level of Significance ..................................................................................................83 
10.4. 
Statistical Analyses .....................................................................................................83 
10.4.1. 
Primary Analysis ........................................................................................................83 
10.4.2. 
Secondary Analysis ....................................................................................................84 
10.4.3. 
Safety Analyses ..........................................................................................................84 
 
85 
10.5. 
Futility Analysis..........................................................................................................85 
10.6. 
Data Monitoring Committee .......................................................................................85 
11. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ..................................................................................................86 


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11.1. 
Investigator Responsibilities .......................................................................................86 
11.2. 
Data Management .......................................................................................................87 
11.3. 
Data Privacy and Confidentiality of Study Records ...................................................88 
11.4. 
Financial Disclosure ...................................................................................................89 
11.5. 
Publication Policy .......................................................................................................89 
11.6. 
Study and Site Closure................................................................................................90 
12. 
REFERENCES ...........................................................................................................91 
APPENDIX A. INFORMATION REGARDING EFFECTIVENESS OF 
CONTRACEPTIVE METHODS ...............................................................................95 
APPENDIX B. PEMBROLIZUMAB DOSE MODIFICATIONS .............................................96 
APPENDIX C. INSTRUCTION TO PARTICIPANTS FOR HANDLING STUDY 
DRUG (PEMIGATINIB) .........................................................................................101 
APPENDIX D. CYP3A4 INHIBITORS AND INDUCERS ....................................................102 
APPENDIX E. FGFR3 GENE ALTERATIONS .....................................................................105 
APPENDIX F. PROTOCOL AMENDMENT SUMMARY OF CHANGES ..........................106 
 


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LIST OF TABLES 
Table 1: 
Primary Objective and Endpoint ................................................................................13 
Table 2: 
Key Study Design Elements .......................................................................................14 
Table 3: 
Treatment Groups for Randomization ........................................................................14 
Table 4: 
Schedule of Activities .................................................................................................17 
Table 5: 
Schedule of Pharmacokinetic and Pharmacodynamic Assessments ..........................22 
Table 6: 
Pharmacokinetic Parameters of Pemigatinib Monotherapy and in 
Combination With Pembrolizumab ............................................................................32 
Table 7: 
Objectives and Endpoints ...........................................................................................34 
Table 8: 
Treatment Groups for Randomization ........................................................................35 
Table 9: 
Exclusionary Laboratory Values ................................................................................41 
Table 10: Study Treatment Information .....................................................................................45 
Table 11: Study Treatment 2 (Phosphate Binders for Japan) .....................................................46 
Table 12: Guidelines for Interruption and Restarting Pemigatinib .............................................50 
Table 13: Recommended Approach for Hyperphosphatemia Management ...............................51 
Table 14: ECOG Performance Status .........................................................................................62 
Table 15: Required Laboratory Analytes ....................................................................................67 
68 
71 
Table 18: Median Progression-Free Survival Assumptions for Standard of Care 
Treatments ..................................................................................................................81 
Table 19: Populations for Analysis .............................................................................................82 
 
LIST OF FIGURES 
Figure 1: 
Study Design Schema .................................................................................................16 
 
70 
 


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LIST OF ABBREVIATIONS 
Abbreviations and 
Special Terms 
Definition 
5-FU 
fluorouracil 
AE 
adverse event 
AESI 
adverse event of special interest 
AIDS 
acquired immunodeficiency syndrome 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
aPTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
AUC 
area under the plasma or serum concentration-time curve 
AUC0-τ 
area under the steady-state plasma or serum concentration-time curve over 1 dose 
interval 
BICR 
blinded independent central review 
CBC 
complete blood count 
 
 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CLss/F 
apparent oral dose clearance at steady state 
Cmax 
maximum observed plasma or serum concentration 
Cmin 
minimum observed plasma or serum concentration over the dose interval 
CNS 
central nervous system 
CPS 
combined positive score 
CR 
complete response  
CrCl 
creatinine clearance 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
DDI 
drug-drug interaction 
DMC 
Data Monitoring Committee 
DNA 
deoxyribonucleic acid 
DOR 
duration of response 
EAU 
European Association of Urology 
ECG 
electrocardiogram 


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Abbreviations and 
Special Terms 
Definition 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EDC 
electronic data capture 
Emax 
maximum effect 
EORTC 
European Organization for the Research and Treatment of Cancer 
EORTC QLQ-C30 
European Organization for the Research and Treatment of Cancer Core Quality 
of Life Questionnaire 
EOT 
end of treatment 
EQ-5D-5L 
5-level version of EuroQol-5D 
FDA 
Food and Drug Administration 
FFPE 
formalin-fixed paraffin-embedded 
FGF 
fibroblast growth factor 
FGFR 
fibroblast growth factor receptor 
GCP 
Good Clinical Practice 
GDPR 
General Data Protection Regulation 
GFR 
glomerular filtration rate 
GI 
gastrointestinal 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
HIV 
human immunodeficiency virus 
HR 
hazard ratio 
IB 
Investigator's Brochure 
ICF 
informed consent form  
ICH 
International Council on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
ICR 
independent central review 
IEC 
independent ethics committee 
IgH 
immunoglobulin H 
IHC 
immunohistochemistry 
INR 
international normalized ratio 
irAE 
immune-related adverse event 
IRB 
institutional review board 
IRT 
interactive response technology 
ITT 
intent-to-treat 


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Abbreviations and 
Special Terms 
Definition 
IV 
intravenously 
LN 
lymph node 
MedDRA 
Medical Dictionary for Regulatory Activities 
MIBC 
muscle-invasive bladder cancer 
MRI 
magnetic resonance imaging 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
NMIBC 
nonmuscle-invasive bladder cancer 
NNRTI 
non-nucleoside reverse transcriptase inhibitor 
NSAID 
nonsteroidal anti-inflammatory drug 
NSCLC 
non–small-cell lung cancer 
OCT 
optical coherence tomography 
OCT2 
organic cation transporter 2 
ORR 
objective response rate 
OS 
overall survival 
PBPK 
physiologically-based pharmacokinetic 
PD 
progressive disease 
PD-1 
programmed cell death protein 1 
PD-L1 
programmed cell death ligand 1 
PD-L2 
programmed cell death ligand 2 
PFS 
progression-free survival 
PK 
pharmacokinetic 
PO 
orally 
PP 
per protocol 
PR 
partial response  
PSA 
prostate-specific antigen 
PT 
prothrombin time 
PTT 
partial thromboplastin time 
QD 
once daily 
QXW 
every X weeks 
RECIST v1.1 
Response Evaluation Criteria in Solid Tumors version 1.1 
RNA 
ribonucleic acid 
RPED 
retinal pigmented epithelium detachment 
SAE 
serious adverse event 
SD 
standard deviation 


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Abbreviations and 
Special Terms 
Definition 
SmPC 
Summary of Product Characteristics 
SOC 
standard of care 
SRD 
serous retinal detachment 
t½  
apparent terminal-phase disposition half-life 
T1DM 
type 1 diabetes mellitus 
TCC 
transitional cell carcinoma 
TEAE 
treatment-emergent adverse event 
tmax 
time to maximum concentration 
TSH 
thyroid-stimulating hormone 
UC 
urothelial carcinoma 
ULN 
upper limit of normal 
Vz/F 
apparent oral dose volume of distribution 
WBC 
white blood cell 


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1. 
PROTOCOL SUMMARY 
Protocol Title:  A Phase 2, Open-Label, Randomized, Multicenter Study to Evaluate the 
Efficacy and Safety of Pemigatinib Plus Pembrolizumab Versus Pemigatinib Alone Versus 
Standard of Care as First-Line Treatment for Metastatic or Unresectable Urothelial Carcinoma in 
Cisplatin-Ineligible Participants Whose Tumors Express FGFR3 Mutation or Rearrangement 
(FIGHT-205) 
Protocol Number:  INCB 54828-205 
Objectives and Endpoints: 
Table 1 presents the primary objective and endpoint. 
Table 1: 
Primary Objective and Endpoint 
Objective 
Endpoint 
Primary 
To evaluate and compare PFS in participants treated 
with pemigatinib in combination with pembrolizumab 
(Treatment Group A) and pemigatinib alone (Treatment 
Group B) versus SOC (Treatment Group C). 
Differences in PFS will be evaluated hierarchically, and 
the comparison between pemigatinib in combination 
with pembrolizumab (Treatment Group A) and SOC 
(Treatment Group C) will be evaluated first, and if 
significant difference is detected, a second comparison 
will be made in PFS between pemigatinib alone 
(Treatment Group B) and SOC (Treatment Group C). 
Hypothesis:  The combination of pembrolizumab plus 
pemigatinib has superior PFS as compared with SOC.  
Contribution of pemigatinib alone to combination will 
be assessed by comparing Treatment Groups A and C 
and Treatment Groups B and C. 
Progression-free survival, defined as the time from 
randomization date until the date of disease progression 
(as measured by BICR per RECIST v1.1) or death due to 
any cause, whichever occurs first. 
Overall Design: 
Table 2 presents the key study design elements.  Further study details are presented after the 
table. 


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Table 2: 
Key Study Design Elements 
Study Phase 
Phase 2 
Clinical Indication 
The treatment of UC in patients who are ineligible to receive cisplatin and whose tumors 
have an FGFR3 mutation or rearrangement 
Population 
Male and female participants at least 18 years of age who have untreated metastatic or 
unresectable UC. 
Number of 
Participants 
Approximately 372 participants will be randomized 1:1:1 to 1 of the following 
3 treatment groups (124 participants per group): 
• Treatment Group A:  Pemigatinib + pembrolizumab 
• Treatment Group B:  Pemigatinib 
• Treatment Group C:  SOC (gemcitabine/carboplatin or pembrolizumab) 
Study Design 
Active-controlled, open-label, and randomized.  Randomization will occur after the 
participant has completed screening.  Participants will be stratified by eligible to receive 
carboplatin vs not eligible to receive carboplatin, PD-L1 CPS ≥ 10 vs CPS < 10, and 
LN-only disease versus other metastatic disease.  This is an event-driven clinical study 
designed to ensure power to detect success of the primary endpoint of PFS.  A total of 
210 PFS events in the combined treatment groups of pemigatinib plus pembrolizumab 
and SOC are needed. 
Estimated Duration of 
Study Participation 
Up to 35 days for screening followed by continuous treatment in consecutive 21-day 
cycles as long as participants are receiving benefit and have not met any criteria for study 
withdrawal, and at least 30 days after the last dose of study treatment for follow-up.  
Participants who receive pembrolizumab may receive up to 35 cycles of pembrolizumab 
(approximately 2 years).  Participants who receive pemigatinib may receive treatment 
until disease progression.  Participants who receive carboplatin and gemcitabine may 
receive 4 to 6 cycles.  The safety follow-up visit is 30 days after the last dose of study 
treatment.  Report SAEs occurring within 90 days after the last dose of study treatment 
or within 30 days after the last dose of study treatment when starting a new anticancer 
therapy, whichever is earlier.  It is estimated that an individual will participate for 
approximately 18 months. 
DMC 
Yes (internal and external) 
Treatment Groups and Duration: 
Table 3: 
Treatment Groups for Randomization 
Treatment 
Group 
Regimen 
A 
Pemigatinib 13.5 mg QD POa until PD + pembrolizumab 200 mg Q3W IV up to 35 cycles 
(approximately 2 years) or PD, whichever occurs first 
B 
Pemigatinib 13.5 mg QD POa until PD 
C 
One of 2 SOC treatment options: 
1. Gemcitabine 1000 mg/m2 Q3W IV on Days 1 and 8 + carboplatin AUC 5 (or AUC 4.5 if 
required per local guidelines) Q3W on Day 1 or 2 for 4 to 6 cycles.  (Participants whose 
tumors express PD-L1 CPS < 10 who are eligible to receive carboplatin.)  
OR 
2. Pembrolizumab 200 mg Q3W IV up to 35 cycles (approximately 2 years).  (Participants 
whose tumors express PD-L1 CPS ≥ 10 or participants who are not considered eligible to 
receive any platinum-containing chemotherapy regardless of PD-L1 expression status [only 
applicable in regions where pembrolizumab is used as SOC for participants who are not 
eligible for any platinum-containing chemotherapy regardless of PD-L1 status].)  
a Participants not reaching the target serum phosphate during Cycle 1 will increase the daily dose to 18 mg starting at Cycle 2 as 
described in Section 6.6.2.1. 


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Figure 1 presents the study design schema. 
Adherence to the study design requirements, including those specified in the schedule of 
activities, is essential and required for study conduct.  All study assessments will be performed 
as indicated in the schedule of activities (see Table 4), and all laboratory assessments will be 
performed as indicated in Table 5.  Table 15 presents a summary of clinical laboratory analytes 
to be assessed.  The order of assessments is suggested by the order of mention within the 
schedule.  See Section 8 for instructions on each assessment.  Further details of study procedures 
and assessments can be found in the study reference manual. 




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Table 4: 
Schedule of Activities 
Visit Day (Range) 
Prescreening 
Screening 
Treatment 
Post-Treatment 
Notes 
Days 
-35 to -1 
Cycle 1 
Cycle 2+ 
EOT 
Safety 
Follow-
Up 
Post-
Treatment 
Follow-Up 
Survival 
Follow-Up 
Day 1 
(± 3 d) 
Day 8  
(± 3 d) 
Day 15  
(± 3 d) 
Day 1  
(± 3 d) 
Day 8 
(± 3 d) 
At 
Treatment 
Discon 
30 d 
(± 5 d) 
Same 
Disease 
Assessment 
(± 7 d) 
Every 
12 Weeks 
(± 14 d) 
Administrative Procedures 
FGFR3 tissue 
genomic testing 
X* 
X* 
 
 
 
 
 
 
 
 
 
*Participants can be randomized 
based on local genomics testing if 
available, but confirmation via 
central laboratory is required.  
Assess in prescreening or 
screening only.  Section 8.7  
Tumor tissue testing 
for PD-L1 
expression (CPS) 
X* 
X* 
 
 
 
 
 
 
 
 
 
*Participants can be randomized 
based on local testing, if 
available, but confirmation via 
central laboratory is required.  
Assess in prescreening or 
screening only.  Section 8.7. 
Prescreening 
informed consent 
X* 
 
 
 
 
 
 
 
 
 
 
*For FGFR3 and PD-L1 testing if 
needed.  Section 8.1.2  
Main informed 
consent 
 
X 
 
 
 
 
 
 
 
 
 
Signed before any Protocol-
specific screening procedures are 
performed.  Section 8.1.1 
Contact IRT 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
 
Section 8.1.3 
Inclusion/exclusion 
criteria 
 
X 
X 
 
 
 
 
 
 
 
 
Sections 5.1 and 5.2 
General and disease 
medical history 
 
X 
 
 
 
 
 
 
 
 
 
Section 8.1.5 
Prior/concomitant 
medications 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Section 6.7 
Dispense 
pemigatinib 
 
 
X 
 
 
X* 
 
 
 
 
 
*Assessments for up-titration will 
be conducted during Cycle 1. 
First possibility to up-titrate a 
participant is at C2D1.  
Section 6.6.2.1  


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Table 4: 
Schedule of Activities (Continued) 
Visit Day (Range) 
Prescreening 
Screening 
Treatment 
Post-Treatment 
Notes 
Days 
-35 to -1 
Cycle 1 
Cycle 2+ 
EOT 
Safety 
Follow-
Up 
Post-
Treatment 
Follow-Up 
Survival 
Follow-Up 
Day 1 
(± 3 d) 
Day 8  
(± 3 d) 
Day 15  
(± 3 d) 
Day 1  
(± 3 d) 
Day 8 
(± 3 d) 
At 
Treatment 
Discon 
30 d 
(± 5 d) 
Same 
Disease 
Assessment 
(± 7 d) 
Every 
12 Weeks 
(± 14 d) 
Administer 
pembrolizumab 
 
 
X* 
 
 
X* 
 
 
 
 
 
*Administered Q3W.  Section 6.1 
Administer 
gemcitabine 
 
 
X 
X 
 
X* 
X* 
 
 
 
 
*Days 1 and 8 of each cycle for 
up to 6 cycles (minimum of 
4 cycles) in the absence of 
progression or per institutional 
standards.  Section 6.1 
Administer 
carboplatin 
 
 
X* 
 
 
X* 
 
 
 
 
 
*Day 1 (or 2) for up to 6 cycles 
(minimum of 4 cycles) in the 
absence of progression or per 
institutional standards.  
Section 6.1 
Distribute reminder 
cards  
 
 
X 
X 
X 
X 
X* 
 
 
 
 
*Only participants scheduled to 
receive chemotherapy.  
Section 8.1.4  


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Table 4: 
Schedule of Activities (Continued) 
Visit Day (Range) 
Prescreening 
Screening 
Treatment 
Post-Treatment 
Notes 
Days 
-35 to -1 
Cycle 1 
Cycle 2+ 
EOT 
Safety 
Follow-
Up 
Post-
Treatment 
Follow-Up 
Survival 
Follow-Up 
Day 1 
(± 3 d) 
Day 8  
(± 3 d) 
Day 15  
(± 3 d) 
Day 1  
(± 3 d) 
Day 8 
(± 3 d) 
At 
Treatment 
Discon 
30 d 
(± 5 d) 
Same 
Disease 
Assessment 
(± 7 d) 
Every 
12 Weeks 
(± 14 d) 
Safety Assessments 
AE assessments* 
 
X 
X 
X 
X 
X 
X** 
X 
X 
X 
 
*Body systems with symptoms 
should be physically examined. 
**Only participants scheduled to 
receive chemotherapy.  
Section 8.5.1 
Full physical 
examination 
 
X 
 
 
 
X* 
 
 
X 
X* 
 
*Targeted examination.  
Section 8.5.2  
Vital signs/body 
weight/height 
 
X* 
X 
X 
X 
X 
X** 
X 
X 
 
 
*Height at screening only. 
**Only participants scheduled to 
receive chemotherapy.  
Section 8.5.3 
12-lead ECG 
 
X 
 
 
 
X* 
 
X 
X 
 
 
*Prior to receipt of study drugs on 
C2D1 and C4D1 and every 
3 cycles thereafter (ie, C7, C10, 
C13, etc).  Section 8.5.4  
Slit lamp, visual 
acuity, funduscopy 
with digital imaging 
and optical 
coherence 
tomography 
 
X 
 
 
 
X* 
 
X 
 
 
 
*Performed every 3 cycles 
(± 7 days) starting with Cycle 3 
and/or as clinically indicated.  
Treatment Groups A and B only.  
Section 8.5.5  


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Table 4: 
Schedule of Activities (Continued) 
Visit Day (Range) 
Prescreening 
Screening 
Treatment 
Post-Treatment 
Notes 
Days 
-35 to -1 
Cycle 1 
Cycle 2+ 
EOT 
Safety 
Follow-
Up 
Post-
Treatment 
Follow-Up 
Survival 
Follow-Up 
Day 1 
(± 3 d) 
Day 8  
(± 3 d) 
Day 15  
(± 3 d) 
Day 1  
(± 3 d) 
Day 8 
(± 3 d) 
At 
Treatment 
Discon 
30 d 
(± 5 d) 
Same 
Disease 
Assessment 
(± 7 d) 
Every 
12 Weeks 
(± 14 d) 
Efficacy Assessments 
CT of the chest, 
CT or MRI of the 
abdomen, and 
pelvis.* 
 
X 
 
 
 
X** 
 
X 
 
X** 
 
*The same modality should be 
used for all scans.   
**Q9W (± 7 days) from date of 
randomization starting at the end 
of Cycle 3 through Week 54 and 
then Q12W (± 7 days; ie, 
Week 66, Week 78, etc) until 
EOT (if applicable).  Follow same 
schedule if treatment is 
discontinued for reason other than 
disease progression.  Sections 8.2 
and 8.10.2 
Bone scan and brain 
imaging 
 
X* 
 
 
 
X** 
 
X** 
 
X** 
 
* Required at baseline within 
35 days prior to randomization if 
participant has clinical symptoms 
of bone or brain metastases. 
**If positive at baseline, follow 
same schedule as CT/MRI.  
During follow-up, can be done 
per SOC.  Follow same schedule 
if treatment is discontinued for 
reason other than disease 
progression.  Section 8.2.1 and 
8.10.2  
ECOG 
 
X 
X 
 
 
X 
 
X 
X 
X 
 
Section 8.2.3  
Survival 
 
 
 
 
 
 
 
 
 
 
X 
Section 8.10.3 
Quality of Life Assessments 
EORTC QLQ-C30 
and EQ-5D-5L 
 
X 
 
 
 
X* 
 
 
X 
 
 
*Every 3 cycles on Day 1 starting 
on Cycle 4.  Section 8.3  


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Table 4: 
Schedule of Activities (Continued) 
Visit Day (Range) 
Prescreening 
Screening 
Treatment 
Post-Treatment 
Notes 
Days 
-35 to -1 
Cycle 1 
Cycle 2+ 
EOT 
Safety 
Follow-
Up 
Post-
Treatment 
Follow-Up 
Survival 
Follow-Up 
Day 1 
(± 3 d) 
Day 8  
(± 3 d) 
Day 15  
(± 3 d) 
Day 1  
(± 3 d) 
Day 8 
(± 3 d) 
At 
Treatment 
Discon 
30 d 
(± 5 d) 
Same 
Disease 
Assessment 
(± 7 d) 
Every 
12 Weeks 
(± 14 d) 
Laboratory Assessments 
Blood chemistries 
 
X 
X 
X 
X 
X* 
X** 
X 
X 
 
 
*Participants who develop 
hyperphosphatemia during 
Cycle 1 must continue to be 
monitored during Cycle 2 (serum 
phosphate only).   
**Only participants scheduled to 
receive chemotherapy.  
Section 8.5.6 
CBC with 
differential  
 
X 
X 
X 
X 
X* 
X** 
X 
X 
 
 
*Must be assessed prior to each 
study treatment administration for 
each treatment group.  
**Only participants scheduled to 
receive chemotherapy.  
Section 8.5.6 
Coagulation 
 
X 
 
 
 
X* 
 
X 
X 
 
 
*Every 2 cycles starting at 
Cycle 2.  Section 8.5.6 
TSH (T3, T4 if 
abnormal TSH) 
 
X 
 
 
 
X* 
 
X 
X 
 
 
*Every 2 cycles starting at 
Cycle 2.  Section 8.5.6 
Parathyroid 
(endocrine) for 
pemigatinib 
participants only 
 
X 
 
 
 
X* 
 
X 
 
 
 
*Every 3 cycles on Day 1 starting 
with Cycle 3.  Section 8.5.6  
Pregnancy testing 
 
X* 
 
 
 
X** 
 
X* 
 
 
 
*Serum only. At screening should 
be performed a maximum of 
7 days before administration of 
study drug. 
**Urine or serum.  Positive urine 
test must be confirmed with a 
serum test.  Section 8.5.6.1  
Serology 
 
X 
 
 
 
 
 
 
 
 
 
Section 8.5.6.2 
Urinalysis 
 
X 
 
 
 
X 
 
X 
 
 
 
Section 8.5.6 


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2. 
INTRODUCTION 
2.1. 
Background 
Pemigatinib is an inhibitor of the FGFR family of receptor tyrosine kinases that is proposed for 
the treatment of UC.  Aberrant signaling through FGFR resulting from gene amplification or 
mutation, chromosomal translocation, and ligand-dependent activation of the receptors has been 
demonstrated in multiple types of human cancers.  Fibroblast growth factor receptor signaling 
contributes to the development of malignancies by promoting tumor cell proliferation, survival, 
migration, and angiogenesis.  In this study, the sponsor is proposing to study pemigatinib 
monotherapy or pemigatinib in combination with pembrolizumab for the treatment of metastatic 
or unresectable UC in the first-line setting in participants who are cisplatin-ineligible and whose 
tumors have an FGFR3 mutation or rearrangement as a monotherapy or in combination with 
pembrolizumab.  Refer to the IB for additional background information on pemigatinib. 
2.1.1. 
Fibroblast Growth Factor Receptor Inhibition in Oncology 
The mammalian FGFR family is composed of 4 highly conserved receptors (FGFR1, FGFR2, 
FGFR3, and FGFR4) that have an extracellular ligand-binding domain, a single transmembrane 
domain, and an intracellular tyrosine kinase domain.  Eighteen FGF ligands, divided into 
canonical and hormonal FGFs, bind to FGFRs, leading to receptor dimerization, activation of the 
kinase domain, and transphosphorylation of the receptors (Eswarakumar et al 2005).  Subsequent 
signal transduction occurs through phosphorylation of substrate proteins, such as FGFR substrate 
2, which leads to activation of the RAS mitogen–activated protein kinase and phosphoinositide 
3-kinase–protein kinase B pathways and of the phospholipase Cγ that activates the protein kinase 
C pathway.  In some cellular context, signal transducer and activator of transcription proteins are 
also activated by FGFRs.  Signaling through the FGF-FGFR pathway is tightly controlled 
through feedback regulation.  Mitogen activated protein kinase phosphatases and Sprouty 
proteins are upregulated upon FGFR stimulation and antagonize FGF-dependent activation of 
extracellular signal-regulated kinases.  In many cases, FGFR pathway activation promotes cell 
proliferation, survival, and migration; however, cellular context plays an important role, and in 
certain tissues, FGFR signaling results in growth arrest and cellular differentiation (Dailey et al 
2005). 
In adults, FGF-FGFR signaling is involved in angiogenesis during wound healing.  The 
hormonal FGF ligands contribute to regulation of metabolic pathways involving lipid, glucose, 
phosphate, and vitamin D (Itoh 2010).  Genetic defects in the FGF23-signaling pathway lead to 
disordered phosphate metabolism:  loss of function mutations in FGF23 or its signaling results in 
retention of phosphate and tissue mineralizing, while gain of function mutations in the FGF23 
pathway manifests as hypophosphatemic Rickets syndrome (Farrow and White 2010). 


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Strong genetic and functional evidence supports that dysregulation of FGFR can lead to the 
establishment and progression of cancer.  Genetic alterations in FGFR1, FGFR2, and FGFR3 
have been described in many tumor types (Knights and Cook 2010, Turner and Grose 2010).  
These include activating mutations, translocations, and gene amplification resulting in ligand 
independent constitutive activation of the receptors or aberrant ligand-dependent signaling 
through FGFRs.  Mutations that lead to activation of FGFR3 occur in 50% to 70% of low-grade 
superficial bladder cancer (Knowles and Hurst 2015).  The most prevalent FGFR3 mutations are 
Ser to Cys changes in the extracellular domain that promote autodimerization and ligand 
independent activation of signaling (di Martino et al 2009).  These mutations match germline 
mutations in FGFR3 that are described in congenital skeletal dysplasias (Greulich and 
Pollock 2011).  In high-grade muscle invasive urothelial bladder cancer, activating mutations of 
FGFR3 occur in 11% of cases and increases in copy number in an additional 3% (Cancer 
Genome Atlas Research Network 2014). 
Translocations involving FGFR3 have also been described in bladder cancer including the 
intrachromosomal rearrangement generating the FGFR3—transforming acidic coiled-coil–
containing protein 3 fusion (Williams et al 2013).  Fibroblast growth factor receptor 3 is a target 
of the t(4;14) translocation that affects approximately 15% of multiple myeloma patients 
(Chesi et al 1997).  This balanced translocation adjoins the FGFR3 coding sequence to the strong 
IgH enhancer elements in plasma cells and drives high levels of FGFR3 expression.  Finally, 
recent large scale tumor sequencing efforts have uncovered multiple, but rare, transforming 
alterations in FGFR genes across a number of tumor histologies (Liao et al 2013, Wu et al 2013).  
In addition to these examples where FGFR dysregulation is a primary driver of tumorigenesis, 
FGFR has been reported to be a mechanism for resistance to hormone therapy in breast cancer 
and to EGFR inhibitors in non–small cell lung cancer by providing an alternative survival 
pathway (Turner et al 2010, Ware et al 2010). 
A substantial body of evidence supports that a genetically activated FGFR pathway sensitizes 
FGFR-altered cancer cells to knockdown or inhibition of these receptors (Kunii et al 2008, 
Lamont et al 2011, Qing et al 2009, Weiss et al 2010).  A large screen of more than 500 tumor 
cell lines with a selective FGFR inhibitor demonstrated that only a small percentage (5.9%) of all 
cells are sensitive to FGFR inhibition, and growth-suppressed cell lines were highly enriched for 
FGFR alterations (Guagnano et al 2012).  These results demonstrate that FGFR inhibitors are 
active in a targeted manner against cancers with activated FGFR pathway.  An implication of 
these data is that selection based on molecular-, genetic-, or protein-based diagnostic tests for 
specific FGFR alterations in tumors may be important for identifying patients most likely to 
benefit from an FGFR inhibitor. 
Results from early clinical studies of selective FGFR inhibitors, including pemigatinib, have 
shown a tolerable safety profile for the class and preliminary signs of clinical benefit in 
participants with FGF/FGFR alterations (Seikfer et al 2019). 


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2.1.2. 
Overview and Treatment of Urothelial Carcinoma 
Globally, bladder cancer was the 11th most common cancer based on 2018 estimates, accounting 
for approximately 549,000 new cases and 200,000 deaths (Global Cancer Observatory 2019).  
Urothelial carcinoma is the predominant histologic type of bladder cancer in the United States 
and Western Europe, where it accounts for approximately 90 percent of bladder cancers.  Also 
known as TCC, bladder cancer describes a range of tumors arising from the urothelial 
endothelium and includes the bladder, renal pelvis, ureter, and urethra.  The majority of patients 
with TCC develop localized, non-invasive disease.  However, approximately 25% of patients 
will have muscle-invasive disease and either present with or later develop metastases 
(von der Maase et al 2005). 
A number of clinical and molecular characteristics have been shown to correlate with survival.  
Poor performance status and the presence of visceral (ie, pulmonary, liver, bone) metastases 
correlate with shortened survival in clinical studies.  This was illustrated by an intergroup study 
that compared cisplatin alone with methotrexate, vinblastine, doxorubicin, and cisplatin in 
patients with metastatic disease (Loehrer et al 1992).  The presence of bone or liver metastases 
and poor performance status were most predictive of poor response and survival.  The presence 
of these unfavorable features was associated with median survival of 4 months, compared with 
18 months in those participants without these features.  No participants with liver or bone 
metastases and only 1 participant with a Karnofsky performance status < 80% survived beyond 
6 years (Saxman et al 1997).  Several subsequent reports confirmed the relationship between 
shortened survival and poor performance status or the presence of visceral metastases.  In the 
second-line setting (patients with platinum-refractory TCC), multivariate analysis identified 
ECOG performance status > 1, hemoglobin level less than 10 g/dL, and the presence of liver 
metastasis as the main adverse prognostic factors for OS (Bellmunt et al 2010).  These factors 
illustrate that since bladder cancer is more often a disease of the elderly and infirm, many 
patients cannot benefit from modern cisplatin-based chemotherapy regimens, and other treatment 
options are needed for this large population of patients. 
Based on NCCN guidelines (NCCN 2019), the current SOC for the initial treatment of 
metastatic, locally advanced bladder cancer is systemic chemotherapy with or without a 
platinum-containing regimen.  The median survival with combination chemotherapy is 
approximately 14 to 15 months (von der Maase et al 2005).  While this is superior to the 
estimated 6-month survival with metastatic disease prior to the development of modern 
chemotherapy regimens, the 5-year survival rate is approximately 15% with contemporary 
chemotherapy regimens.  Second-line chemotherapy, usually as a single agent, has had only a 
limited role, with a modest increase in median 2-month OS), which was at best 6.9 months as 
compared with best supportive care (Bellmunt et al 2009). 
NCCN guidelines for recommendation of chemotherapy also highlight specific medical 
comorbidities, such as performance status along with cardiac function and renal dysfunction, in 
consideration of the appropriate treatment.  A Phase 3 study comparing gemcitabine/carboplatin 
with methotrexate/carboplatin/vinblastine in cisplatin-ineligible participants demonstrated a 
median survival of only 8 to 9 months with both regimens (De Santis et al 2012).  Notably, those 
with both poor renal function and poor performance status fared especially poorly with 
combination chemotherapy in this study.  Thus, there remains a significant unmet medical need 
for well-tolerated active therapies in this population. 


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Treatment for bladder cancer has evolved over time to encompass not only traditional 
chemotherapy, but has been particularly impacted by the use of immunotherapy 
(Bellmunt et al 2017).  The PD-1/PD-L1 inhibitors such as atezolizumab, pembrolizumab, 
nivolumab, and durvalumab have demonstrated activity and are currently being evaluated in 
randomized clinical studies in patients with UC.  These include studies as first- and second-line 
therapy and as well as in the adjuvant setting.  Pembrolizumab, atezolizumab, nivolumab, 
durvalumab, and avelumab recently received accelerated approval from the FDA for the 
treatment of advanced UC that has progressed during or after previous platinum-based 
chemotherapy.  In addition, atezolizumab received accelerated approval from the FDA for the 
treatment of advanced UC who were not eligible for cisplatin-containing chemotherapy. 
On 18 MAY 2017, the FDA granted accelerated approval to pembrolizumab for patients with 
locally advanced or metastatic UC who were not eligible for cisplatin-containing chemotherapy, 
based on data from a multicenter, open-label, single-arm study, KEYNOTE-052 
(NCT02335424), investigating pembrolizumab in 370 participants.  On that same day, the FDA 
granted regular approval to pembrolizumab for patients with locally advanced or metastatic UC 
with disease progression on or after platinum-containing chemotherapy.  Approval was based on 
data from a multicenter, randomized, active-controlled study, KEYNOTE-045.  Participants were 
randomized to receive either pembrolizumab 200 mg Q3W IV (N = 270) or the investigator’s 
choice of paclitaxel, docetaxel, or vinflunine (Bellmunt et al 2017, Keytruda® 2019). 
In addition to pembrolizumab, atezolizumab was also granted an accelerated approval 
(18 MAY 2016) for the treatment of adults with locally advanced or metastatic UC who were not 
eligible for cisplatin-containing chemotherapy based on data from IMvigor210, which was a 
single-arm, open-label study that included 310 participants.  Patients received 1200 mg of 
atezolizumab Q3W IV (Balar et al 2017b, Tecentriq® 2019). 
Subsequent to the accelerated approvals of pembrolizumab and atezolizumab, on 18 MAY 2018, 
the FDA initiated guidance on decreased survival associated with the use of pembrolizumab or 
atezolizumab as monotherapy compared to platinum-based chemotherapy in clinical studies to 
treat patients with metastatic UC who have not received prior therapy and who have low 
expression of the protein PD-L1 (FDA 2018b).  For these patients, systemic chemotherapy 
continues to be the recommended treatment option.  Based on the revised indication, 
Pembrolizumab is indicated for the treatment of patients with locally advanced or metastatic UC 
who are not eligible for cisplatin-containing therapy and whose tumors express PD-L1 
(CPS ≥ 10) or in patients who are not eligible for any platinum-containing chemotherapy 
regardless of PD-L1 status.  More effective and less toxic treatments are greatly needed in this 
patient population, and immunotherapy offers additional options for patients progressing after 
their initial systemic therapy.  


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2.2. 
Study Rationale 
Pemigatinib is a potent selective inhibitor of FGFR1, FGFR2, and FGFR3.  This compound, as 
monotherapy or in combination with pembrolizumab, is proposed for the first-line treatment of 
participants with metastatic or unresectable UC with FGFR3 mutations or rearrangements who 
are not eligible to receive platinum containing regimens. 
2.2.1. 
Scientific Rationale for Study Design 
The planned study will evaluate the safety of pemigatinib as a monotherapy or in combination 
with pembrolizumab as a first-line treatment in participants with metastatic or unresectable UC 
with FGFR3 mutations or rearrangements.  Current practice guidelines (NCCN 2019) for 
metastatic or unresectable bladder cancer indicate that patients who are not eligible to receive 
cisplatin as the preferred regimen in combination with gemcitabine, should instead receive the 
combination of carboplatin and gemcitabine.  In addition, patients whose tumors express PD-L1, 
or who are not eligible for any platinum-containing chemotherapy regardless of PD-L1, may also 
receive approved checkpoint inhibitors (ie, pembrolizumab or atezolizumab).  Based on available 
data from a large Phase 2/3 study conducted in this population, the median PFS in a gemcitabine 
and carboplatin group is expected to be 5.8 months (De Santis et al 2012). 
Pembrolizumab was approved based on efficacy results observed in KEYNOTE-052.  An ORR 
of 29% was observed in all participants with 21% and 47% ORR in those with PD-L1 CPS < 10 
and ≥ 10 respectively.  Both CRs and PRs were also higher in the PD-L1 CPS ≥ 10 group (15% 
and 32%, respectively) as compared with those in all participants and PD-L1 CPS < 10 
(Keytruda 2019).  Based on data from study KEYNOTE-052, median PFS in first-line treatment 
of cisplatin-ineligible patients, regardless of tumor CPS score, with pembrolizumab was 
2.3 months, and median OS was 11.5 months.  In participants whose tumors expressed CPS ≥ 10, 
the median PFS was 4.9 months, and the median OS was 18.5 months. 
Preliminary data from the ongoing Phase 2 study (INCB 54828-201) with pemigatinib as 
monotherapy in second-line or greater treatment have shown clinical activity and tolerable safety 
in 159 UC participants with FGFR alterations (more pronounced in FGFR3 mutations or 
translocations) has shown an ORR of 21.3% and a median PFS of 4.1 months.  As of a data 
cutoff date of 25 NOV 2018, the safety and tolerability of pemigatinib administered alone or in 
combination with another chemotherapy/immunotherapy was being evaluated in 5 ongoing 
clinical studies in participants with advanced malignancies.  Participants with metastatic or 
unresectable UC had received pemigatinib 13.5 mg QD on a 2-weeks-on/1-week-off therapy 
schedule or on a continuous schedule; 99 participants with FGFR3 mutations or fusions received 
the interval schedule, and 7 participants with FGFR3 mutations or fusions received the 
continuous schedule.  Based on preliminary unaudited data from these ongoing studies, the most 
frequently occurring TEAEs (ie, incidence > 20%) were (in descending order of frequency) 
hyperphosphatemia, diarrhea, alopecia, fatigue, dry mouth, stomatitis, constipation, dysgeusia, 
nausea, decreased appetite, and anemia. 




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No change in PK parameters is expected for continuous administration, as steady-state 
concentrations are expected to be reached at Day 4 based on a half-life of 20.2 hours.  However, 
at the 13.5 mg dose, the continuous dose regimen increased the average per cycle exposure of 
pemigatinib by 50%. 
Hyperphosphatemia is an expected on-target pharmacological effect of FGFR inhibition.  The 
magnitude and frequency of hyperphosphatemia (defined as any postbaseline phosphate level 
exceeding 5.5 mg/dL), which is managed with a low-phosphate diet and introduction of 
phosphate binders, appears to be dose-dependent as demonstrated in Parts 1 and 2 of 
Study INCB 54828-101 (refer to the IB).  The majority of participants treated at 13.5 mg 
experienced hyperphosphatemia. 
Although hyperphosphatemia has been observed in the majority of participants treated with 
pemigatinib, some participants do not achieve hyperphosphatemia where pharmacological 
concentrations of pemigatinib in these participants may be lower. 
In a population Emax model, those participants treated with pemigatinib 13.5 mg who did not 
develop hyperphosphatemia, the AUC with pemigatinib 18 mg was estimated using a linear 
exposure relationship.  The simulation suggested that the serum phosphate may increase above 
5.5 mg/dL after treatment with pemigatinib 18 mg for the participants treated with pemigatinib 
13.5 mg who did not develop hyperphosphatemia. 
Any participant who does not reach the target serum phosphate level of > 5.5 mg/dL at any time 
during Cycle 1 and who is compliant with taking study drug and does not experience an ongoing 
Grade 2 or higher treatment-related AEs will increase the daily dose to 18 mg QD starting at 
Cycle 2 Day 1. 
Refer to the IB for more information. 
Dose modifications for tolerability issues are noted in Section 6.6. 
2.2.2.2. 
Pembrolizumab 
The planned dose of pembrolizumab for this study is 200 mg Q3W up to 35 cycles.  Based on the 
totality of data generated in the KEYTRUDA development program, 200 mg Q3W is the 
appropriate dose of pembrolizumab for adults across all indications and regardless of tumor type.  
As outlined below, this dose is justified by: 
• Clinical data from 8 randomized studies demonstrating flat dose- and exposure- 
efficacy relationships from 2 mg/kg Q3W to 10 mg/kg Q2W. 
• Clinical data showing meaningful improvement in benefit-risk including OS at 
200 mg Q3W across multiple indications. 
• Pharmacology data showing full target saturation in both systemic circulation 
(inferred from PK data) and tumor (inferred from PBPK analysis) at 200 mg Q3W. 


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Among the 8 randomized dose-comparison studies, a total of 2262 participants were enrolled 
with melanoma and NSCLC, covering different disease settings (ie, treatment naive, previously 
treated, PD-L1 enriched, and all-comers) and different treatment settings (monotherapy and in 
combination with chemotherapy).  Five studies compared 2 mg/kg Q3W versus 10 mg/kg Q2W 
(KEYNOTE-001 B2, -001 D, -002, -010, and -021), and 3 studies compared 10 mg/kg Q3W 
versus 10 mg/kg Q2W (KEYNOTE-001 B3, -001 F2, and -006).  All of these studies 
demonstrated flat dose- and exposure-response relationships across the doses studied 
representing an approximate 5- to 7.5-fold difference in exposure.  The 2 mg/kg (or 200 mg fixed 
dose) Q3W provided similar responses to the highest doses studied.  Subsequently, flat 
dose/exposure-response relationships were also observed in other tumor types including head 
and neck cancer, bladder cancer, gastric cancer and classical Hodgkin lymphoma, confirming 
200 mg Q3W as the appropriate dose independent of the tumor type.  These findings are 
consistent with the mechanism of action of pembrolizumab, which acts by interaction with 
immune cells, and not via direct binding to cancer cells. 
Additionally, pharmacology data clearly show target saturation at 200 mg Q3W.  First, PK data 
in KEYNOTE-001 evaluating target-mediated drug disposition conclusively demonstrated 
saturation of PD-1 in systemic circulation at doses much lower than 200 mg Q3W.  Secondly, a 
PBPK analysis was conducted to predict tumor PD-1 saturation over a wide range of tumor 
penetration and PD-1 expression.  This evaluation concluded that pembrolizumab at 200 mg 
Q3W achieves full PD-1 saturation in both blood and tumor. 
Finally, population PK analysis of pembrolizumab, which characterized the influence of body 
weight and other participant covariates on exposure, has shown that the fixed-dosing provides 
similar control of PK variability as weight based dosing, with considerable overlap in the 
distribution of exposures from the 200 mg Q3W fixed dose and 2 mg/kg Q3W dose.  Supported 
by these PK characteristics, and given that fixed-dose has advantages of reduced dosing 
complexity and reduced potential of dosing errors, the 200 mg Q3W fixed-dose was selected for 
evaluation across all pembrolizumab protocols. 
A pembrolizumab monotherapy arm is added in this study in order to establish the magnitude of 
benefit from pemigatinib in the pembrolizumab plus pemigatinib combination regimen. 
Dose modifications for tolerability issues are noted in Section 6.6. 
2.2.2.3. 
Gemcitabine and Carboplatin 
Cisplatin-based combination chemotherapy is standard first-line treatment for patients with 
advanced or metastatic bladder cancer based on NCCN guidelines (NCCN 2019) and EAU 
guidelines (EAU 2019).  However, cisplatin ineligibility is common in bladder cancer patients 
because of renal dysfunction (CrCl < 60 mL/min), poor performance status (ECOG performance 
status ≥ 2), New York Heart Association Class III heart failure, or Grade 2 or higher neuropathy 
or hearing loss (Galsky 2015).  As a result, the guidelines recommend alternative treatments that 
include carboplatin plus gemcitabine or pembrolizumab monotherapy. 




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The most frequently reported TEAE in combination with pembrolizumab for the intermittent 
dosing schedule of pemigatinib was hyperphosphatemia (14 participants [82%]; serum phosphate 
> 5.5 mg/dL) and for the continuous dosing schedule of pemigatinib in combination with 
pembrolizumab, the most frequently reported TEAE was dry mouth (4 participants [67%]).  
Other frequently reported TEAEs for intermittent dosing schedule included decreased appetite 
(6 participants at 13.5 mg [64%], anemia (8 participants at 13.5 mg [57%]), and diarrhea 
(7 participants at 13.5 mg [50%] and 1 participant at 9 mg [33%]).  For continuous dosing 
pemigatinib (13.5 mg) plus pembrolizumab, additional TEAEs included dysgeusia (3 participants 
[50%]) and hyperphosphatemia (3 participants [50%]).  Twenty participants (87%) across all 
doses and regimens had treatment-related AEs. 
Thirteen participants (57%) had a Grade 3 event or higher across all doses and regimens in the 
combination.  Serious AEs were reported in a total of 8 participants (35%) who received 
pemigatinib plus pembrolizumab (all doses and dose regimens combined).  One participant (4%) 
had a TEAE with a fatal outcome (9 mg intermittent dosing; completed suicide).  It was not 
considered related to study drug. 
One participant (4%) discontinued treatment due to an AE (13.5 mg intermittent dosing plus 
pembrolizumab).  One participant (4%) had a dose reduction of pemigatinib (13.5 mg continuous 
dosing) due to TEAE, and 11 participants (48%) had treatment interruptions due to a TEAE 
(across all doses and regimens).  This safety data from Study INCB 54828-101 show that the 
continuous dosing regimen of pemigatinib at 13.5 mg in combination with pembrolizumab was 
tolerable. 
No DDI is expected based on metabolic pathways of pembrolizumab and pemigatinib.  
Furthermore, PK parameters of pemigatinib are not different when it was given as monotherapy 
and in combination with pembrolizumab (see Table 6; refer to the IB for more information). 
Table 6: 
Pharmacokinetic Parameters of Pemigatinib Monotherapy and in 
Combination With Pembrolizumab 
Dose 
N 
Cmax  
(nmol/L) 
tmax  
(h)a 
Cmin  
(nmol/L) 
CLss/F  
(L/h) 
Vz/F 
(L) 
AUC0-τ  
(h·nmol/L) 
t½  
(h) 
Pemi 13.5 mg 
QD 
53 
262 ± 150 
(228) 
1 
(0.5, 6) 
68.4 ± 59.7 
(51.8) 
12.0 ± 5.77 
(10.6) 
320 ± 200 
(273) 
2980 ± 1910 
(2600) 
20.2 ± 12.9 
(17.5) 
Pemi 13.5 mg 
QD + pembro 
15 
258 ± 115 
(232) 
1 
(0.5, 8) 
59.8 ± 35.4 
(48.1) 
12.3 ± 6.32 
(11.0) 
322 ± 150 
(296) 
2740 ± 1110 
(2510) 
18.3 ± 8.87 
(16.2) 
Pemi = pemigatinib; pembro = pembrolizumab. 
a Values are presented in the format of “Mean ± SD (Geometric Mean) except tmax, which is presented in the format of “Median 
(Min, Max).” 
2.3. 
Benefit/Risk Assessment 
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of pemigatinib, pembrolizumab, gemcitabine and carboplatin may be found in the 
IB or package insert for each compound. 




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3. 
OBJECTIVES AND ENDPOINTS 
The objectives and endpoints apply to a study population of male or female participants at least 
18 years of age with a histologically confirmed diagnosis of metastatic or unresectable UC, 
whose tumors have an FGFR3 mutation or rearrangement and who are medically ineligible to 
receive cisplatin-based chemotherapy and have not received prior treatment. 
This study will be considered to have met its primary objective if pembrolizumab plus 
pemigatinib or pemigatinib alone is superior to SOC for the primary endpoint. 
Table 7 presents the objectives and endpoints. 
Table 7: 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
To evaluate and compare PFS in participants treated 
with pemigatinib in combination with pembrolizumab 
(Treatment Group A) and pemigatinib alone (Treatment 
Group B) versus SOC (Treatment Group C). 
Differences in PFS will be evaluated hierarchically, and 
the comparison between pemigatinib in combination 
with pembrolizumab (Treatment Group A) and SOC 
(Treatment Group C) will be evaluated first, and if 
significant difference is detected, a second comparison 
will be made in PFS between pemigatinib alone 
(Treatment Group B) and SOC (Treatment Group C). 
Hypothesis:  The combination of pembrolizumab plus 
pemigatinib has superior PFS as compared with SOC.  
Contribution of pemigatinib alone to combination will 
be assessed by comparing Treatment Groups A and C 
and Treatment Groups B and C. 
Progression-free survival, defined as the time from 
randomization date until the date of disease progression 
(as measured by BICR per RECIST v1.1) or death due to 
any cause, whichever occurs first. 
Secondary 
To evaluate and compare the efficacy of the 3 treatment 
groups with respect to OS. 
Overall survival, defined the time from the date of 
randomization until death due to any cause. 
To evaluate and compare the efficacy of the 3 treatment 
groups with respect to overall tumor response and DOR. 
• Objective response rate, defined as the proportion of 
participants with best overall response of CR or PR 
determined by BICR per RECIST v1.1. 
• Duration of response, defined as the time from the 
date of the first assessment of CR or PR until the date 
of the first disease progression per BICR per 
RECIST v1.1 or death, whichever occurs first. 
To evaluate the safety of the 3 treatment groups. 
Safety and tolerability of pemigatinib with or without 
pembrolizumab and SOC will be assessed by evaluating 
the frequency and severity of AEs, physical examination 
findings, vital sign changes, and clinical laboratory 
assessments. 
To evaluate changes from baseline in patient-reported 
outcomes. 
Patient-reported outcome scales (ie, EORTC QLQ-C30, 
EQ-5D-5L) at each timepoint and change from baseline 
to each timepoint. 


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Table 7: 
Objectives and Endpoints (Continued) 
4. 
STUDY DESIGN 
4.1. 
Overall Design 
This is a Phase 2, open-label, randomized and active-controlled study of pemigatinib plus 
pembrolizumab or pemigatinib alone versus the SOC for participants with metastatic or 
unresectable UC not eligible to receive cisplatin and harboring FGFR3 mutation or 
rearrangement and who have not received prior treatment.  Randomization will occur after the 
participant has completed screening.  Participants will be stratified by eligible to receive 
carboplatin versus not eligible to receive carboplatin, PD-L1 CPS ≥ 10 versus CPS < 10, and 
LN-only disease versus other metastatic disease.  This is an event-driven clinical study designed 
to ensure power to detect success of the primary endpoint of PFS.  A total of 210 PFS events in 
the combined treatment groups of pemigatinib plus pembrolizumab and SOC are needed to 
support the primary objective, where PFS is defined as the time from randomization date until 
the date of disease progression or death due to any cause, whichever occurs first. 
Participants who are screened and found to have the FGFR3 mutation or rearrangement) will be 
randomized 1:1:1 into 1 of the 3 treatment groups indicated in Table 8. 
Table 8: 
Treatment Groups for Randomization 
Treatment 
Group 
Regimen 
A 
Pemigatinib 13.5 mg QD POa until PD + pembrolizumab 200 mg Q3W IV up to 35 cycles 
(approximately 2 years) or PD, whichever occurs first 
B 
Pemigatinib 13.5 mg QD POa until PD 
C 
One of 2 SOC treatment options: 
1. Gemcitabine 1000 mg/m2 Q3W IV on Days 1 and 8 + carboplatin AUC 5 (or AUC 4.5 if 
required per local guidelines) Q3W on Day 1 or 2 for 4 to 6 cycles.  (Participants whose 
tumors express PD-L1 CPS < 10 who are eligible to receive carboplatin.)  
OR 
2. Pembrolizumab 200 mg Q3W IV up to 35 cycles (approximately 2 years).  (Participants 
whose tumors express PD-L1 CPS ≥ 10 or participants who are not considered eligible to 
receive any platinum-containing chemotherapy regardless of PD-L1 expression status [only 
applicable in regions where pembrolizumab is used as standard of care for participants who 
are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status].)  
a Participants not reaching the target serum phosphate during Cycle 1 will increase the daily dose to 18 mg starting at Cycle 2 as 
described in Section 6.6.2.1. 


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Participant eligibility will be based on genomic testing for FGFR3.  Participants can be 
randomized based on local results, if available, and results will be retrospectively confirmed by 
the sponsor's central laboratory.  Previous therapies may include only neo-adjuvant or adjuvant 
treatment with platinum-containing chemotherapy if completed at least 12 months before the 
start of treatment for this study; otherwise, participants should be treatment naive before 
screening and according criteria outlined in Section 5. 
Treatment will start on Cycle 1 Day 1.  Participants will undergo regular safety assessments 
during treatment, as well as regular efficacy assessments.  Participants will be allowed to 
continue administration in 3-week cycles, as per protocol for each treatment, until disease 
progression per RECIST v1.1 as assessed by BICR or unacceptable toxicity is reported. 
A futility analysis will be performed as described in Section 10.5. 
See Figure 1 for the study design. 
Full study drug administration information can be found in Section 6. 
4.2. 
Overall Study Duration 
The study begins when the first participant signs the ICF and enters into the screening period.  
The end of the study is defined as the date of the last scheduled procedure shown in the schedule 
of activities for the last participant in the study globally. 
A participant is considered to have completed the study if he/she has completed all phases of the 
study including the last scheduled procedure shown in the schedule of activities (see Table 4), or 
the participant has died, and the date of death is available. 
If approximately 210 PFS events have been reported, a database lock of the study may occur to 
allow the analysis of the study data.  Any remaining participants may continue to receive study 
treatment and be seen by the investigator as per institutional guidelines or standard clinical 
practice.  The investigator will be expected to monitor for AEs and report any SAEs, and 
pregnancies, as detailed in Section 9, and continue to follow procedures for drug accountability.  
The remaining participants are considered to be on study until a discontinuation criterion is met 
and written notification is provided to the sponsor. 
4.3. 
Study Termination 
The investigator retains the right to terminate study participation at any time, according to the 
terms specified in the study contract.  The investigator/head of study site (Japan) is to notify the 
IRB/IEC in writing of the study's completion or early termination, send a copy of the notification 
to the sponsor or sponsor's designee, and retain 1 copy for the site study regulatory file. 
The sponsor may terminate the study electively, if required by regulatory decision or upon 
advice of the DMC (see Section 10.6).  If the study is terminated prematurely, the sponsor will 
notify the investigators/head of study site (Japan), the IRBs and IECs, and regulatory bodies of 
the decision and reason for termination of the study. 
For Japan, the head of study sites will notify the investigators and the IRBs of the decision and 
reason for termination of the study. 


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5. 
STUDY POPULATION 
Deviations from eligibility criteria are not allowed because they can potentially jeopardize the 
scientific integrity of the study, regulatory acceptability, and/or participant safety.  Therefore, 
adherence to the criteria as specified in the Protocol is essential.  Prospective approval of 
Protocol deviations to recruitment and enrollment criteria, also known as Protocol waivers or 
exemptions, are not permitted. 
5.1. 
Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria apply: 
1.  Male or female participants aged 18 years and older at the time of signing the informed 
consent; a legally minor participant from Japan needs written parental or legal guardian's 
consent. 
2. Histologically documented metastatic or unresectable UC; may include primary site from 
bladder, ureters, upper tract, renal pelvis, urethra, or urachus.  Both transitional cell and 
mixed transitional cell histologies are allowed, provided urothelial component is ≥ 50%. 
Note:  Participants with non-UC of the urinary tract are not allowed. 
3. Have at least 1 measurable target lesion per RECIST v1.1 as assessed by the local site 
investigator/radiologist. 
Eligibility for chemotherapy is defined as meeting either criterion #4 OR #5 as described below. 
4. Cisplatin ineligibility, defined by the presence of one of the following criteria: 
a. Creatinine clearance of < 60 mL/min but ≥ 30 mL/min (measured by the Cockcroft-Gault 
formula or 24-hour urine). 
b. ECOG performance status 2 (within 7 days prior to randomization). 
c. ≥ Grade 2 audiometric hearing loss (25 db in 2 consecutive wave ranges; CTCAE v5.0). 
d. New York Heart Association Class III heart failure. 
e. ≥ Grade 2 peripheral neuropathy (CTCAE v5.0). 
OR 
5. Ineligibility to receive any platinum-based chemotherapy (ie, ineligible for cisplatin and 
carboplatin), defined as ECOG performance status 2 (within 7 days prior to randomization) AND 
at least one of the following: 
a. Documented visceral metastatic disease (due to poor prognosis and lack of benefit). 
b. Creatinine clearance of < 60 mL/min but ≥ 30 mL/min (measured by the Cockcroft-Gault 
formula or 24-hour urine). 
c. ≥ Grade 2 audiometric hearing loss (25 db in 2 consecutive wave ranges; CTCAE v5.0). 
d. ≥ Grade 2 peripheral neuropathy (CTCAE v5.0). 
e. Other reason, identified on the eCRF, for the participant being unable to receive carboplatin 
safely.  Additional criteria for platinum ineligibility will be considered and allowed on a case-
by-case basis, following consultation with the sponsor. 
Note:  The reason(s) for ineligibility for cisplatin or any platinum-based chemotherapy must be 
documented in the participant's medical record and on the eCRF. 
Note:  Only applicable in regions where pembrolizumab is used as SOC for participants who are not 
eligible for any platinum-containing chemotherapy regardless of PD-L1 status. 


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6. Must have known FGFR3 mutation or rearrangement (participant can be randomized 
based on a local report, but this will need to be retrospectively confirmed by the sponsor's 
central laboratory; see Appendix E).  See Section 8.7.1 for details on tumor tissue 
requirements. 
Note:  Participants with gene amplifications only are excluded. 
7. Local or central laboratory test result of PD-L1 is mandatory at screening.  Participants 
can be randomized based on a local genomics report, but this will need to be 
retrospectively confirmed by the sponsor's central laboratory.  If local result is not 
available, formalin-fixed, paraffin-embedded tissue blocks or slides must be sent to the 
sponsor's central laboratory.   Formalin-fixed, paraffin-embedded tissue blocks are 
preferred to slides.  If submitting unstained cut slides, newly cut slides should be 
submitted to the testing laboratory within 30 days from the date slides are cut 
(see Section 8.7.1 for details on tumor tissue requirements). 
Note:  In the event the participant does not have local PD-L1 results or the sample is not 
evaluable for PD-L1, the participant will not be eligible. If a local result is available and 
the participant is randomized, but the sample fails or the local result is not confirmed by 
the central laboratory, the site should contact the medical monitor. 
8. Have received no prior systemic chemotherapy for metastatic or unresectable UC except: 
a. Adjuvant platinum-based chemotherapy, following radical cystectomy, with 
recurrence > 12 months from completion of therapy. 
b. Neo-adjuvant platinum-based chemotherapy, with recurrence > 12 months since 
completion of therapy. 
Note:  Low-dose chemotherapy (eg, low-dose cisplatin, cisplatin + 5-FU, mitomycin 
+ 5-FU, or cisplatin + paclitaxel) given concurrently with radiation to the primary 
tumor site is not considered as systemic therapy.  A washout period of 3 weeks before 
the first dose of study treatment is required.  In the clinical setting, chemotherapy is 
given with the sole purpose of sensitizing the tumor to local radiation.  It is not 
administered at doses with any systemic efficacy.  Surgery is not considered first-line 
therapy following diagnosis of advanced/metastatic disease. 
9. ECOG performance status 0 to 2. 
10. Willingness to avoid pregnancy or fathering children based on the criteria below 
(excluding participants in Japan). 
a. Men must agree to take appropriate precautions to avoid fathering children (defined 
as the use of an effective method [barrier method] in combination with a highly 
effective method in preventing pregnancy [see Appendix A]) from screening through 
120 days after the last dose of pemigatinib and/or pembrolizumab or 180 days after 
the last dose of chemotherapy, and must refrain from donating sperm during this 
period.  Permitted methods that are highly effective (at least 99% effective) and 
effective in preventing pregnancy (see Appendix A) should be communicated to the 
participants and their understanding confirmed.  
Note:  Men being treated with gemcitabine must be advised to seek further advice 
regarding cryoconservation of sperm before treatment because of the possibility of 
infertility due to therapy with gemcitabine. 


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b. Women of childbearing potential must have a negative serum pregnancy test at 
screening (a maximum of 7 days before the first dose on Day 1) and must agree to 
take appropriate precautions to avoid pregnancy (defined as the use of an effective 
method [barrier method] in combination with a highly effective method in preventing 
pregnancy [see Appendix A]) from screening through 120 days after the last dose of 
pemigatinib and/or pembrolizumab or 180 days after the last dose of chemotherapy.  
Permitted methods that are highly effective (at least 99% effective) and effective in 
preventing pregnancy (see Appendix A) should be communicated to the participants 
and their understanding confirmed. 
c. Women of nonchildbearing potential (ie, surgically sterile with a hysterectomy and/or 
bilateral oophorectomy OR ≥ 12 months of amenorrhea) are eligible. 
11. For Japanese participants only, willingness to avoid pregnancy or fathering children 
based on the criteria below. 
a. Female participants should agree to use medically acceptable contraceptive measures 
(see Appendix A), should not be breastfeeding, and must have a negative pregnancy 
test before the start of study treatment administration if of childbearing potential.  All 
female participants of childbearing potential must understand and accept that 
pregnancy must be avoided during participation in the study from screening through 
120 days after the last dose of pemigatinib and/or pembrolizumab (based on 
menstrual cycle) and 180 days after last dose of chemotherapy. 
OR 
Female participants must have evidence of nonchildbearing potential by fulfilling 
one of the following criteria at screening: 
− Postmenopausal, defined as aged > 50 years and amenorrheic for at least 
12 months after cessation of all exogenous hormonal treatments. 
Note:  Female participants who have been amenorrheic for ≥12 months resulting 
from chemotherapy/radiotherapy are considered of childbearing potential and 
should agree to use adequate contraceptive measures. 
− Documentation of irreversible surgical sterilization by hysterectomy, bilateral 
oophorectomy, or bilateral salpingectomy but not tubal ligation. 
b. Male participants should avoid unprotected sex with women of childbearing potential 
during the study and for a washout period of 120 days after the last dose of 
pemigatinib and/or pembrolizumab or 180 days after the last dose of chemotherapy.  
Participants should refrain from donating sperm from the start of the study treatment 
administration until 180 days after discontinuing study treatment. 


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5.2. 
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
1. Prior receipt of a selective FGFR inhibitor (eg, erdafitinib, rogaratinib, infigratinib, 
dovitinib, vofatamab) for any indication or reason. 
2. Completion of prior therapy with an anti–PD-1, anti–PD-L1, or anti–PD-L2 agent, or 
with an agent directed to another co-inhibitory T-cell receptor, ≤ 18 months prior to the 
start of treatment for this study. 
3. Receipt of anticancer medications or investigational drugs for unresectable and/or 
metastatic disease (not including adjuvant/neo-adjuvant treatment with platinum-
containing chemotherapy completed ≥ 12 months prior to the start of treatment for this 
study).  
4. Concurrent anticancer therapy (eg, chemotherapy, radiation therapy, surgery, 
immunotherapy, biologic therapy, hormonal therapy, investigational therapy, tumor 
embolization), except for treatment allowed per protocol.  
5. Has disease that is suitable for local therapy administered with curative intent. 
6. Has tumor with any neuroendocrine or small cell component. 
7. Current evidence of clinically significant corneal (including but not limited to 
bullous/band keratopathy, corneal abrasion, inflammation/ulceration, and 
keratoconjunctivitis, etc) or retinal disorder (including but not limited to macular/retinal 
degeneration, diabetic retinopathy, retinal detachment, etc) as confirmed by 
ophthalmologic examination. 
8. Has received prior radiotherapy to a metastatic site within 3 weeks of the first dose of 
study treatment, with the exception of palliative radiotherapy to bone lesions, which is 
allowed if completed 2 weeks before the start of study treatment.  Participants must have 
recovered from all radiation-related toxicities and must not require corticosteroids. 
9. Has CNS metastases, unless the participant has completed local therapy (eg, whole brain 
radiation therapy, surgery, radiosurgery) and has discontinued use of corticosteroids for 
this indication for at least 4 weeks before starting treatment in this study.  Any signs 
(eg, radiologic) or symptoms of CNS metastases must be stable for at least 4 weeks 
before starting study treatment. 
10. Known additional malignancy that is progressing or required active treatment within the 
past 3 years. 
a. Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the 
skin, or carcinoma in situ (eg, breast carcinoma, cervical cancer in situ) that have 
undergone potentially curative therapy are not excluded.  


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b. A history of prostate cancer (T2NXMX or lower with Gleason score ≤ 7) treated with 
definitive intent (surgically or with radiation therapy) at least 1 year prior to study 
entry is acceptable, provided that the participant is considered prostate cancer-free 
and the following criteria are met: 
− Participants who have undergone radical prostatectomy must have undetectable 
PSA for > 1 year and at screening. 
− Participants who have had radiation must have a PSA doubling time > 1 year 
(based on at least 3 values determined > 1 month apart) and a total PSA value that 
does not meet Phoenix criteria for biochemical recurrence (ie, < 2.0 ng/mL above 
nadir). 
c. Participants with untreated low-risk prostate cancer (Gleason score ≤ 6) on active 
surveillance with PSA doubling time > 1 year (based on at least 3 values determined 
> 1 month apart) are also eligible. 
11. Participants with laboratory values at screening defined in Table 9. 
Table 9: 
Exclusionary Laboratory Values 
Laboratory Parameter 
Exclusion Criterion 
Hematology 
a 
Platelets 
≤ 100,000 (transfusion allowed with 2-week washout period) 
b 
Hemoglobin 
≤ 9.0 g/dL (transfusion allowed within 2-week washout period) 
c 
ANC 
 ≤ 1.5 × 109/L 
Hepatic 
d 
ALT and AST 
≥ 2.5 × ULN (5 × ULN for liver mets) 
e 
Total bilirubin 
≥ 1.5 × ULN (Note:  Participants excluded based on total bilirubin 
may be enrolled if direct bilirubin ≤ ULN; 2.5 × ULN if Gilbert’s 
syndrome or liver mets) 
Renal 
f 
Measured or calculated CrCl (GFR can 
be used in place of CrCl) 
< 30mL/min 
CrCl = [[140 - age(yr)]*weight(kg)]/[72*serum Cr(mg/dL)] (multiply by 0.85 for women) 
Chemistry 
g 
Serum phosphate 
> institutional ULN 
h 
Serum calcium 
Outside of normal range or serum albumin-corrected calcium 
outside of the normal range when serum albumin is outside of the 
normal range 
Coagulation 
i 
INR or PT, aPTT or PTT 
≥ 1.5 × ULN unless the participant is receiving anticoagulation 
therapy as long as PT or aPTT is within therapeutic range of 
intended use of anticoagulants 


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12. History of calcium and phosphate hemostasis disorder or systemic mineral imbalance 
with ectopic calcification of soft tissues (exceptions:  commonly observed calcifications 
in soft tissues such as the skin, kidney tendon or vessels due to injury, disease, or aging in 
the absence of systemic mineral imbalance). 
13. Inability to swallow and retain oral medication. 
14. Clinically significant or uncontrolled cardiac disease, including unstable angina, acute 
myocardial infarction within 6 months from Day 1 of study treatment administration, 
New York Heart Association Class IV congestive heart failure, and uncontrolled 
arrhythmia (participants with pacemakers or with atrial fibrillation and well-controlled 
hear rates are allowed). 
15. History or presence of an abnormal ECG that, in the investigator's opinion, is clinically 
meaningful.  A screening QTcF interval > 480 ms is excluded.  For participants with an 
intraventricular conduction delay (QRS interval ≥ 120 ms), the JTc interval may be used 
in place of the QTc with sponsor approval.  The JTc must be ≤ 340 ms if JTc is used in 
place of the QTc. 
16. Active chronic or current infectious disease requiring systemic antibiotic, antifungal, or 
antiviral treatment within 2 weeks prior to the first dose of study treatment (participants 
with asymptomatic chronic infections on prophylactic treatment are allowed). 
17. Has a known history of HBV (defined as HBsAg reactive) or known active HCV (defined 
as HCV RNA [qualitative] is detected) infection. 
18. Known HIV infection. 
Note:  HIV screening test is optional for participants enrolled in the United States, but 
participants with known HIV infection in the United States will be excluded. 
19. Use of any potent CYP3A4 inhibitors or inducers or moderate CYP3A4 inducers within 
14 days or five half-lives (whichever is longer) before the first dose of study treatment 
(see Appendix D). 
20. Known hypersensitivity or severe reaction to pemigatinib or excipients of pemigatinib 
(refer to the IB).  
21. Inability or unlikeliness of the participant to comply with the dose schedule and study 
evaluations, in the opinion of the investigator. 
22. Inadequate recovery from toxicity and/or complications from a major surgery before 
starting therapy. 
23. Women who are pregnant or breastfeeding. 
24. Any condition that would, in the investigator's judgment, interfere with full participation 
in the study, including administration of study treatment and attending required study 
visits; pose a significant risk to the participant; or interfere with interpretation of study 
data. 
25. Inability of the participant (or parent, guardian, or legally authorized representative) to 
comprehend the ICF or unwillingness to sign the ICF. 


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26. History of autoimmune disease that has required systemic treatment in past 2 years 
(ie, with use of disease modifying agents, corticosteroids, or immunosuppressive drugs). 
a. Replacement therapy (eg, thyroxine, insulin, physiologic corticosteroid replacement 
therapy for adrenal or pituitary insufficiency) is not considered a form of systemic 
treatment and is allowed. 
b. Brief (< 7 days) use of systemic corticosteroids is allowed when use is considered 
SOC. 
c. Participants with vitiligo, psoriasis, type 1 diabetes mellitus, hypothyroidism, or 
resolved childhood asthma/atopy will not be excluded. 
d. Participants requiring intermittent use of bronchodilators, inhaled steroids, or local 
steroid injections will not be excluded. 
e. Participants with hypothyroidism that is stable with hormone replacement or 
Sjögren's syndrome will not be excluded. 
27. Has a history of (noninfectious) pneumonitis that required steroids or has current 
pneumonitis or evidence of interstitial lung disease. 
28. Has received therapy with hematopoietic growth factor such as granulocyte colony-
stimulating factor or granulocyte-macrophage colony-stimulating factor in the 14 days 
prior to the start of study treatment. 
29. Has received a live vaccine within 30 days prior to the first dose of study drug.  Examples 
of live vaccines include, but are not limited to:  measles, mumps, rubella, varicella/zoster 
(chicken pox), Bacillus Calmette-Guerin.  Seasonal influenza vaccines for injection are 
allowed; however, intranasal influenza vaccine (eg, FluMist®) are not allowed. 
30. Has hypersensitivity to monoclonal antibodies (including pembrolizumab) and/or any of 
their excipients. 
31. Has severe hypersensitivity (≥ Grade 3) to carboplatin and/or gemcitabine and any of 
their excipients. 
32. Has a known psychiatric or substance abuse disorder that would interfere with the 
participant’s ability to cooperate with the requirements of the study. 
33. Has had an allogenic tissue/solid organ transplant. 
34. Has a known history of active tuberculosis (Bacillus tuberculosis). 
35. Is receiving hemodialysis. 
36. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy (at a dose 
exceeding 10 mg daily of prednisone equivalent) or any other form of 
immunosuppressive therapy within 7 days prior to randomization. 
37. History of hypovitaminosis D requiring supraphysiologic doses (eg, 50,000 UI/weekly) to 
replenish the deficiency.  Participants receiving vitamin D supplements are allowed. 
38. Any contraindication to pembrolizumab, gemcitabine, or carboplatin as per each package 
insert or SmPC. 


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5.3. 
Lifestyle Considerations 
5.3.1. 
Meals and Dietary Restrictions 
Based on the preliminary results from food-effect cohort in Study INCB 54828-101, no 
significant food effect was observed.  Pemigatinib may be administrated with or without food. 
Refrain from consumption of red wine, Seville oranges, and grapefruit or grapefruit juice 
(pomelos, exotic citrus fruits, grapefruit hybrids, or fruit juices) for 7 days before the start of 
study treatment until after the final dose since these can impact the bioavailability of pemigatinib. 
5.4. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently randomly assigned to study treatment and enrolled in the study. 
Tests with results that fail eligibility requirements may be repeated during screening if the 
investigator believes the result to be in error.  Additionally, a participant who fails screening may 
repeat the screening process 1 time if the investigator believes that there has been a change in 
eligibility status.  A participant who is rescreened is not required to sign another ICF if the 
rescreening occurs within 35 days from the previous ICF signature date. 
5.5. 
Replacement of Participants  
No participants will be replaced at any time during this study. 


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6. 
STUDY TREATMENT 
6.1. 
Study Treatments Administered 
Please see Table 10 for the list of possible treatments that will be tested in this study. 
Table 10: 
Study Treatment Information 
 
Study Treatment 
Study treatment 
name: 
Pemigatinib 
Pembrolizumab 
Gemcitabinea 
Carboplatina 
Dosage 
formulation: 
Tablet 
Solution, vial 
Sterile, lyophilized 
powder, liquid solution, 
or concentrate solution 
Sterile, lyophilized 
powder, liquid 
solution, or 
concentrate solution 
Unit dose 
strength(s) 
/dosage level(s): 
4.5, 9, 13.5, and 
18 mg tabletsb 
Dose:  13.5 mg 
daily dose 
100 mg/4 mL vial 
Dose:  200 mg daily 
200 mg/single-use vial 
or 1 g/single-use vial 
Dose:  1000 mg/m2 per 
administration 
Dose:  AUC 
5 mg/mL/min (or 
AUC 4.5 mg/mL/min 
if required per local 
guidelines) 
Route of 
administration:  
PO 
IV 
IV 
IV 
Administration 
instructions: 
Administered PO 
QD every day for 
each 21-day cycle 
until disease 
progression. 
Administered IV on 
Day 1 of each 21-day 
cycle for up to 
35 cycles 
Administered IV over 
30 minutes on Days 1 
and 8 of each 3-week 
cycle for up to 6 cycles 
(minimum of 4 cycles) 
in absence of 
progression or per 
institutional standard. 
Administered IV on 
Day 1 or 2 of each 
21-day cycle for up to 
6 cycles (minimum of 
4 cycles) in absence of 
progression or per 
institutional standard 
Packaging and 
labeling: 
Provided in 
14-count bottles. 
Each bottle will be 
labeled as required 
per country 
requirement. 
Provided in 
25 mg/mL solution 
for infusion. 
Gemcitabine will be 
obtained from each 
site's pharmacy stock.c 
Carboplatin will be 
obtained from each 
site's pharmacy stock.c 
Storage: 
Room temperature 
15°C-30°C 
(59°F-86°F) 
Refrigerated 2°C-8°C 
(36°F-46°F) 
Room temperature 
(refer to the applicable 
package insert) 
Room temperature, 
protect from light 
(refer to the applicable 
package insert) 
a Clinical supply concentration and formulation of chemotherapy may vary by local sourcing. 
b 18 mg tablets only administered if Protocol criteria are met for up-titration from 13.5 mg as described in 
Section 6.6.2.1. 
c The sponsor may provide certain reference therapies, such as gemcitabine or carboplatin, where required by 
applicable law or regulation, or under other limited circumstances when a participant may not otherwise have 
access to the therapies. 


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6.2. 
Phosphate Binders in Japan 
Details on phosphate binders in Japan only are provided in Table 11.  The phosphate binders are 
provided by the sponsor.  These binders should only be used for management of 
hyperphosphatemia during the study according to the recommendations described in 
Section 6.6.2. 
Table 11: 
Study Treatment 2 (Phosphate Binders for Japan) 
Study treatment name: 
Bixalomer 
Lanthanum carbonate hydrate 
Dosage formulation: 
Capsule 
Tablet 
Unit dose strength(s) 
/dosage level(s): 
250 mg 
250 mg 
Route of administration:  Oral 
Oral 
Administration 
instructions: 
The usual starting dose of bixalomer for 
adults is 500 mg 3 times daily just before 
meals.  The dose can be adjusted based on 
symptoms and serum phosphorus 
concentration.  The maximum daily dose 
should not exceed 7500 mg. 
The usual starting dose of lanthanum 
carbonate hydrate for adults is 750 mg  
3 times daily immediately after meals.  
The dose can be adjusted based on 
symptoms and serum phosphorus 
concentration.  The maximum daily dose 
should not exceed 2250 mg. 
Packaging and labeling: 
Bixalomer will be labeled as required per 
country requirement. 
Lanthanum carbonate hydrate will be 
labeled as required per country 
requirement. 
Storage: 
Per JP pharmacopeia, room temperature 
(1°C-30°C). 
Per JP pharmacopeia, room temperature 
(1°C-30°C). 
6.3. 
Preparation, Handling, and Accountability 
The investigator, investigational drug storage manager,  or designee must confirm appropriate 
temperature conditions have been maintained during transit for all study treatments received and 
any discrepancies are reported and resolved before use of the study treatment. 
Only participants enrolled in the study may receive study treatment, and only authorized site 
staff may supply or administer study treatment.  All study treatment must be stored in a secure, 
environmentally controlled, and monitored (manual or automated) area in accordance with the 
labeled storage conditions with access limited to the investigator, investigational drug storage 
manager, and authorized site staff. 
The investigator, investigational drug storage manager, or designee is responsible for study 
treatment accountability, reconciliation, and record maintenance (ie, receipt, reconciliation, and 
final disposition records).  Inventory and accountability records must be maintained and readily 
available for inspection by the study monitor and are open to inspection at any time by any 
applicable regulatory authorities.  The investigator, investigational drug storage manager, or 
designee must maintain records that document: 
• Delivery of study drug(s) to the study site. 
• Inventory of study drug(s) at the site. 


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• Participant use of the study drug(s) including pill and vial counts from each supply 
dispensed. 
• Lot numbers and/or vial numbers (as applicable) of study drug used to prepare the 
infusion solution. 
• Return of study drug(s) to the investigator, investigational drug storage manager, or 
designee by participants. 
Note:  Returned study treatment should not be redispensed to the participants. 
The investigational product must be used only in accordance with the Protocol (see Appendix C).  
The investigator or investigational drug storage manager will also maintain records adequately 
documenting that the participants were provided the specified study drug.  These records should 
include dates, quantities, and any available batch or serial numbers or unique code numbers 
assigned to the investigational product and study participants. 
Completed accountability records will be archived by the site.  The investigator, investigational 
drug storage manager, or designee will be expected to collect and retain all used, unused, and 
partially used containers of study drug until verified by the study monitor (unless otherwise 
agreed to by the sponsor).  At the conclusion of the study, the investigator, investigational drug 
storage manager, or designee will oversee shipment of any remaining study drug back to the 
sponsor or its designee for destruction according to institutional standard operating procedures.  
If local procedures mandate on-site destruction of investigational supply, the site should (where 
local procedures allow) maintain the investigational supply until the study monitor inspects the 
accountability records in order to evaluate compliance and accuracy of accountability by the 
investigative site.  At sites where the study drug is destroyed before monitor inspection, the 
monitors rely on documentation of destruction per the site's standard operating procedure. 
Further guidance and information for the final disposition of unused study treatments are 
provided in the Pharmacy Manual. 
For Japan, phosphate binders are provided by the sponsor.  Requirements for the accountability, 
reconciliation, and record maintenance of the binders is the same as for study drug as described 
above.  Further guidance and information are provided in the Japan-specific Pharmacy Manual. 
6.4. 
Measures to Minimize Bias:  Randomization and Blinding 
The study will be open-label due to the clear pharmacodynamic impact of pemigatinib on the 
participant (elevation of serum phosphate/hyperphosphatemia).  It is difficult to effectively blind 
the study, even with a double-dummy, due to serum phosphate elevation that occurs in most 
participants treated with pemigatinib. 
An ICR committee that is blinded to the assigned treatment will be used to evaluate radiographic 
tumor response to support the primary and secondary endpoints to minimize bias.  All 
participants will be centrally assigned to study treatment using an IRT.  Before the study is 
initiated, the telephone number and call-in directions for the IRT and/or the log in information 
and directions for the IRT will be provided to each site.  Full details will be provided in the IRT 
Study Reference Manual. 


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Study treatment will be dispensed at the study visits summarized in the schedule of activities (see 
Table 4).  See Table 8 for study treatment groups to be randomized. 
6.4.1. 
Stratification 
The stratification factors were selected to ensure that baseline characteristics known to have 
prognostic impact are distributed equally among the three treatment groups. 
Participants will be stratified by: 
• Carboplatin-eligible versus not eligible 
• PD-L1 CPS ≥ 10 versus PD-L1 CPS < 10 
• LN-only disease versus other metastatic disease 
6.4.1.1. 
PD-L1 CPS Results 
Recently acquired or archived tumor tissue (obtained since most recent therapy) from an 
unresectable or metastatic site must be analyzed and be evaluable for PD-L1 status during 
screening in order for a participant to be randomized.  PD-L1 status can be evaluated locally or 
centrally prior to randomization. 
For participants who have PD-L1 status evaluated centrally, investigators will be blinded to the 
central vendor's PD-L1 CPS results and will be alerted to completion of a participant's PD-L1 
evaluation, as well as to instances where the tumor tissue sample is inadequate for PD-L1 
evaluation (not evaluable).  PD-L1 CPS will influence stratification of patients prior to 
randomization into treatment groups.  
Note:  In the event the participant does not have local PD-L1 results or the sample is not 
evaluable for PD-L1, the participant will not be eligible. If a local result is available and the 
participant is randomized but the sample fails or the local result is not confirmed by the central 
laboratory, the site should contact the medical monitor. 
Treatment Group C 
• For carboplatin-eligible participants, all participants with PD-L1 CPS ≥ 10 will be 
assigned to pembrolizumab if randomized to Treatment Group C. 
• For carboplatin-ineligible participants, all participants who are carboplatin 
ineligible will be assigned to pembrolizumab regardless of their PD-L1 status, if 
randomized to Treatment Group C. 
Note:  Only applicable in regions where pembrolizumab is used as standard of care for 
participants who are not eligible for any platinum-containing chemotherapy regardless of 
PD-L1 status. 
6.5. 
Study Treatment Compliance 
Compliance with all study-related treatments should be emphasized to the participant by the site 
personnel, and appropriate steps should be taken to optimize compliance during the study.  
Compliance with pemigatinib will be monitored/calculated by the sponsor based on the drug 


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accountability documented by the site staff and monitored by the sponsor/designee 
(bottle/pill/vial counts). 
Participants will be instructed to bring all pemigatinib bottles/pills with them to the study visits 
in order for site personnel to conduct bottle/pill counts to assess study drug accountability.  The 
drug accountability documentation will be used by the sponsor to calculate treatment 
compliance. 
Compliance with study drug administration of pembrolizumab, gemcitabine, and carboplatin will 
be calculated by the sponsor based on study drug accountability and infusion records 
documented by the site staff and monitored by the sponsor/designee. 
Refer to Section 9.10 for additional information on overdose. 
6.6. 
Dose Modifications 
Individual decisions regarding dose modifications of pemigatinib, pembrolizumab, gemcitabine, 
and carboplatin should be made using clinical judgment and in consultation with the sponsor's 
medical monitor, taking into account relatedness of the AE to the study treatment and the 
participant's underlying condition.  Adverse events that have a clear alternative explanation, or 
transient (≤ 72 hours) abnormal laboratory values without associated clinically significant signs 
or symptoms, may be exempt from dose-reduction rules. 
Safety concerns should be discussed with the sponsor immediately upon occurrence or awareness 
to determine if the participant should continue or discontinue study treatment. 
6.6.1. 
Criteria and Procedures for Dose Interruptions and Adjustments of Pemigatinib 
Treatment with pemigatinib may be delayed up to 2 weeks (14 days) to allow for resolution of 
toxicity.  Participants may resume treatment if no medical condition or other circumstance exists 
that, in the opinion of the investigator, would make the participant unsuitable for further 
participation in the study.  The treating investigator should contact the sponsor to discuss the 
case of any participant whose treatment may be delayed for more than 14 days before restarting 
treatment with pemigatinib. 
For participants who present with possible or confirmed serous retinal detachment/retinal 
pigmented epithelium detachment (SRD/RPED) based on OCT, the guidelines in Table 12 
should be followed.  It is recommended to discuss the findings with the Incyte medical monitor 
before making changes to the participant's treatment. 
For participants randomized to receive pemigatinib in combination with pembrolizumab 
(Treatment Group A), participants may continue to receive pemigatinib or pembrolizumab as a 
monotherapy if criteria are met for dose interruption or discontinuation of either component. 
Guidelines for interrupting/restarting pemigatinib are provided in Table 12. 


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Table 12: 
Guidelines for Interruption and Restarting Pemigatinib 
ADVERSE EVENT 
ACTION TAKEN 
Chemistry 
• AST and/or ALT is > 5.0 × ULN. 
Note:  In participants with liver metastasis-related 
elevations at baseline, contact sponsor to discuss 
clinical management and possible dose reductions. 
Step 1:  Interrupt pemigatinib up to 2 weeks 
(14 days) until the toxicity has resolved to 
≤ Grade 1 except by approval of the medical 
monitor. 
Step 2:  Restart pemigatinib at same dose.  If 
assessed as related to pemigatinib, restart 
pemigatinib at next lower dose; monitor as 
clinically indicated. 
Other Toxicities, including SRD/RPED 
Any Grade 1 or Grade 2 toxicity. 
Continue pemigatinib treatment and treat the 
toxicity; monitor as clinically indicated. 
Any Grade 3 toxicity, if clinically significant and 
not manageable by supportive care. 
Step 1:  Interrupt pemigatinib up to 2 weeks 
(14 days) until the toxicity resolves to ≤ Grade 1. 
Step 2:  Restart pemigatinib at same dose.  If 
assessed as related to pemigatinib, restart 
pemigatinib at next lower dose; monitor as 
clinically indicated. 
Any recurrent Grade 3 toxicity after 2 dose 
reductions. 
Discontinue pemigatinib administration and 
follow-up per Protocol.  (Exceptions require 
approval of sponsor.) 
• Any other Grade 4 toxicity. 
• QT/QTcF to > 500 ms or to > 60 ms over 
baseline. 
Discontinue pemigatinib administration and 
follow-up per Protocol. 
For pemigatinib dose adjustments, the following dose reductions are permitted:  
• Participants dosed at 13.5 mg can reduce a maximum of 2 dose levels down; they can 
decrease to 9 mg, and, if additional dose reduction is required, participants can 
decrease to 4.5 mg. 
• Participants who are up-titrated to 18 mg as described in Section 6.6.2.1 can reduce a 
maximum of 3 dose levels down (13.5 mg then 9 mg) to 4.5 mg if indicated. 
Dose reductions below 4.5 mg are not allowed for any treatment group receiving pemigatinib.  
The frequency of dosing remains the same (QD) as well as the schedule (continuous dosing). 
6.6.2. 
Management of Hyperphosphatemia 
Hyperphosphatemia is an expected on-target pharmacologic effect of FGFR inhibition.  
Hyperphosphatemia should be managed with diet modifications, phosphate binders and diuretics, 
or a dose reduction per the recommendations in Table 13. 
If binders are used to manage hyperphosphatemia during treatment, it is recommended to stop 
binders at the same time pemigatinib is stopped to reduce risk of hypophosphatemia. 


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For Japanese participants, the phosphate binders bixalomer or lanthanum carbonate hydrate will 
be provided by the sponsor for treatment of hyperphosphatemia, when required (see Table 11). 
Table 13: 
Recommended Approach for Hyperphosphatemia Management 
Serum Phosphate 
Level 
Supportive Care 
Guidance for 
Interruption/Discontinuation 
of Pemigatinib 
Guidance for Restarting 
Pemigatinib 
> 5.5 mg/dL and 
≤ 7 mg/dL 
Initiate a low-phosphate 
diet. 
No action. 
Not applicable. 
> 7 mg/dL and 
≤ 10 mg/dL 
Initiate/continue a low-
phosphate diet and initiate 
phosphate-binding therapy 
once serum phosphate level 
is > 7 mg/dL.  Monitor 
serum phosphate at least 
twice a week and adjust the 
dose of binders as needed; 
continue to monitor serum 
phosphate at least twice a 
week until return to normal 
range. 
If serum phosphate level 
continues to be > 7 mg/dL and 
≤ 10 mg/dL with concomitant 
phosphate-binding therapy for 
2 weeks, or if there is 
recurrence of serum phosphate 
level in this range, interrupt 
pemigatinib for up to 2 weeks 
(not including the planned dose 
interruption per treatment 
cycle). 
Restart at the same dose 
when serum phosphate is 
< 7 mg/dL.  If serum 
phosphate level recurs at 
> 7 mg/dL, restart 
pemigatinib with dose 
reduction. 
> 10 mg/dL 
Continue to maintain a 
low-phosphate diet, adjust 
phosphate-binding therapy, 
and start/continue 
phosphaturic agent.  
Continue to monitor serum 
phosphate at least twice a 
week until return to normal 
range. 
If serum phosphate level is 
> 10 mg/dL for 1 week 
following phosphate-binding 
therapy and low phosphate diet, 
interrupt pemigatinib.  If there 
is recurrence of serum 
phosphate level in this range 
following 2 dose reductions, 
permanently discontinue 
pemigatinib. 
Restart pemigatinib at 
reduced dose with 
phosphate binders when 
serum phosphate is 
< 7 mg/dL. 
6.6.2.1. 
Up-Titration 
Any participant who does not reach the target serum phosphate level of > 5.5 mg/dL at any time 
during Cycle 1 and who is compliant with taking study drug and does not experience an ongoing 
Grade 2 or higher treatment-related AE will increase the daily dose to 18 mg starting at Cycle 2 
Day 1. 
Participants who are titrated up to 18 mg QD must begin the next cycle at the new dose level and 
must agree to all Cycle 1 assessments (
 safety assessments [hematology and blood 
chemistry]).  Up-titration may not occur earlier than on Day 1 of Cycle 2 so that participants are 
observed for phosphate level and AEs at least for 1 cycle. 
See Section 6.6.1 for maximum dose adjustments allowed for participants who are up-titrated. 


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6.6.3. 
Criteria for Permanent Discontinuation of Pemigatinib 
The occurrence of unacceptable toxicity not caused by the underlying disease will require that 
the pemigatinib be permanently discontinued.  Unacceptable toxicity is defined as follows: 
• Occurrence of an AE that is related to pemigatinib that, in the judgment of the 
investigator or the sponsor's medical monitor, compromises the participant's ability to 
continue study-specific procedures or is considered to not be in the participant's best 
interest. 
• An AE requiring more than the maximum amount of dose reductions. 
• Persistent AE requiring a delay of therapy for more than 3 weeks (21 days) unless a 
greater delay has been approved by the sponsor. 
• Increase in QT/QTcF to > 500 ms or to > 60 ms over baseline.  In case of a QTcF 
> 500 ms, the participant must be hospitalized, and a continuous ECG monitoring 
must be set up until the measure of the QTcF interval decreases below 500 ms and 
until acceptable in the opinion of a local cardiologist. 
See Section 7 for discontinuation procedures. 
6.6.4. 
Criteria for Procedures for Doses Interruptions or Adjustments of 
Pembrolizumab, Gemcitabine, and Carboplatin 
These agents are approved therapies and have specific participant safety management guidelines 
within the prescribing information; the treating investigator should refer to and follow the 
labeled guidances.  See Appendix B for criteria specific for pembrolizumab. 
6.7. 
Concomitant Medications and Procedures 
All concomitant medications and treatments (including over-the-counter or prescription 
medicines, vitamins, vaccines, and/or herbal supplements) must be recorded in the eCRF.  Any 
prior medication received up to 28 days before the first dose of study treatment and 30 days after 
the last dose of study treatment, or until the participant begins a new anticancer therapy, 
whichever occurs first, will be recorded in the eCRF.  Any addition, deletion, or change in the 
dose of these medications will also be recorded. 
Concomitant medications administered 90 days after the last dose of study treatment should be 
recorded for SAEs as defined in Section 9.  Concomitant treatments/procedures that are required 
to manage a participant's medical condition during the study will also be recorded in the eCRF. 
The medical monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
6.7.1. 
Restricted Medications and Procedures 
Pemigatinib is predominantly metabolized by CYP3A4.  There is a sufficient safety margin, with 
doses greater than the recommended Phase 2 dose of 13.5 mg QD having been tested, and up to 
20 mg QD is tolerable.  The expected 50% increase in exposure in participants who 
concomitantly use CYP3A4 moderate inhibitors is covered by the safety margin.  Therefore, the 
use of moderate CYP3A4 inhibitors should involve careful monitoring, especially in relation to 


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safety, while moderate CYP3A4 inducers and potent CYP3A4 inhibitors and inducers are 
prohibited (see Appendix D). 
Careful monitoring is required when pemigatinib is concomitantly administered with OCT2 
substrates such as dofetilide and metformin. 
Calcium-based phosphate binding medications should not be used due to a concern for soft tissue 
mineralization.  However, if other types of phosphate binders (eg, calcium-free sevelamer or 
lanthanum) are not available in certain regions, calcium-based binders may be used with 
appropriate clinical monitoring. 
6.7.2. 
Prohibited Medications and Procedures 
6.7.2.1. 
Prohibited Medications and Procedures for Pemigatinib 
A CYP3A4-mediated DDI study (INCB 54828-104) indicated there is evidence of a clinically 
significant effect on pemigatinib exposure when coadministered with a potent CYP3A4 inhibitor, 
itraconazole (increased pemigatinib AUC by 88%) or potent CYP3A4 inducer, rifampin 
(decreased pemigatinib AUC by 85%).  A PBPK model was developed and validated using in 
vitro and clinical DDI data.  PBPK model-simulated pemigatinib AUCs were increased by 
approximately 50% for moderate CYP3A4 inhibitors and decreased by more than 50% for 
moderate CYP3A4 inducers.  In addition, PBPK modeling showed no DDI effect when 
pemigatinib was coadministered with a weak CYP3A4 inhibitor or inducer. 
The following medications and measures are prohibited for pemigatinib. 
• The concomitant administration of potent CYP3A4 inhibitors and inducers and 
moderate CYP3A4 inducers (see Appendix D).  Based on the low overall 
bioavailability of topical ketoconazole, there are no restrictions on topical 
ketoconazole.   
• Any concomitant use of a selective FGFR inhibitor (other than pemigatinib). 
• Investigational study drug for any indication. 
• Use of any anticancer medications other than the study medications being tested in 
this Protocol. 
• Medications or vaccinations specifically prohibited in the exclusion criteria are not 
allowed during the ongoing study. 
Refer to the IB for more information on DDIs. 
Dose modifications for tolerability issues are noted in Section 6.6. 
6.7.2.2. 
Prohibited Medications and Procedures for Pembrolizumab, Gemcitabine, and 
Carboplatin 
Refer to the package inserts and SmPCs for restricted medications and procedures for 
gemcitabine and carboplatin. 


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Listed below are prohibited concomitant medications or vaccinations during the course of 
the study for pembrolizumab: 
• Antineoplastic systemic chemotherapy or biological therapy. 
• Immunotherapy not specified in this Protocol. 
• Chemotherapy not specified in this Protocol. 
• Investigational agents other than pembrolizumab. 
• Systemic glucocorticoids for any purpose other than to modulate symptoms from an 
AE that is suspected to have immunologic etiology.  Physiologic doses of 
corticosteroids not exceeding 10 mg daily of prednisone equivalent may be used 
during the study. 
Note:  Inhaled steroids are allowed for management of asthma or seasonal allergies. 
• Radiation therapy:  Palliative radiotherapy is permitted to a single lesion or to the 
brain (after discussion with the sponsor) if considered medically necessary by the 
treating physician, as long as the lesion is NOT a RECIST v1.1-defined target lesion 
and radiotherapy is NOT administered for tumor control. 
• Live vaccines within 30 days prior to the first dose of study intervention and while 
participating in the study.  Examples of live vaccines include, but are not limited to 
the following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, and 
typhoid vaccine.  Seasonal influenza vaccines for injection are generally killed virus 
vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist) are 
live attenuated vaccines and are not allowed. 
For participants who, in an assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management, continuation of study treatment and further 
participation in the study must be discussed and agreed upon with the sponsor.  If participants 
receive additional anticancer therapies, this will be judged to represent evidence of PD, and study 
treatment will be discontinued.  These participants should complete all end-of- treatment 
assessments and continue to be followed for survival in the follow-up period. 
6.7.3. 
Permitted Medications and Procedures 
6.7.3.1. 
Rescue Medications and Supportive Care for Pembrolizumab 
Participants should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.  Suggested supportive care measures for the management of AEs with 
potential immunologic etiology are outlined along with the dose modification guidelines in 
Appendix B.  Where appropriate, these guidelines include the use of oral or IV treatment with 
corticosteroids, as well as additional anti-inflammatory agents if symptoms do not improve with 
administration of corticosteroids.  Note that several courses of steroid tapering may be necessary 
as symptoms may worsen when the steroid dose is decreased.  For each disorder, attempts should 
be made to rule out other causes such as metastatic disease or bacterial or viral infection, which 
might require additional supportive care.  The treatment guidelines are intended to be applied 
when the investigator determines the events to be related to pembrolizumab.  


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Note:  If after the evaluation of the event, it is determined not to be related to pembrolizumab, the 
investigator does not need to follow the treatment guidance.  It may be necessary to perform 
conditional procedures such as bronchoscopy, endoscopy, or skin photography as part of 
evaluation of the event. 
6.8. 
Treatment After the End of the Study 
There is no treatment for the participant once criteria have been met for study discontinuation as 
described in Section 7. 
7. 
DISCONTINUATION OF STUDY TREATMENT AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
7.1. 
Discontinuation of Study Treatment 
7.1.1. 
Reasons for Discontinuation 
Participants must be withdrawn from study treatment for the following reasons.  Please note that 
if a participant discontinues study treatment for reasons other than disease progression or 
withdraw of consent, the participant should be followed until disease progression is documented. 
• The participant or participant's legally acceptable representative requests to 
discontinue study intervention. 
• The participant interrupts pemigatinib administration for more than 21 days (unless 
Sponsor has given approval to continue). 
• The participant interrupts pembrolizumab administration for more than 12 weeks 
(unless Sponsor has given approval to continue). 
• The participant has a confirmed positive serum pregnancy test. 
• Disease progression has been reported per RECIST v1.1. 
• Other anticancer treatment is initiated. 
• Consent is withdrawn.   
Note:  Consent withdrawn means that the participant has explicitly indicated that they 
do not want to be followed any longer; in this case no further data, except data in 
public domain, may be solicited from or collected on the participant.  Participants 
may choose to discontinue study treatment and remain in the study to be followed for 
progression and survival. 
• Further participation would be injurious to the participant's health or well-being, in 
the investigator's medical judgment. 
• Unacceptable toxicity as noted in Section 6.6.1. 
• The study is terminated by the sponsor, local health authority, IRB, or IEC. 


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• Completion of 35 treatment cycles (approximately 2 years) with pembrolizumab plus 
pemigatinib or pembrolizumab monotherapy.  Note:  Participants in Treatment 
Group A (pembrolizumab + pemigatinib) must discontinue pembrolizumab after 
35 treatment cycles but can continue pemigatinib until PD. 
• Intercurrent illness other than another malignancy as noted above that prevents 
further administration of treatment 
• Recurrent Grade 3 colitis/diarrhea. 
• Any progression or recurrence of any malignancy, or any occurrence of another 
malignancy that requires active treatment. 
• Recurrent Grade 2 pneumonitis. 
A participant may be discontinued from study treatment as follows: 
• If, during the course of the study, a participant is found not to have met eligibility 
criteria, the medical monitor, in collaboration with the investigator, will determine 
whether the participant should be withdrawn from study treatment. 
• If a participant is noncompliant with study procedures or study treatment 
administration in the investigator's opinion, the sponsor should be consulted for 
instruction on handling the participant. 
7.1.2. 
Discontinuation Procedures 
In the event that the decision is made to permanently discontinue the study treatment, the EOT 
visit should be conducted.  Reasonable efforts should be made to have the participant return for a 
follow-up visit.  These visits are described in the schedule of activities (see Table 4).  The last 
date of the last dose of study treatment and the reason for discontinuation of study treatment will 
be recorded in the eCRF. 
If a participant is discontinued from study treatment: 
• The study monitor or sponsor must be notified immediately. 
• The reason(s) for withdrawal must be documented in the participant's medical record, 
and the primary reason for withdrawal must be included in the eCRF. 
• The EOT visit should be performed. 
• The date of the EOT visit should be recorded in the IRT. 
• Participants must be followed for safety until the time of the follow-up visit or until 
study treatment–related toxicities resolve, return to baseline, or are deemed 
irreversible, whichever is longest. 
If the participant discontinues study treatment and actively withdraws consent for collection of 
follow-up data (safety follow-up or disease assessment), then no additional data collection 
should occur; however, participants will have the option of withdrawing consent for study 
treatment but continuing in the follow-up period of the study for safety, efficacy, and survival 
assessments. 


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7.2. 
Participant Withdrawal From the Study 
A participant may withdraw from the study at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioral, compliance, or 
administrative reasons. 
If the participant withdraws consent for disclosure of future information, the sponsor may retain 
and continue to use any data collected before such a withdrawal of consent. 
If a participant withdraws from the study, he/she may request destruction of any samples taken 
and not tested, and the investigator must document this in the site study records. 
See Table 4 and Table 5 for data to be collected at the time of study discontinuation and 
follow-up and for any further evaluations that need to be completed. 
7.3. 
Lost to Follow-Up 
A participant will be considered lost to follow-up if he/she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
• The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible and counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the participant wishes to and/or 
should continue in the study. 
• Before a participant is deemed lost to follow-up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant's last known mailing address 
or local equivalent methods).  These contact attempts should be documented in the 
participant's medical record. 
• Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 


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






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Bone scans and brain imaging will be performed at baseline for all participants with clinical 
symptoms of bone or brain metastases.  Bone scans at baseline must be sent to central imaging 
vendor for review with initial tumor imaging.  Participants with positive bone scans at baseline 
will be followed with additional scans performed every 9 weeks (± 7 days) from date of 
randomization, or more frequently if clinically indicated.  For participants with new symptoms 
suggestive of osseous metastasis, a bone scan should be obtained.  Additionally, plain X-ray 
evaluation should be obtained for symptomatic sites with negative bone scan evaluations. 
When the investigator identifies radiographic progression per RECIST v1.1, the central imaging 
vendor will perform expedited verification of radiologic PD, and communicate the results to the 
study site and sponsor.  Treatment should continue until PD has been verified.  
For participants who discontinue study treatment for reasons other than disease progression, 
every effort should be made to continue monitoring their disease status by radiographic imaging 
until the start of new anticancer treatment, disease progression, pregnancy, death, withdrawal of 
consent, or the end of the study, whichever occurs first. 
8.2.1.1. 
Initial Tumor Imaging 
Initial tumor imaging at screening must be performed within 35 days prior to the date of 
randomization.  Any imaging obtained after Cycle 1 Day 1 cannot be included in the screening 
assessment.  The site study team must review screening images to confirm that the participant 
has measurable disease per RECIST v1.1. 
Screening images must be submitted to the BICR committee for retrospective review. 
Tumor imaging performed as part of routine clinical management is acceptable as screening 
imaging if it is of diagnostic quality and performed within 35 days prior to the date of 
randomization and can be assessed by BICR. 
Tumor imaging required at baseline includes the following: 
• CT (preferred) or MRI of the abdomen and pelvis 
• CT of the chest 
• Bone scan (whole body) and brain imaging only if participant has clinical symptoms 
of brain or bone metastases 
If brain imaging is performed to document the stability of existing metastases, MRI should be 
used if possible.  If MRI is medically contraindicated, CT with contrast is an acceptable 
alternative. 
8.2.2. 
Tumor Imaging During the Study 
The first on-study imaging assessment should be performed at 9 weeks (63 days + 7 days) from 
the date of randomization.  Subsequent tumor imaging should be performed every 9 weeks 
(63 days ± 7 days) or more frequently if clinically indicated.  After 54 weeks (378 days 
± 7 days), participants who continue receiving study intervention will have imaging every 
12 weeks (84 days ± 7 days).  Imaging timing should follow calendar days and not be adjusted 
for delays in cycle starts.  Imaging should continue to be performed until disease progression is 
identified by the investigator and verified by BICR, the start of new anticancer treatment, 


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withdrawal of consent, or death.  All supplemental imaging must be submitted to the imaging 
central vendor as soon as possible.  Brain imaging and bone scans must be repeated at the same 
frequency as other imaging assessments if positive at baseline or if participants exhibit 
symptoms indicative of bone or brain metastases. 
Objective response should be confirmed by a repeat imaging assessment.  Tumor imaging to 
confirm PR or CR should be performed at least 4 weeks after the first indication of a response.  
Participants will then return to regular scheduled imaging, starting with the next scheduled 
imaging time point.  Participants who have additional imaging for confirmation do not need to 
undergo the next scheduled tumor imaging if it is less than 4 weeks later; tumor imaging may 
resume at the subsequent scheduled imaging timepoint. 
Note:  Response does not typically need to be verified in real time by BICR. 
8.2.2.1. 
End of Treatment and Follow-Up Tumor Imaging 
For participants who discontinue study treatment, tumor imaging should be performed at the time 
of treatment discontinuation (± 4 weeks).  If previous imaging was obtained within 4 weeks prior 
to the date of discontinuation, imaging at treatment discontinuation is not mandatory.  For 
participants who discontinue study treatment due to documented disease progression, this is the 
final required tumor imaging. 
For participants who discontinue study treatment without documented disease progression, every 
effort should be made to continue monitoring disease status by tumor imaging with the same 
imaging schedule used during treatment, calculated from the date of randomization until the start 
of new anticancer treatment, disease progression, pregnancy, death, withdrawal of consent, or the 
end of the study, whichever occurs first. 
8.2.3. 
ECOG Performance Status 
ECOG performance status (see Table 14) will be assessed at the visits specified in the schedule 
of activities (see Table 4). 
Table 14: 
ECOG Performance Status 
Grade 
Performance Status 
0 
Fully active, able to carry on all predisease performance without restriction. 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light 
or sedentary nature, eg, light house work, office work. 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities.  Up and 
about more than 50% of waking hours. 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours. 
4 
Completely disabled.  Cannot carry on any self-care.  Totally confined to bed or chair. 
5 
Dead. 
Source:  Oken et al 1982. 


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8.3. 
Quality of Life Assessments 
The EORTC QLQ-C30 and EQ-5D-5L are not pure efficacy or safety endpoints because they are 
affected by both disease progression and treatment tolerability.  Participants will be asked to 
complete the EORTC QLQ-C30 and EQ-5D-5L.  Questionnaires must be completed at each 
interval prior to receiving study treatment as indicated in the schedule of activities (see Table 4). 
8.3.1. 
EORTC QLQ-C30 
The EORTC QLQ-C30 is the most widely used cancer specific health-related quality of life 
instrument, which contains 30 items and measures 5 functional dimensions (ie, physical, role, 
emotional, cognitive, and social), 3 symptom items (ie, fatigue, nausea/vomiting, and pain), 
6 single items (ie, dyspnea, sleep disturbance, appetite loss, constipation, diarrhea, and financial 
impact), and a global health and quality of life scale (Aaronson et al 1993).  The reliability, 
validity, and practicality of these instruments have been reported.  This instrument is translated 
and validated into more than 80 languages.  For each scale and single item, a linear 
transformation will be applied to standardize the scores between 0 (worst) and 100 (best) as 
described in the EORTC QLQ-C30 Scoring Manual. 
8.3.2. 
EQ-5D-5L 
The EQ-5D-5L is a standardized instrument for use as a measure of health outcome (Rabin and 
de Charro 2001).  The EQ-5D-5L will provide data for use in economic models and analyses 
including developing health utilities or quality adjusted life years.  The 5 health state dimensions 
in this instrument include the following:  mobility, self -care, usual activities, pain/discomfort, 
and anxiety/depression.  Each dimension is rated on a three point scale from 1 (extreme problem) 
to 3 (no problem).  The EQ-5D-5L also includes a graded (0 to 100) vertical visual analog scale 
on which the participant rates his or her general state of health at the time of the assessment.  The 
EQ-5D-5L will always be completed by participants first before completing the EORTC 
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8.5. 
Safety Assessments 
See Section 6.6 for guidelines regarding the management of relevant laboratory or other safety 
assessment abnormalities. 
8.5.1. 
Adverse Events 
Adverse events (CTCAE v5.0) will be monitored from the time the participant signs the ICF 
until at least 30 days for after the last dose of study treatment.  SAEs must be reported up until 
90 days after the last dose of study treatment or 30 days if participant starts a new anticancer 
therapy, whichever is earlier.  Adverse events that begin or worsen after informed consent should 
be recorded on the Adverse Events Form in the eCRF regardless of the assumption of a causal 
relationship with the study treatments.  Conditions that were already present at the time of 
informed consent should be recorded on the Medical History Form in the eCRF.  Adverse events 
(including laboratory abnormalities that constitute AEs) should be described using a diagnosis 
whenever possible rather than by individual underlying signs and symptoms. 
Adverse events will be reported by the participant (or, when appropriate, by a caregiver, 
surrogate, or the participant's legally authorized representative).  The investigator and any 
qualified designees are responsible for detecting, documenting, and recording events that meet 
the definition of an AE or SAE and remain responsible for following-up on AEs that are serious, 
considered related to the study treatment/procedures, or that caused the participant to discontinue 
the study treatment.  Care will be taken not to introduce bias when detecting AEs and/or SAEs.  
Open-ended and nonleading verbal questioning of the participant, such as "How are you 
feeling?" is the preferred method to inquire about AE occurrences.  Adverse events may also be 
detected when they are volunteered by the participant during the screening process or between 
visits, or through physical examinations, laboratory tests, or other assessments.  The definition, 
reporting, and recording requirements for AEs are described in Section 9. 
All SAEs will be recorded and reported to the sponsor or designee within 24 hours.  The 
investigator will submit any updated SAE data to the sponsor within 24 hours of it being 
available. 
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts.  All SAEs will be followed until resolution, stabilization, the event 
is otherwise explained, or the participant is lost to follow-up (as defined in Section 7.3). 
For Japanese participants, the relationship to phosphate binders should also be collected on the 
Adverse Events Form in the eCRF. 
8.5.2. 
Physical Examinations 
Physical examinations must be performed by a medically qualified individual, such as a licensed 
physician, physician's assistant, or an advanced registered nurse practitioner, as local law 
permits.  Abnormalities identified after the first dose of study treatment constitute an AE if they 
are considered clinically meaningful, induce clinical signs or symptoms, require concomitant 
therapy, or require changes in study treatment.  Investigators should pay special attention to 
clinical signs related to previous serious illnesses. 
At the screening visit, a comprehensive physical examination should be conducted.  The 
comprehensive physical examination will include height and body weight, and assessment(s) of 


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the following organ or body systems:  skin; head, eyes, ears, nose, and throat; thyroid; lungs; 
cardiovascular system; abdomen (liver, spleen); extremities; and lymph nodes; as well as a brief 
neurological examination. 
During the study, participants will be assessed by the investigator or medically qualified 
designee per institutional SOC.  These targeted examinations should be an evaluation as 
indicated by participant symptoms, AEs, or other findings and documented on the AE eCRF. 
8.5.3. 
Vital Signs 
Vital sign measurements (to be taken before blood collection for laboratory tests), include blood 
pressure, pulse, respiratory rate, and body temperature.  If vital signs cannot be taken before 
blood collection for laboratory tests, there must be a minimum of 30 minutes from the 
completion of the blood collection procedures to the beginning of the vital signs collection.  
Blood pressure and pulse will be taken with the participant in the recumbent, semirecumbent, or 
sitting position after 5 minutes of rest.  Weight will also be assessed at each study visit.  
Abnormal vital sign results identified after the first dose of study treatment constitute an AE if 
they are considered clinically meaningful, induce clinical signs or symptoms, require 
concomitant therapy, or require changes in study treatment. 
8.5.4. 
Electrocardiograms 
A single 12-lead ECG will be obtained at the study visits noted in the schedule of activities (see 
Table 4).  The ECGs will be performed with the participant in a supine or semisupine position 
after approximately 5 to 10 minutes of rest.  Sites should use an ECG machine that automatically 
calculates the heart rate and measures PR, QRS, QT, and QTc intervals.  If the screening ECG 
renders abnormal but not clinically significant results, the investigator should use clinical 
judgement to perform additional monitoring during study treatment.  Clinically notable 
abnormalities that are considered clinically significant in the judgment of the investigator are to 
be reported as AEs.  In the event that a single QTc is > 480 ms at screening, the participant may 
enroll if the average QTc for the 3 ECGs is ≤ 480 ms or with approval from the medical monitor.  
For participants with an intraventricular conduction delay (QRS interval > 120 ms) at screening, 
the JTc interval may be used in place of the QTc with medical monitor approval.  The JTc must 
be ≤ 340 ms if JTc is used in place of the QTc.  In addition, the JTc interval should be used for 
all subsequent assessments. 
8.5.5. 
Comprehensive Eye Examination 
A comprehensive eye examination should be performed by a qualified ophthalmologist at 
screening on all participants, once every 3 cycles (± 7 days starting with Cycle 3) for participants 
randomized to Treatment Groups A and B only, at EOT for all participants, and as clinically 
indicated.  The eye examination should include a visual acuity test, slit-lamp examination, 
funduscopy with digital imaging, and OCT.  Every effort should be made to ensure that all 
subsequent examinations are performed by the same ophthalmologist. 
8.5.6. 
Laboratory Assessments 
See Table 15 for the list of clinical laboratory tests to be performed and the schedule of activities 
for the timing and frequency (see Table 4).  The site's local laboratory will perform all clinical 


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laboratory assessments for safety (ie, blood chemistries, hematology assessments, coagulation 
tests, endocrine function, and urinalysis).  
 
  Additional testing may be required by the sponsor based on emerging 
safety data.  All Protocol-required laboratory assessments must be conducted in accordance with 
the Laboratory Manual and the schedule of activities (see Table 4).  Information regarding 
collection, processing, and shipping of laboratory assessments is provided in the Laboratory 
Manual. 
Serum phosphate testing is required on a more frequent basis if a participant develops 
hyperphosphatemia during Cycle 1 and is up-titrated (see Section 6.6.2.1).  Parathyroid hormone 
(endocrine) testing will be required at baseline and every 3 cycles starting with Cycle 3 (only for 
participants who are randomized to receive a regimen that includes pemigatinib) as parathyroid 
hormone plays a role in calcium and phosphate hemostasis (Khundmiri et al 2016). 
Clinically significant abnormal laboratory findings are those which are not associated with the 
underlying disease, unless judged by the investigator to be more severe than expected for the 
participant's condition.  All laboratory tests with values considered clinically significantly 
abnormal during participation in the study or within 30 days after the last dose of study treatment 
should be repeated until the values return to normal or baseline or are no longer considered 
clinically significant by the investigator or medical monitor. 
Screening laboratory assessments must be performed within 14 days of Cycle 1 Day 1.  If 
performed more than 14 days before Cycle 1 Day 1, then the tests must be repeated and 
eligibility confirmed before study treatment administration on Cycle 1 Day 1.  Laboratory 
samples collected on study Day 1 must be performed before study treatment administration.  
After Cycle 1, predose laboratory procedures can be conducted up to 72 hours before study 
treatment administration (within the 3-day study window), and results should be reviewed by the 
investigator or qualified designee and found to be acceptable before a new cycle of treatment is 
initiated. 
See Section 9.1 for information regarding laboratory abnormalities that should be recorded as an 
AE in the eCRF.  Additionally, if laboratory values from laboratory assessments performed at the 
institution's local laboratory require a change in participant management (eg, require treatment), 
or are considered clinically significant by the investigator (eg, SAE or AE or dose modification), 
then the result(s) of the specific laboratory assessment(s) must be recorded in the eCRF. 


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Table 15: 
Required Laboratory Analytes 
Blood Chemistries 
Hematology 
Urinalysis With 
Microscopic Examination 
Serology 
Coagulation 
Albumin 
ALP 
ALT 
AST 
Amylase 
Bicarbonate or CO2 a 
Blood urea nitrogen or urea 
Calcium 
Chloride 
Creatinine 
Glucose 
Lactate dehydrogenase 
Lipase 
Phosphate 
Potassium 
Sodium 
Total bilirubin 
Direct bilirubin (if total bilirubin is 
elevated above ULN) 
Total protein 
Uric acid 
Vitamin D (25-hydroxyvitamin D 
and 1,25-dihydrosyvitamin D) 
CBC, including: 
• Hemoglobin 
• Hematocrit 
• Platelet count 
• Red blood cell count 
• WBC count 
 
Differential count, including: 
• Basophils 
• Eosinophils 
• Lymphocytes 
• Monocytes 
• Neutrophils 
 
Absolute values must be 
provided for: 
• WBC differential 
laboratory results 
Color and appearance 
pH and specific gravity 
Bilirubin 
Glucose 
Ketones 
Leukocytes 
Nitrite 
Occult blood 
Protein 
HBsAg 
HBsAg antibody 
Hepatitis B core antibody 
HCV antibody 
Note:  If any of the above are 
positive, HBV DNA, HCV 
RNA to assess risk of 
reactivation. 
HIV (if applicable)  
INR 
PT 
aPTT or PTT 
Endocrine Function 
Pregnancy Testing 
Parathyroid hormone 
TSH (T3, T4 if TSH 
abnormal) 
Women of childbearing 
potential only require a 
serum test at screening 
(maximum 7 days before 
study drug 
administration) and EOT, 
and a urine pregnancy 
test for all other 
assessments. 
Pregnancy tests (serum or 
urine) should be repeated 
on Day 1 of each cycle, if 
required by local 
regulations. 
Note:  Additional tests may be required, as agreed upon by the investigator and sponsor, based on emerging safety data, or as required by local regulations. 
a Not required in Japan. 


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8.5.6.1. 
Pregnancy Testing 
A serum pregnancy test will be required for all women of childbearing potential during screening 
(a maximum of 7 days before the first dose of study treatment) and at the EOT visit.  Urine 
pregnancy tests will be performed locally as outlined in Table 4, as medically indicated (eg, in 
case of loss of menstrual cycle, when pregnancy is suspected), or per country-specific 
requirement (note that country-required urine pregnancy testing will be outlined and 
communicated to investigational sites under separate cover).  If a urine pregnancy test is positive, 
the results should be confirmed with a serum pregnancy test. 
If the serum pregnancy test is negative after a urine test was positive, the investigator will assess 
the potential benefit/risk to the participant and determine whether it is in the participant's best 
interest to resume study treatment and continue participation in the study. 
If a pregnancy is confirmed by a serum pregnancy test, see Section 9.7 for reporting 
requirements. 
8.5.6.2. 
Serology 
Hepatitis screening assessments will be performed at the screening visit to rule out hepatitis 
infection; required analytes are shown in Table 15.  Generally, hepatitis tests should be 
performed early in the screening process due to the length of time needed to obtain the results.  
Additional tests may be performed if clinically indicated. 


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8.7. 
Pharmacodynamic and Translational Assessments 
Refer to Table 4, Table 5, Table 17, and Figure 2 for additional information on timing of 
assessments. 
8.7.1. 
Tumor Tissue Collection and Requirements 
All potential participants must have documented FGFR3 mutation or rearrangement and PD-L1 
status prior to randomization; screening and randomization  may be based on local genomics 
and PD-L1 results, but confirmatory testing through the sponsor’s central laboratory will be 
performed on all participants during the study.  Participants who have a Dako PD-L1 IHC 22C3 
pharmDx report will not need to have their PD-L1 status confirmed centrally.  Participants who 
have a documented FGFR3 mutation or rearrangement confirmed by Foundation Medicine do 
not need the FGFR status reconfirmed centrally if the report is within 24 months.  Since 
confirmation via central laboratory is required, a pathologist review/quality check of samples 
should be performed prior to shipment.  Based on data from study INCB 54828-201, the 
concordance rate for FGFR testing was about 90% for approximately 20 participants. 
Requirement of biopsies for FGFR3 genomic alteration (see Section 8.7.1.1) and PD-L1 test (see 
Section 8.7.1.2):  a tumor tissue sample from < 24 months prior to screening from the primary or 
metastatic lesion or newly obtained core or excisional biopsy from the primary or metastatic 
lesion that were not previously irradiated must be provided to the central laboratory for testing.  
Formalin fixed, paraffin-embedded tissue blocks are preferred to slides.  If providing slides, the 
requirement is 15 to 25 unstained consecutive FFPE slides (see Figure 2).  Newly obtained 
biopsies are preferred to archived tissue. Tissue from a metastatic lesion or advanced bladder 
cancer is preferred to NMIBC or MIBC.  Detailed instructions for tissue collection, handling, 
processing, and shipment are provided in the Laboratory Manual. 
8.7.1.1. 
Tumor For Genomics Testing for FGFR Genetic Alterations and Gene 
Expression 
If submitting unstained cut slides, 10 unstained, consecutive FFPE, newly cut slides should be 
submitted to the testing laboratory (Foundation Medicine) within 30 days from the date they are 
cut (details pertaining to tumor submission are in the Procedures Manual).  Details for sample 
collection, processing, and shipping will be provided in the Laboratory Manual.  Participants 
who have a documented FGFR3 mutation or rearrangement confirmed by Foundation Medicine 
do not need the FGFR status reconfirmed centrally if the report is within 24 months. 
Refer to Appendix E for a list of known FGFR3 alterations.  Novel alterations may be discovered 
in which case the Sponsor must be contacted to review eligibility. 
8.7.1.2. 
Tumor Tissue Collection for Testing PD-L1 Expression 
PD-L1 expression must be tested by a local or central laboratory as part of the prescreening or 
screening process using an approved IHC companion diagnostic (ie, Dako PD-L1 IHC 22C3 
pharmDx).  A participant can be randomized using a local report but this will need to be 
retrospectively confirmed by the sponsor’s central lab. Patients who have a Dako PD-L1 IHC 
22C3 pharmDx report will not need to have their PD-L1 status confirmed centrally. PD-L1 status 
(CPS ≥10 or CPS < 10) must be determined during the screening period prior to randomization.  
If submitting unstained cut slides, 3 unstained, consecutive FFPE, newly cut slides should be 


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submitted to the testing laboratory within 30 days from the date they are cut (details pertaining to 
tumor submission are in the Procedures Manual).  Details for sample collection, processing, and 
shipping will be provided in the Laboratory Manual. 


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8.8. 
Unscheduled Visits 
Unscheduled visits may occur as clinically indicated.  They can be used for visits that occur 
outside of visit windows and should be noted in the eCRF as an unscheduled visit. 
8.9. 
End of Treatment and/or Early Termination 
When the participant permanently discontinues study treatment, whether the participant is 
terminating the study early or the participant has completed the study, the EOT visit should be 
conducted.  If the EOT visit coincides with a regular study visit, the EOT evaluations will 
supersede those of that scheduled visit, and the data should be entered in the EOT visit in the 
eCRF.  The participant should be encouraged to return for the follow-up visit. 


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8.10. 
Follow-Up 
8.10.1. 
Safety Follow-Up 
The safety follow-up period is the interval between the EOT visit and the scheduled follow-up 
visit, which should occur no later than 30 days after the EOT visit (or after the last dose of study 
treatment if the EOT visit was not performed).  Adverse events and SAEs must be reported up 
until 1) at least 30 days after the last dose of study treatment, the date of the follow-up visit, or 
the start of a new anticancer therapy or 2) until toxicities resolve, return to baseline, or are 
deemed irreversible, whichever is longer.  Reasonable efforts should be made to have the 
participant return for the follow-up visit and report any AEs that may occur during this period.  If 
the participant cannot return to the site for the safety follow-up visit (eg, lives far away), the 
participant should be contacted by telephone for assessment of AEs and SAEs.  Sites should 
document this contact in the source. 
If a participant is scheduled to begin a new anticancer therapy before the end of the 30-day safety 
follow-up period, the safety follow-up visit should be performed before new anticancer therapy 
is started.  Once new anticancer therapy has been initiated, the participant will move into the 
survival follow-up period. 
8.10.2. 
Post-Treatment Disease Follow-Up 
Participants who discontinue study treatment for a reason other than disease progression will 
move into the disease status follow-up period and should continue to be assessed by radiologic 
imaging to monitor disease status at the same schedule as if continuing on treatment per the 
schedule of activities (see Table 4).  Every effort should be made to collect information 
regarding disease status until: 
• The start of new anticancer therapy. 
• Disease progression (confirmed by BICR). 
• Pregnancy. 
• Death. 
• Withdrawal of consent. 
• The end of the study. 
8.10.3. 
Survival Follow-Up 
Once a participant has received the last dose of study treatment, has confirmed disease 
progression, or starts a new anticancer therapy, the participant moves into the survival follow-up 
period and should be contacted by telephone, email, or visit at least every 12 weeks to assess for 
survival status until death, withdrawal of consent, or the end of the study, whichever occurs first. 
For participants having entered the survival follow-up period of the study, the site will use 
continuing participant records to supply data on subsequent treatment regimens, tumor 
assessments (if discontinued treatment for a reason other than progression), and OS in the eCRF.  
For participants who do not intend to return to the study investigator for their ongoing care, 
follow-up should be maintained by phone contact, participant records, and public 


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records/databases at intervals of no longer than 6 weeks.  After the final primary analysis is 
performed, the follow-up interval for subsequent anticancer treatments and survival may be 
reduced to every 12 weeks. 
9. 
ADVERSE EVENTS:  DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING 
9.1. 
Definition of Adverse Event 
Adverse Event Definition 
• An AE is any untoward medical occurrence associated with the use of a drug in humans, whether or not 
considered drug-related. 
• An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease (new or exacerbated) temporally associated with the use of study 
treatment. 
Events Meeting the Adverse Event Definition  
• Any safety assessments (eg, ECG, vital signs measurements), including those that worsen from 
baseline, considered clinically significant in the medical and scientific judgment of the investigator (ie, 
not related to progression of underlying disease). 
• Abnormal laboratory test results constitute an AE if they are considered clinically meaningful, induce 
clinical signs or symptoms, require concomitant therapy, or require changes in study drug.  Whenever 
possible, a diagnosis (eg, anemia, thrombocytopenia) should be recorded in the eCRF rather than the 
abnormal lab result (eg, low hemoglobin, platelet count decreased). 
• Exacerbation of a chronic or intermittent pre-existing condition including either an increase in 
frequency and/or intensity of the condition. 
• New conditions detected or diagnosed after study treatment administration even though they may have 
been present before the start of the study. 
• Signs, symptoms, or the clinical sequelae of a suspected DDI. 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study treatment or a 
concomitant medication.  Overdose per se will not be reported as an AE/SAE unless it is an intentional 
overdose taken with possible suicidal/self-harming intent.  Such overdoses should be reported 
regardless of sequelae. 
• "Lack of efficacy" or "failure of expected pharmacological action" per se will not be reported as an AE 
or SAE.  Such instances will be captured in the efficacy assessments.  However, the signs, symptoms, 
and/or clinical sequelae resulting from lack of efficacy will be reported as an AE or SAE if they fulfill 
the definition of an AE or SAE. 


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Events NOT Meeting the Adverse Event Definition 
• Any clinically significant abnormal laboratory findings or other abnormal safety assessments that are 
associated with the underlying disease, unless judged by the investigator to be more severe than 
expected for the participant's condition. 
• The disease/disorder being studied or expected progression, signs, or symptoms of the disease/disorder 
being studied, unless more severe than expected for the participant's condition or considered to be 
treatment-related by the investigator. 
• Efficacy endpoints as outlined in Section 3 will not be reported as AE/SAEs, specifically, any event 
that is related to disease progression of the cancer under study.  Unblinded aggregated efficacy endpoint 
events and safety data will be monitored to ensure the safety of the participants in the study.  Any 
suspected endpoint that upon review is not progression of the cancer under study will be forwarded to 
Incyte Pharmacovigilance as a SAE within 24 hours of determination that the event is not progression 
of the cancer under study. 
• Medical or surgical procedure (eg, endoscopy, appendectomy):  the condition that leads to the 
procedure is the AE if it occurred after signing informed consent.  If present before entering the study, 
the condition should be captured as medical history. 
• Situations in which an untoward medical occurrence did not occur (social and/or convenience 
admission to a hospital). 
• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or detected at the 
start of the study that do not worsen. 
9.2. 
Definition of Serious Adverse Event 
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met (eg, hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease). 
A Serious Adverse Event is defined as any untoward medical occurrence that, at any dose: 
a. Results in death 
b. Is life-threatening 
The term 'life-threatening' in the definition of 'serious' refers to an adverse drug experience that places the 
participant, in the opinion of the initial reporter, at immediate risk of death from the adverse experience as 
it occurred.  This does not include an adverse drug experience that, had it occurred in a more severe form, 
might have caused death. 
c.  Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the participant has been detained (usually involving at least an 
overnight stay) at the hospital or emergency ward for observation and/or treatment that would not have 
been appropriate in the physician's office or outpatient setting.  Complications that occur during 
hospitalization are AEs.  If a complication prolongs hospitalization or fulfills any other serious criteria, 
the event is serious.  When in doubt as to whether "hospitalization" occurred or was necessary, the AE 
should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from baseline is not 
considered an AE. 


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d. Results in persistent or significant disability/incapacity 
• The term disability means a substantial disruption of a person's ability to conduct normal life functions. 
• This definition is not intended to include experiences of relatively minor medical significance, such as 
uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental trauma (eg, sprained 
ankle), that may interfere with or prevent everyday life functions but do not constitute a substantial 
disruption. 
e.  Is a congenital anomaly/birth defect 
f. Other situations (Important Medical Event) 
An event that may not result in death, be immediately life-threatening, or require hospitalization, but may 
be considered serious when, based on appropriate medical judgment, the event may jeopardize the 
participant and may require medical or surgical intervention to prevent one of the outcomes listed in the 
above definition.  Examples of such events include invasive or malignant cancers (excluding the 
disease[s] under study in oncology protocols), intensive treatment in an emergency department or at home 
for allergic bronchospasm, blood dyscrasias, or convulsions that do not result in hospitalization, or 
development of drug dependency or drug abuse. 
g. May lead to disability (for Japanese participants) 
An event that exposes a participant to a risk of dysfunction to the extent that it interferes with daily life 
when the adverse drug reaction occurred.  It does not mean that the adverse drug reaction could have 
caused disability if the reaction were more severe. 
9.3. 
Recording and Follow-Up of Adverse Events and/or Serious Adverse 
Events 
Adverse Event and Serious Adverse Event Recording 
• An AE/SAE that begins or worsens after informed consent is signed should be recorded on the Adverse 
Event Form in the eCRF.  Conditions that were present at the time informed consent was given should 
be recorded on the Medical History Form in the eCRF. 
• When an AE/SAE occurs, it is the responsibility of the investigator to review all documentation (eg, 
hospital progress notes, laboratory reports, and diagnostics reports) related to the event. 
• The investigator (or delegate) will then record all relevant AE/SAE information in the eCRF and submit 
the appropriate SAE report. 
• It is not acceptable for the investigator to send photocopies of the participant's medical records in lieu 
of completing the AE eCRF page or the SAE report. 
• There may be instances when copies of medical records for certain cases are requested.  In this case, all 
participant identifiers, with the exception of the participant number, will be redacted on the copies of 
the medical records before submission. 
• The investigator will attempt to establish a diagnosis of the event based on signs, symptoms, and/or 
other clinical information.  Whenever possible, the diagnosis (not the individual signs/symptoms) will 
be documented as the AE/SAE.  When a clear diagnosis cannot be identified, each sign or symptom 
should be reported as a separate AE/SAE. 
To the extent possible, each AE/SAE should be evaluated to determine: 
• The severity grade (CTCAE Grade 1 to 5).  See below for further instructions on the assessment of 
intensity. 
• Whether there is at least a reasonable possibility that the AE is related to the study treatments (including 
study drug(s) and/or reference therapy):  suspected (yes) or not suspected (no).  See below for further 
instructions on the assessment of causality. 


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• The start and end dates, unless unresolved at final follow-up. 
• The action taken with regard to study drug as a result of the AE/SAE(s). 
• The event outcome (eg, not recovered/not resolved, recovered/resolved, recovering/resolving, 
recovered/resolved with sequelae, fatal, unknown). 
• The seriousness, as per the SAE definition provided in Section 9.2. 
• The action taken with regard to the event.  Note:  If an AE is treated with a concomitant medication or 
nondrug therapy, this action should be recorded on Adverse Event Form and the treatment should be 
specified on the appropriate eCRF (eg, Prior/Concomitant Medications, Procedures and Non-Drug 
Therapy). 
Assessment of Intensity 
The severity of AEs will be assessed using CTCAE v5.0 Grades 1 through 5.  If an event is not classified 
by CTCAE, the severity of the AE will be graded according to the scale below to estimate the grade of 
severity: 
The investigator will make an assessment of intensity for each AE and SAE reported during the study and 
assign it to 1 of the following categories: 
• Grade 1:  Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; treatment 
not indicated. 
• Grade 2:  Moderate; minimal, local, or noninvasive treatment indicated; limiting age appropriate 
activities of daily living. 
• Grade 3:  Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care activities of daily living. 
• Grade 4:  Life-threatening consequences; urgent treatment indicated. 
• Grade 5:  Fatal. 
Assessment of Causality 
• The investigator is obligated to assess the relationship between study treatment and each occurrence of 
each AE/SAE.  If reference therapy is used in combination with an Incyte study drug or multiple Incyte 
study drugs are used, the relationship to each study drug/reference therapy must be assessed (ie, for the 
Incyte product(s) and for the other product(s) that is used in combination with the Incyte product).  If 
appropriate, the relationship to the combination may be assessed as well. 
• A "reasonable possibility" of a relationship conveys that there are facts, evidence, and/or arguments to 
suggest a causal relationship, rather than that a relationship cannot be ruled out. 
• The investigator will use clinical judgment to determine the relationship. 
• The investigator will also consult the reference safety information in the IB and/or Product Information, 
for marketed products, in his/her assessment. 
• Alternative causes, such as underlying disease(s), concomitant therapy, and other risk factors, as well as 
the temporal relationship of the event to study treatment administration, will be considered and 
investigated. 
• For each AE/SAE, the investigator must document in the medical notes that he/she has reviewed the 
AE/SAE and has provided an assessment of causality. 
• With regard to assessing causality of SAEs: 
− There may be situations in which an SAE has occurred and the investigator has minimal information 
to include in the initial report.  However, the causality assessment is one of the criteria used when 
determining regulatory reporting requirements.  Therefore, it is very important that the 
investigator always make an assessment of causality for every event before the initial 
transmission of the SAE. 


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− The investigator may change his/her opinion of causality in light of follow-up information and send a 
follow-up SAE report with the updated causality assessment. 
Follow-Up of Adverse Events and Serious Adverse Events 
• The investigator is obligated to perform or arrange for the conduct of supplemental measurements 
and/or evaluations as medically indicated or as requested by the sponsor to elucidate the nature and/or 
causality of the AE or SAE as fully as possible.  This may include additional laboratory tests or 
investigations, histopathological examinations, or consultation with other health care professionals. 
• If a participant dies during participation in the study or during a recognized follow-up period, the 
investigator will provide the sponsor with a copy of any postmortem findings including histopathology. 
• New or updated information will be recorded in the originally completed eCRF. 
• Any updated SAE data will be submitted to the sponsor (or designee) within 24 hours of receipt of the 
information. 
• Once an AE is detected, it should be followed until it has resolved or until it is judged to be permanent; 
assessment should be made at each visit (or more frequently if necessary) of any changes in severity, 
the suspected relationship to the study drug, the interventions required to treat the event, and the 
outcome. 
• When the severity of an AE changes over time for a reporting period (eg, between visits), each change 
in severity will be reported as a separate AE until the event resolves. 
9.4. 
Reporting of Serious Adverse Events 
Regardless of suspected causality (eg, relationship to study drugs, reference therapies, or study 
procedure[s]), all SAEs occurring after the participant has signed the ICF through 90 days after 
the last dose of study treatment or 30 days after the last dose of study treatment when starting a 
new anticancer therapy, whichever occurs earlier must be reported to the sponsor (or designee) in 
English within 24 hours of learning of its occurrence, unless otherwise specified by the Protocol.  
The investigator will submit any updated SAE data to the sponsor (or designee) within 24 hours 
of it being available.  For Japan, this information must also be reported immediately to the head 
of the study site. 
Investigators are not obligated to actively seek AE or SAE information after conclusion of the 
study participation.  However, if the investigator learns of any SAE, including a death, at any 
time after a participant has been discharged from the study, and he/she considers the event to be 
reasonably related to the study treatment or study participation, the investigator must notify the 
sponsor (or designee) within 24 hours of becoming aware of the event. 
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts.  All SAEs will be followed until resolution, stabilization, the event 
is otherwise explained, or the participant is lost to follow-up (as defined in Section 7.3). 
Prompt notification by the investigator to the sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a study 
treatment under clinical investigation are met. 
If the SAE is not documented in the IB for the study drug (new occurrence) and is thought to be 
related to the sponsor's study drug, the sponsor or its designee may urgently require further 
information from the investigator for reporting to health authorities.  The sponsor or its designee 
may need to issue an Investigator Notification to inform all investigators involved in any study 


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with the same drug that this SAE has been reported.  Suspected Unexpected Serious Adverse 
Reactions will be collected and reported to the competent authorities and relevant ethics 
committees in accordance with national regulatory requirements in participating countries. 
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study treatment under clinical investigation.  The 
sponsor will comply with country-specific regulatory requirements relating to safety reporting to 
the regulatory authority, IRB/IEC, and investigators.  For Japan, suspected expected deaths and 
life-threatening events will also be reported to the PMDA as per local regulatory requirements. 
Investigator safety reports must be prepared for suspected unexpected adverse reactions 
according to local regulatory requirements and sponsor policy and forwarded to investigators as 
necessary. 
An investigator who receives an investigator safety report describing a SAE or other specific 
safety information (eg, summary or listing of SAEs) from the sponsor will review and then file it 
along with the Investigator's Brochure and will notify the IRB/IEC, if appropriate according to 
local requirements. 
Serious Adverse Event Reporting 
• Information about all SAEs is collected and recorded on the Adverse Event Form in the eCRF. 
• The investigator must also complete the Incyte Serious Adverse Event Report Form, in English.  Refer 
to the Incyte Reference Guide for Completing the Serious Adverse Event Report Form. 
o Facsimile or email transmission of the Serious Adverse Event Report Form is the preferred method to 
transmit this information to the Incyte Pharmacovigilance Department at 
SafetyReporting@incyte.com.  The contact information of the sponsor's study-specific 
representatives is listed in the Study Reference Manual provided to each site.  The original copy of 
the Serious Adverse Event Report Form and the confirmation sheet must be kept at the study site. 
• Follow-up information is recorded on an amended or new Serious Adverse Event Report Form, with an 
indication that it is follow-up to the previously reported SAE and the date of the original report.  The 
follow-up report should include information that was not provided on the previous Serious Adverse 
Event Report Form, such as the outcome of the event (eg, resolved or ongoing), treatment provided, 
action taken with study drug because of the SAE (eg, dose reduced, interrupted, or discontinued), or 
participant disposition (eg, continued or withdrew from study participation).  Each recurrence, 
complication, or progression of the original event should be reported as follow-up to that event, 
regardless of when it occurs. 
• In rare circumstances and in the absence of facsimile or computer equipment, notification by telephone 
is acceptable with a copy of the Incyte Serious Adverse Event Report Form sent by overnight mail or 
courier service.  Initial notification via telephone does not replace the need for the investigator to 
complete and sign the Serious Adverse Event Report Form within the designated reporting time frames. 
• Contacts for SAE reporting can be found in the Investigator Manual. 
• For Japan, any SAE relating to phosphate binders that were used for treatment of hyperphosphatemia 
should also be reported in the same manner. 


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9.5. 
Adverse Events of Special Interest 
Dose modification guidelines for select AESIs for pembrolizumab are presented in Appendix B.  
A comprehensive summary of AESIs for pembrolizumab is presented in the pembrolizumab IB.  
There are no AESIs for pemigatinib. 
9.6. 
Emergency Unblinding of Treatment Assignment 
Not applicable. 
9.7. 
Pregnancy 
Pregnancy, in and of itself, is not regarded as an AE unless there is suspicion that study drug may 
have interfered with the effectiveness of a contraceptive medication or method.  When a 
pregnancy has been confirmed in a participant during maternal or paternal exposure to study 
drug, the following procedures should be followed in order to ensure safety: 
• The study drug must be discontinued immediately (female participants only; see 
Section 6.6 for the maximum permitted duration of study drug interruption).  
• The investigator must complete and submit the Incyte Clinical Trial Pregnancy Form 
to the sponsor or its designee within 24 hours of learning of the pregnancy. 
Data on fetal outcome are collected for regulatory reporting and drug safety evaluation.  
Follow-up should be conducted for each pregnancy to determine outcome, including spontaneous 
or voluntary termination, details of the birth, and the presence or absence of any birth defects, 
congenital abnormalities, or maternal and/or newborn complications, by following until the first 
well-baby visit.  Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported 
by the investigator to the sponsor or its designee.  Pregnancy follow-up information should be 
recorded on the same form and should include an assessment of the possible causal relationship 
to the sponsor's study drug to any pregnancy outcome, as well as follow-up to the first well-baby 
visit or the duration specified in local regulations, whichever is later.  Refer to the Incyte 
Reference Guide for Completing the Clinical Trial Pregnancy Form. 
Any SAE occurring during pregnancy of a study participant must be recorded on the 
Serious Adverse Event Report Form and submitted to the sponsor or designee. 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, or ectopic pregnancy) are considered SAEs (if occurring in the study participant) and 
must be reported as described in Section 9.4.  If an abnormal pregnancy outcome is reported in a 
study participant's partner, the event should be reported to the sponsor on the Clinical Trial 
Pregnancy Form. 
9.8. 
Warnings and Precautions 
Special warnings or precautions for the study treatments, derived from safety information 
collected by the sponsor or its designee, are presented in the IB.  Additional safety information 
collected between IB updates will be communicated in the form of Investigator Notifications.  
Any important new safety information should be discussed with the participant during the study, 
as necessary.  If new significant risks are identified, they will be added to the ICF. 


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9.9. 
Product Complaints 
The sponsor collects product complaints on study drugs, medical devices (Japan), and drug 
delivery systems used in clinical studies in order to ensure the safety of study participants, 
monitor quality, and facilitate process and product improvements. 
All product complaints associated with material packaged, labeled, and released by the sponsor 
or its designee will be reported to the sponsor, and for Japan, complaints associated with 
unapproved medical devices will be reported to the sponsor with a Medical Device Defect 
Report Form.  For Japan, the sponsor will report medical device defects to the PMDA as per 
local regulatory requirements.  All product complaints associated with other study material will 
be reported directly to the respective manufacturer. 
The investigator or his/her designee is responsible for reporting a complete description of the 
product complaint via email or other written communication to the sponsor contact or respective 
manufacturer as noted in the packaging information.  Any AE associated with a product 
complaint should be recorded as described in Section 9.3. 
If the investigator is asked to return the product for investigation, he/she will return a copy of the 
product complaint communication with the product. 
9.10. 
Treatment of Overdose 
No specific information is available on the treatment of overdose of pemigatinib or 
pembrolizumab. 
For this study, any dose of pemigatinib greater than 20 mg and any dose higher than ≥ 1000 mg 
(5 times the dose) of pembrolizumab within a 24-hour time period [± 4 hours] will be considered 
an overdose.  In the event of an overdose, the participant should be observed closely for signs of 
toxicity.  Appropriate supportive treatment should be provided if clinically indicated. 
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the medical monitor based on the clinical evaluation of the participant. 


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10. 
STATISTICS 
10.1. 
Sample Size Determination 
The sample size calculation is based on the primary endpoint PFS. 
The SOC treatment group in this study consists of participants who will receive pembrolizumab 
or chemotherapy depending on the participant carboplatin eligibility and PD-L1 CPS.  In 
KEYNOTE-052, a large single arm, Phase 2 study with pembrolizumab conducted in cisplatin-
ineligible patients who had not been previously treated with systemic chemotherapy, the median 
PFS was 2.1 months (95% CI:  2, 3; Balar et al 2017a).  In EORTC 30968, a randomized Phase 
2/3 study comparing gemcitabine and carboplatin versus methotrexate/carboplatin/vinblastine, 
the median PFS was 5.8 months in the gemcitabine/carboplatin group as compared with 4.2 
months in the other group(s) (De Santis et al 2012).  Based on available data from 
KEYNOTE-052 and EORTC Study 30968 and participants' distribution percentages (see 
Table 18), it is estimated that the median PFS in the SOC treatment group (pembrolizumab or 
gemcitabine/carboplatin) is expected to be 5 months based on simulation. 
Table 18: 
Median Progression-Free Survival Assumptions for Standard of Care 
Treatments 
Patient Population 
Total (%) 
(N = 132) 
Median PFS Assumption 
Carboplatin-ineligible participants who will 
receive pembrolizumab 
26 (20%) 
2.1 months 
Carboplatin-eligible participants who will 
receive pembrolizumab (CPS ≥ 10) 
16 (12%) 
4.9 months 
Carboplatin-eligible participants who will 
receive gemcitabine/carboplatin (CPS < 10) 
90 (68%) 
5.8 months 
It is expected that treatment with pemigatinib plus pembrolizumab will result in an HR of 0.68 
for PFS compared to SOC, which corresponds to an increase in median PFS of 2.4 months under 
the exponential model assumption.  It is calculated that a total of 210 PFS events in the combined 
treatment groups of pemigatinib plus pembrolizumab and SOC need to be observed to ensure 
80% power to test the null hypothesis:  PFS HR = 1, versus the specific alternative hypothesis:  
PFS HR = 0.68 for pemigatinib plus pembrolizumab versus SOC.  This calculation assumes 
analysis using a 1-sided log-rank test at a 0.025 overall significance level and participants are 
randomized to the treatment groups in a 1:1 ratio. 
To keep a minimum meaningful hazard ratio of 0.68 for PFS in participants with pemigatinib 
alone versus SOC, a total of 210 PFS events in the combine treatment groups of pemigatinib 
alone and SOC need to be observed to achieve 80% power to test the null hypothesis:  PFS 
HR = 1, versus the specific alterative hypothesis:  PFS HR = 0.68 for pemigatinib alone versus 
SOC.  This calculation assumes analysis using a 1-sided log-rank test at a 0.025 overall 
significance level and participants are randomized to the treatment groups in a 1:1 ratio. 


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Assuming uniform accrual of the participants over a 36-month period, an 8-month follow-up 
after the last participant is randomized, and a 5% lost to follow-up rate, a total of approximately 
372 participants will needed to be randomized to observe the targeted PFS events at 
approximately 44 months after first participant is randomized. 
The median OS for the SOC group is about 10 months based on EORTC Study 30968 and 
KEYNOTE-052.  It is calculated that a total of 194 deaths in the combined treatment groups of 
pemigatinib plus pembrolizumab and SOC need to have been observed to achieve 76% power to 
detect an HR of 0.68 using a 1-sided log-rank test at a 0.025 overall significant level.  Final OS 
analysis is expected to occur at approximately 52 months after first participant is randomized.  
At the time when final PFS analysis is conducted, it is expected that about 169 deaths will be 
observed in the combined treatment groups of pemigatinib plus pembrolizumab and SOC.  
Overall survival comparison for pemigatinib plus pembrolizumab versus SOC will be conducted 
at nominal 1-sided alpha of 0.0147 according to the O’Brien-Fleming spending function.  Final 
OS analysis comparing pemigatinib plus pembrolizumab versus SOC will be conducted at 
nominal 1-sided alpha of 0.0103 when approximately 194 deaths are observed in the combined 
treatment groups of pemigatinib plus pembrolizumab and SOC.  The actual boundaries will be 
re-calculated from the actual number of deaths at the time when final PFS analysis is conducted 
using the alpha- and beta-spending functions. 
10.2. 
Populations for Analysis 
Table 19 presents the populations for analysis. 
Table 19: 
Populations for Analysis 
Population 
Description 
ITT  
The ITT population includes all participants who are randomized into the study.  
Treatment groups for this population will be determined according to the treatment 
assignment at the time of randomization. 
All efficacy analyses will be conducted using the ITT population. 
PP 
Participants in the ITT who are considered to be sufficiently compliant with the 
Protocol comprise the PP population.  This population includes all ITT participants 
who meet all major inclusion and no major exclusion criteria based on blinded review 
of clinical data.  Specific criteria and review of this population will be defined in the 
statistical analysis plan. 
The primary endpoint will be analyzed using the PP population as a sensitivity 
analysis. 
Safety 
The safety population includes all randomized participants who received at least one 
dose of study treatment.  Treatment groups for this population will be determined 
according to the actual treatment the participant received regardless of assigned study 
drug treatment. 
All safety analyses will be conducted using the safety population. 


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10.3. 
Level of Significance 
The overall level of significance is strongly controlled for primary and key secondary objectives 
at 1-sided 0.025 using a fixed sequential testing procedure.  The primary and key secondary 
efficacy endpoints at final analysis will be tested in the following order: 
1. PFS comparison for pemigatinib plus pembrolizumab versus SOC at 1-sided 0.025. 
2. OS comparison for pemigatinib plus pembrolizumab versus SOC at 1-sided 0.0147 at the 
time when primary analysis of PFS is conducted; OS comparison for pemigatinib plus 
pembrolizumab versus SOC at 1-sided 0.0103 at final OS analysis. 
3. PFS comparison for pemigatinib only versus SOC at 1-sided 0.025.  If the pemigatinib 
group is discontinued early after futility analysis (see Section 10.5), this analysis will not 
be performed. 
4. OS comparison for pemigatinib only versus SOC at 1-sided 0.0147 at the time when 
primary analysis of PFS is conducted; OS comparison for pemigatinib only versus SOC 
at 1-sided 0.0103 at final OS analysis.  If the pemigatinib group is discontinued early 
after futility analysis (see Section 10.5), this analysis will not be performed. 
10.4. 
Statistical Analyses 
10.4.1. 
Primary Analysis 
Progression-free survival is defined as the time from the date of randomization to the date of the 
first documented progression or death due to any cause, whichever occurs first.  Progression-free 
survival will be assessed via BICR according to RECIST v1.1 criteria.  Participants without a 
PFS event at the time of analysis will be censored.  Censoring for PFS will follow the FDA 
Guidance for Industry:  Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics 
(FDA 2018a).  The primary analysis of PFS will be based on ITT population and will compare 
PFS difference between treatment groups (pemigatinib plus pembrolizumab vs SOC, pemigatinib 
alone vs SOC) using a log-rank test stratified by eligibility to receive carboplatin, primary 
disease location, and PD-L1 CPS.  The stratification will be based on the randomization 
stratification factors.  Kaplan-Meier curves, medians, and 95% CIs of the medians will be 
presented for each treatment group.  The HR for PFS will be calculated, along with its 95% CI, 
from a stratified Cox model using the same stratification factors as for the log-rank test with 
Efron's likelihood approximation to account for ties in event times.  Progression-free survival 
analysis for the comparison of pemigatinib plus pembrolizumab versus SOC as well as the 
comparison of pemigatinib alone versus SOC will be conducted separately. 
As sensitivity analyses, difference in PFS between pemigatinib plus pembrolizumab and SOC 
will be analyzed using log-rank test stratified by eligibility to receive carboplatin, primary 
disease location, and PD-L1 CPS in the PP population; difference in PFS between pemigatinib 
alone and SOC will be analyzed using log-rank test stratified by same stratification factors in the 
PP population.  Difference in PFS between pemigatinib plus pembrolizumab and SOC as well as 
the difference between pemigatinib alone and SOC will also be analyzed using a log-rank test 
stratified by the same stratification factors in the randomized subjects who have known FGFR3 
mutation or rearrangement confirmed by the central laboratory. 


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10.4.2. 
Secondary Analysis 
Secondary efficacy analyses will be conducted for the ITT population.  All the secondary 
analyses for pemigatinib plus pembrolizumab versus SOC and for pemigatinib alone versus SOC 
will be conducted separately. 
Overall survival is defined as the time from date of randomization until death due to any cause.  
Participants without death observed at the time of analysis will be censored at last date known to be 
alive.  The log-rank test stratified by eligibility to receive carboplatin, primary disease location, 
and PD-L1 CPS will be used to analyze the OS differences between treatment groups.  Kaplan-
Meier curves, medians, and 95% CIs of the medians will be presented for each treatment group.  
The HR for OS will be calculated, along with its 95% CI, from a stratified Cox model using the 
same stratification factors as for the log-rank test with Efron's likelihood approximation to 
account for ties in event times. 
Objective response rate is defined as the proportion of participants with best overall response of 
CR or PR per RECIST v1.1 by BICR.  Objective response rate will be presented by treatment 
groups along with 95% CIs.  Objective response rates between treatment groups will be 
compared using Cochran–Mantel–Haenszel test stratified by eligibility to receive carboplatin, 
primary disease location, and PD-L1 CPS. 
Duration of response is defined as the time from the date of the first assessment of CR or PR 
until the date of the first progressive disease per RECIST v1.1 or death.  For participants who 
achieve a response, Kaplan-Meier curves, medians, and 95% CIs of the medians will be 
presented for each treatment group.  Participants who are still responding at the time of analysis 
will be censored.  Censoring of DOR will follow the same algorithm as the censoring of PFS. 
EORTC QLQ-C30 and EQ-5D-5L scales as well as change and percent change from baseline 
will be summarized with descriptive statistics by visit. 
10.4.3. 
Safety Analyses 
Safety analyses will be conducted for the safety population. 
Adverse events will be coded by the MedDRA dictionary, and TEAEs (ie, AEs reported for the 
first time or worsening of a pre-existing event after first dose of study treatment) will be 
tabulated by preferred term and system organ class for all events, related events, and events of 
Grade 3 or higher.  Quantitative safety variables and their changes from baseline (laboratory, 
vital signs, etc) will be summarized with descriptive statistics.  Clinically notable abnormal 
values will be flagged and tabulated based on predefined criteria. 
The clinical laboratory data will be analyzed using summary statistics; no formal treatment group 
comparisons are planned.  In addition, distributions of key laboratory parameters may be plotted 
over time; these values will also be classified into CTCAE v5.0 toxicity grades and tabulated.  
Descriptive statistics and mean change from baseline will be determined for vital signs at each 
assessment time.  Vital sign results will be reviewed for clinically notable abnormalities. 
Descriptive statistics and mean change from baseline will be determined for each ECG parameter 
at each assessment time.  Electrocardiogram results will be reviewed for clinically notable 
abnormalities according to predefined criteria.  Participants exhibiting clinically notable ECG 
abnormalities will be listed. 


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Measures of exposure to study drug will be summarized by means of summary statistics. 
10.5. 
Futility Analysis 
A futility analysis will be performed when a total of approximately 150 participants across all 
3 treatment groups have been randomized and have had at least 1 tumor assessment or have 
permanently discontinued from study.  Enrollment will not be held while the futility analysis is 
being conducted.  The study can be stopped for futility if the ORR difference between 
pemigatinib plus pembrolizumab group versus SOC group is less than 5%.  In addition, if ORR 
in the pemigatinib monotherapy group is inferior to SOC group (ie, ORR observed in Treatment 
Group B is less than ORR observed in Treatment Group C), the monotherapy group may 
discontinue further enrollment.  This rule is just a guidance and nonbinding. 
10.6. 
Data Monitoring Committee 
An independent DMC will be formed.  The DMC will consist of qualified individuals who are 
not involved with the conduct of the study.  The establishment, composition, roles, duties, and 
responsibilities of the DMC are addressed in the DMC Charter.  Final decision regarding the 
study will be made by the sponsor internal team in discussion with the DMC. 


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


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− All eCRF data entered by the site (including audit trail), as well as computer 
hardware and software (for accessing the data), will be maintained or made 
available at the site in compliance with applicable record retention regulations.  
The sponsor will retain the original eCRF data and audit trail. 
• For Japan:  The record retainer at the study site will retain the J-GCP–defined 
essential documentation until the regulatory approval of pemigatinib or at least 
3 years after the discontinuation or completion of the study conduct, whichever is 
later.  If the sponsor requires retention of these documents for a longer period of time, 
the duration and method of retention will be decided upon through discussion 
between the sponsor and the study site.  It is the responsibility of the sponsor to 
inform the head of the study site as to when the documents no longer need to be 
retained. 
11.2. 
Data Management 
Data management will be performed in a validated EDC system.  The investigator will be 
provided with access to an EDC system so that an eCRF can be completed for each participant. 
The site will be provided with eCRF completion guidelines for instructions on data entry in the 
eCRF.  The study monitor will reference the Monitoring Plan in order to ensure that each issue 
identified is appropriately documented, reported, and resolved in a timely manner in accordance 
with the plan's requirements.  Other data outside the EDC system required in the study conduct 
of the protocol such as documents or results transmitted to the sponsor via a central laboratory or 
specialized technical vendors, and as designated by the sponsor, will have their own data flow 
management plans, or study charters, 
, as applicable. 
The sponsor (or designee) will be responsible for: 
• Managing the integrity of the data and the quality of the conduct of the study, such as  
ensuring that study monitors perform ongoing source data verification to confirm that 
data entered into the eCRF by authorized site personnel are accurate, complete, and 
verifiable from source documents; that the safety and rights of participants are being 
protected; and that the study is being conducted in accordance with the currently 
approved protocol and any other study agreements, ICH GCP, and all applicable 
regulatory requirements. 
• Managing and reconciling the data generated, and/or collected including documents 
and results such as laboratory or imaging data analyzed centrally by a designated 
vendor of the sponsor. 
The investigator will be responsible for: 
• Recording, or ensuring the recording of, all relevant data relating to the study in the 
eCRF.  
• Delivering, or ensuring the delivery of, all other results, documents, data, know-how, 
or formulas relating to the study to the sponsor or designee electronically and/or 
centrally (e.g., laboratory data, imaging data, 
 photographs, diary 
data), or as otherwise specified in the Protocol.   


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• Verifying that data entries are accurate and correct by physically or electronically 
signing the eCRF. 
• Maintaining accurate documentation (source data) that supports the information 
entered in the eCRF, or sent to a central vendor designated by the sponsor, or as 
described in other study and data flow manuals. 
− Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected.  Source documents are filed at 
the investigator's site. 
− Data entered in the eCRF that are transcribed from source documents must be 
consistent with the source documents or the discrepancies must be explained.  
The investigator may need to request previous medical records or transfer 
records, depending on the study.  Also, current applicable medical records 
must be available. 
• May have responsibility for sending participants’ data, either as unique samples, or 
copies, or photographs, to be evaluated centrally or analyzed centrally, or both, by a 
qualified vendor designated by the sponsor.  
• Permitting study-related monitoring, sponsor audits, IRB/IEC review, and regulatory 
inspections by providing direct access to source data and other relevant clinical study 
documents. 
− Monitoring:  Qualified representatives of the sponsor or its designee, study 
monitors, will monitor the study according to a predetermined plan.  The 
investigator must allow the study monitors to review any study materials and 
participant records at each monitoring visit. 
− Auditing:  Qualified representatives of the sponsor or its designee may audit the 
clinical study site and study data to evaluate compliance with the Protocol, 
applicable local clinical study regulations, and overall study conduct.  The 
investigator must allow the auditors to review original source records and study 
documentation for all participants. 
− Regulatory inspection:  Regulatory authorities may conduct an inspection of the 
study and the site at any time during the development of an investigational 
product.  The investigator and staff are expected to cooperate with the inspectors 
and allow access to all source documents supporting the eCRFs and other study 
related documents.  The investigator must immediately notify the sponsor when 
contacted by any regulatory authority for the purposes of conducting an 
inspection. 
11.3. 
Data Privacy and Confidentiality of Study Records 
The investigator and the sponsor or its designee must adhere to applicable data protection laws 
and regulations.  The investigator and the sponsor or its designee are responsible for ensuring 
that sensitive personal information is handled in accordance with local data protection laws 
(including but not limited to HIPAA and GDPR) as applicable.  Appropriate consent for 


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collection, use and disclosure and/or transfer (if applicable) of personal information must be 
obtained in accordance with local data protection laws. 
Participant names will not be supplied to the sponsor or its designee.  Only the participant 
number will be recorded in the eCRF; if the participant's name appears on any other document 
(eg, laboratory report), it must be obliterated on the copy of the document to be supplied to the 
sponsor or its designee.  Study findings stored on a computer will be stored in accordance with 
appropriate technical and organizational measures as required by local data protection laws. 
Records and documents, including signed ICFs, pertaining to the conduct of this study must be 
retained by the investigator for 10 years after study completion unless local regulations or require 
otherwise.  No records may be destroyed during the retention period without the written approval 
of the sponsor.  No records may be transferred to another location or party without written 
notification to the sponsor. 
11.4. 
Financial Disclosure 
Before study initiation, all clinical investigators participating in clinical studies subject to FDA 
Regulation Title 21 CFR Part 54 – Financial Disclosure by Clinical Investigators (ie, "covered 
studies") are required to submit a completed Clinical Investigator Financial Disclosure form that 
sufficiently details any financial interests and arrangements that apply.  For the purpose of this 
regulation, "clinical investigator" is defined as any investigator or subinvestigator who is directly 
involved in the treatment or evaluation of research participants, including the spouse and each 
dependent child of the clinical investigator or subinvestigator.  These requirements apply to both 
US and foreign clinical investigators conducting covered clinical studies. 
Any new clinical investigators added to the covered clinical study during its conduct must also 
submit a completed Investigator Financial Disclosure Form.  During a covered clinical study, 
any changes to the financial information previously reported by a clinical investigator must be 
reported to the sponsor or its designee.  At the conclusion of the covered clinical study, the 
clinical investigators will be reminded of their obligations.  In the event that the clinical 
investigator is not reminded, they nevertheless will remain obligated to report to the sponsor or 
its designee any changes to the financial information previously reported, as well as any changes 
in their financial information for a period of 1 year after completion of the covered clinical study. 
11.5. 
Publication Policy 
By signing the study Protocol, the investigator and his/her institution agree that the results of the 
study may be used by the sponsor, Incyte Corporation (Incyte), for the purposes of national and 
international registration, publication, and information for medical and pharmaceutical 
professionals.  Study results will be published in accordance with applicable local and national 
regulations.  If necessary, the authorities will be notified of the investigator's name, address, 
qualifications, and extent of involvement.  The terms regarding the publication of study results 
are contained in the agreement signed with the sponsor or its designee.  A signed agreement will 
be retained by the sponsor or its designee. 
The results of this study may be published or presented at scientific meetings.  If this is foreseen, 
the investigator agrees to submit all manuscripts or abstracts to the sponsor before submission.  
This allows the sponsor to protect proprietary information and to provide comments. 


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The sponsor will comply with the requirements for publication of study results.  In accordance 
with standard editorial and ethical practice, the sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data.  In this case, a 
coordinating investigator will be designated by mutual agreement. 
Authorship will be determined in line with International Committee of Medical Journal Editors 
authorship requirements. 
11.6. 
Study and Site Closure 
The sponsor designee reserves the right to close the study site or terminate the study at any time 
for any reason at the sole discretion of the sponsor.  Study sites will be closed upon study 
completion.  A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
For Japan:  When the study is completed, the investigator should inform the head of the study 
site of the completion in writing and submit a written summary of the study's outcome, then the 
head of the study site should promptly inform the IRB and sponsor or designee of the completion 
in writing. 
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to: 
• Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines. 
• Inadequate recruitment of participants by the investigator. 
• Discontinuation of further study treatment development. 


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12. 
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therapeutically tractable FGFR1 dependency in squamous cell lung cancer. Sci Transl Med 
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Williams SV, Hurst CD, Knowles MA. Oncogenic FGFR3 gene fusions in bladder cancer. Hum 
Mol Genet 2013;22:795-803. 
Wu YM, Su F, Kalyana-Sundaram S, et al. Identification of targetable FGFR gene fusions in 
diverse cancers. Cancer Discov 2013;3:636-647. 


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APPENDIX A. INFORMATION REGARDING EFFECTIVENESS OF 
CONTRACEPTIVE METHODS 
For male participants in the study: 
Male participants must agree to take appropriate precautions to avoid fathering children (defined as the use of an 
effective method [barrier method] in combination with a highly effective method in preventing pregnancy).  Male 
participants should use a condom from screening through 120 days after the last dose of pemigatinib and/or 
pembrolizumab or 180 days after the last dose of chemotherapy.  If the male participant has a partner that is of 
childbearing potential, the partner should also use contraception during the study and through 120 days after the last 
dose of pemigatinib and/or pembrolizumab or 180 days after the last dose of chemotherapy.  In addition, male 
participants must refrain from donating sperm from screening through 120 days after the last dose of pemigatinib 
and/or pembrolizumab or 180 days after the last dose of chemotherapy.  Males who have had a vasectomy qualify as 
having met the requirement for a highly effective birth control method. 
For female participants in the study: 
Female participants must agree to take appropriate precautions to avoid pregnancy (defined as the use of an effective 
method [barrier method] in combination with a highly effective method in preventing pregnancy) from screening 
through 120 days after the last dose of pemigatinib and/or pembrolizumab or 180 days after the last dose of 
chemotherapy. 
The following methods that can achieve a failure rate of less than 1% per year when used consistently and correctly 
are considered as highly effective birth control methods: 
• Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of 
ovulationa 
− oral 
− intravaginal (not applicable in Japan) 
− transdermal (not applicable in Japan) 
• Progestogen-only hormonal contraception associated with inhibition of ovulationa 
− oral 
− injectable 
− implantableb 
• Intrauterine deviceb 
• Intrauterine hormone-releasing systemb 
• Bilateral tubal occlusionb 
• Vasectomized partnerbc 
• Sexual abstinence (not applicable in Japan) d  
Acceptable birth control methods that result in a failure rate of more than 1% per year include: 
• Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the primary mode of action 
• Male or female condom with or without spermicidee 
• Cap, diaphragm, or sponge with spermicidee 
• Tubal ligation 
a Hormonal contraception may be susceptible to interaction with the investigational medicinal product, which may reduce the 
efficacy of the contraception method. 
b Contraception methods that in the context of this guidance are considered to have low user dependency. 
c Vasectomized partner is a highly effective method of avoiding pregnancy provided that partner is the sole sexual partner of the 
woman of childbearing potential study participant and that the vasectomized partner has received medical assessment of the 
surgical success. 
 d In the context of this guidance, sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study treatments.  The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the clinical study and the preferred and usual lifestyle of the 
participant. 
e A combination of male condom with either cap, diaphragm, or sponge with spermicide (double barrier methods) are also 
considered acceptable, but not highly effective, birth control methods. 
Source:  Clinical Trial Facilitation Group 2014. 


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APPENDIX B. PEMBROLIZUMAB DOSE MODIFICATIONS 
Dose Modifications and Toxicity Management for Immune-Related Adverse Events 
Associated With Pembrolizumab 
AEs associated with pembrolizumab exposure may represent an immunologic etiology.  These 
irAEs may occur shortly after the first dose or several months after the last dose of 
pembrolizumab treatment and may affect more than 1 body system simultaneously.  Therefore, 
early recognition and initiation of treatment is critical to reduce complications.  Based on 
existing clinical study data, most irAEs were reversible and could be managed with interruptions 
of pembrolizumab, administration of corticosteroids and/or other supportive care.  For suspected 
irAEs, ensure adequate evaluation to confirm etiology or exclude other causes.  Additional 
procedures or tests such as bronchoscopy, endoscopy, skin biopsy may be included as part of the 
evaluation.  Based on the severity of irAEs, withhold or permanently discontinue pembrolizumab 
and administer corticosteroids.  Dose modification and toxicity management guidelines for irAEs 
associated with pembrolizumab are provided. 
Table B1: 
Dose Modification and Toxicity Management Guidelines for Immune-
Related Adverse Events Associated With Pembrolizumab 
General instructions: 
• Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 weeks. 
• For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been reduced to Grade 1 
or 0 and corticosteroid has been tapered.  Pembrolizumab must be permanently discontinued if AE does not resolve within 
12 weeks of last dose or corticosteroids cannot be reduced to ≤10 mg prednisone or equivalent per day within 12 weeks.  
• For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid.  Other 
immunosuppressive treatment should be initiated if irAEs cannot be controlled by corticosteroids. 
irAE 
Toxicity Grade or 
Conditions 
(CTCAE v5.0) 
Action Taken to 
Pembrolizumab 
irAE Management 
With Corticosteroid 
and/or Other 
Therapies 
Monitor and Follow-Up 
Pneumonitis  
Grade 2 
Withhold  
• Administer 
corticosteroids 
(initial dose of 
1-2 mg/kg 
prednisone or 
equivalent) followed 
by taper 
• Monitor participants for 
signs and symptoms of 
pneumonitis 
• Evaluate participants with 
suspected pneumonitis 
with radiographic 
imaging and initiate 
corticosteroid treatment 
• Add prophylactic 
antibiotics for 
opportunistic infections 
Grade 3 or 4, or 
recurrent Grade 2 
Permanently 
discontinue 


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Table B1: 
Dose Modification and Toxicity Management Guidelines for Immune-
Related Adverse Events Associated With Pembrolizumab (Continued) 
irAE 
Toxicity Grade or 
Conditions 
(CTCAE v5.0) 
Action Taken to 
Pembrolizumab 
irAE Management 
With Corticosteroid 
and/or Other 
Therapies 
Monitor and Follow-Up 
Diarrhea/Colitis  
Grade 2 or 3 
Withhold 
• Administer 
corticosteroids 
(initial dose of 
1-2 mg/kg 
prednisone or 
equivalent) followed 
by taper 
• Monitor participants for 
signs and symptoms of 
enterocolitis (ie, diarrhea, 
abdominal pain, blood or 
mucus in stool with or 
without fever) and of 
bowel perforation 
(ie, peritoneal signs and 
ileus) 
• Participants with 
≥ Grade 2 diarrhea 
suspecting colitis should 
consider GI consultation 
and performing 
endoscopy to rule out 
colitis 
• Participants with 
diarrhea/colitis should be 
advised to drink liberal 
quantities of clear fluids.  
If sufficient oral fluid 
intake is not feasible, 
fluid and electrolytes 
should be substituted via 
IV infusion. 
Grade 4 or recurrent 
Grade 3 (colitis) 
Permanently 
discontinue 
AST/ALT elevation 
or Increased 
Bilirubin 
Grade 2 
Withhold 
• Administer 
corticosteroids 
(initial dose of 
0.5-1 mg/kg 
prednisone or 
equivalent) followed 
by taper 
• Monitor with liver 
function tests (consider 
weekly or more 
frequently until liver 
enzyme value returned to 
baseline or is stable) 
Grade 3 or 4  
Permanently 
discontinue 
• Administer 
corticosteroids 
(initial dose of 
1-2 mg/kg 
prednisone or 
equivalent) followed 
by taper 
Type 1 diabetes 
mellitus (T1DM) or 
Hyperglycemia 
New onset T1DM or 
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of β-cell 
failure 
Withhold 
• Initiate insulin 
replacement therapy 
for participants with 
T1DM 
• Administer 
anti-hyperglycemic 
in participants with 
hyperglycemia 
• Monitor participants for 
hyperglycemia or other 
signs and symptoms of 
diabetes 
Hypophysitis 
Grade 2 
Withhold 
• Administer 
corticosteroids and 
initiate hormonal 
replacements as 
clinically indicated 
• Monitor for signs and 
symptoms of hypophysitis 
(including 
hypopituitarism and 
adrenal insufficiency) 
Grade 3 or 4 
Withhold or 
permanently 
discontinuea 


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Table B1: 
Dose Modification and Toxicity Management Guidelines for Immune-
Related Adverse Events Associated With Pembrolizumab (Continued) 
irAE 
Toxicity Grade or 
Conditions 
(CTCAE v5.0) 
Action Taken to 
Pembrolizumab 
irAE Management 
With Corticosteroid 
and/or Other 
Therapies 
Monitor and Follow-Up 
Hyperthyroidism  
Grade 2 
Continue 
• Treat with 
non-selective 
beta-blockers 
(eg, propranolol) or 
thionamides as 
appropriate 
• Monitor for signs and 
symptoms of thyroid 
disorders 
Grade 3 or 4 
Withhold or 
permanently 
discontinuea 
Hypothyroidism 
Grade 2-4 
Continue 
• Initiate thyroid 
replacement 
hormones 
(eg, levothyroxine or 
liothyronine) per 
SOC 
• Monitor for signs and 
symptoms of thyroid 
disorders 
Skin reactions 
Grade 3 or suspected 
Stevens-Johnson 
syndrome (SJS) or 
toxic epidermal 
necrolysis (TEN) 
Withhold 
• Based on severity of 
AE administer 
topical and IV 
corticosteroids, 
topical emollients, 
oral antihistamines 
and immune 
suppression if 
needed. 
• Withhold until adverse 
reaction recovers to 
Grade 0-1 
Grade 4 or confirmed 
SJS or TEN 
Permanently 
discontinue 
Nephritis and renal 
dysfunction 
Grade 2 
Withhold 
• Administer 
corticosteroids 
(prednisone 
1-2 mg/kg or 
equivalent) followed 
by taper 
• Monitor changes of renal 
function 
Grade 3 or 4 
Permanently 
discontinue 
Myocarditis 
Grade 1 or 2 
Withhold 
• Based on severity of 
AE administer 
corticosteroids 
• Ensure adequate 
evaluation to confirm 
etiology and/or exclude 
other causes 
Grade 3 or 4 
Permanently 
discontinue 
All other irAEs 
Intolerable/ 
persistent Grade 2 
Withhold 
• Based on severity of 
AE administer 
corticosteroids 
• Ensure adequate 
evaluation to confirm 
etiology or exclude other 
causes 
Grade 3 
Withhold or 
discontinue based on 
the type of event.  
Events that require 
discontinuation 
include and not 
limited to:  Guillain-
Barre Syndrome, 
encephalitis 
Grade 4 or recurrent 
Grade 3 
Permanently 
discontinue 
a Decision to withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician. 
Note:  For participants with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is required, 
pembrolizumab may be resumed when AE resolves to ≤ Grade 2 and is controlled with hormonal replacement therapy or 
achieved metabolic control (in case of T1DM). 
Note:  For nephritis and renal failure: the guideline for pembrolizumab renal failure or nephritis modification should only be 
followed if the etiology is determined to be immune-mediated with supporting biopsy 


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Dose Modification and Toxicity Management of Infusion Reactions Related to 
Pembrolizumab 
Pembrolizumab may cause severe or life-threatening infusion-reactions including severe 
hypersensitivity or anaphylaxis.  Signs and symptoms usually develop during or shortly after 
drug infusion and generally resolve completely within 24 hours of completion of infusion.  Dose 
modification and toxicity management guidelines on pembrolizumab associated infusion reaction 
are provided. 
Table B2: 
Pembrolizumab Infusion Reaction Dose Modification and Treatment 
Guidelines 
NCI CTCAE Grade 
Treatment 
Premedication at Subsequent 
Dosing 
Grade 1 
Mild reaction; infusion interruption 
not indicated; intervention not 
indicated. 
Increase monitoring of vital signs as medically 
indicated until the participant is deemed medically 
stable in the opinion of the investigator. 
None. 
Grade 2 
Requires therapy or infusion 
interruption but responds promptly 
to symptomatic treatment (eg, 
antihistamines, NSAIDs, narcotics, 
IV fluids); prophylactic medications 
indicated for ≤ 24 hours. 
Stop Infusion. 
Additional appropriate medical therapy may include 
but is not limited to: 
• IV fluids 
• Antihistamines 
• NSAIDs 
• Acetaminophen 
• Narcotics 
Increase monitoring of vital signs as medically 
indicated until the participant is deemed medically 
stable in the opinion of the investigator. 
If symptoms resolve within 1 hour of stopping drug 
infusion, the infusion may be restarted at 50% of the 
original infusion rate (eg, from 100 mL/hr to 
50 mL/hr).  Otherwise dosing will be held until 
symptoms resolve and the participant should be 
premedicated for the next scheduled dose. 
Participants who develop Grade 2 toxicity despite 
adequate premedication should be permanently 
discontinued from further study drug intervention. 
Participant may be premedicated 
1.5 h (± 30 min) prior to 
infusion of pembrolizumab 
with: 
• Diphenhydramine 50 mg PO 
(or equivalent dose of 
antihistamine) 
• Acetaminophen 500-1000 mg 
PO (or equivalent dose of 
analgesic) 


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Grades 3 or 4 
Grade 3: 
Prolonged (ie, not rapidly responsive 
to symptomatic medication and/or 
brief interruption of infusion); 
recurrence of symptoms following 
initial improvement; hospitalization 
indicated for other clinical sequelae 
(eg, renal impairment, pulmonary 
infiltrates). 
Grade 4: 
Life-threatening; pressor or 
ventilatory support indicated. 
Stop Infusion. 
Additional appropriate medical therapy may include 
but is not limited to: 
• Epinephrine** 
• IV fluids 
• Antihistamines 
• NSAIDs 
• Acetaminophen 
• Narcotics 
• Oxygen 
• Pressors 
• Corticosteroids 
Increase monitoring of vital signs as medically 
indicated until the participant is deemed medically 
stable in the opinion of the investigator. 
Hospitalization may be indicated. 
**In cases of anaphylaxis, epinephrine should be 
used immediately. 
Participant is permanently discontinued from further 
study drug intervention. 
No subsequent dosing. 
Note:  Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the period 
of drug administration. 
Note:  For further information, please refer to the CTCAE v5.0 at http://ctep.cancer.gov. 
Other Allowed Dose Interruptions for Pembrolizumab 
Pembrolizumab may be interrupted for situations other than treatment-related AEs such as 
medical/surgical events or logistical reasons not related to study therapy.  Participants should be 
placed back on study therapy within 3 weeks of the scheduled interruption, unless otherwise 
discussed with the sponsor.  The reason for interruption should be documented in the 
participant's study record. 


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APPENDIX C. INSTRUCTION TO PARTICIPANTS FOR HANDLING 
STUDY DRUG (PEMIGATINIB) 
The participant must be instructed in the handling of study drug (pemigatinib) as follows: 
• Store the study drug at room temperature. 
• Only remove the number of tablets needed at the time of administration. 
• Do not remove doses in advance of the next scheduled administration. 
• Make every effort to take doses on schedule. 
• Report any missed doses/lost tablets/capsules. 
• Take study drug with a full glass of water. 
• Do not take another dose if vomiting after taking study drug occurs. 
• Keep study drug in a safe place and out of reach of children. 
• Bring all used and unused study drug bottles to the site at each visit. 
• If a dose of pemigatinib is missed by more than 4 hours, that dose should be skipped 
and the next scheduled dose should be administered at the usual time. 


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APPENDIX D. CYP3A4 INHIBITORS AND INDUCERS 
Refer to FDA for Drug Development and Drug Interactions:  Table of Substrates, Inhibitors and 
Inducers for the most current list (FDA 2016). 
CYP3A Inducers 
Inducers 
Therapeutic class 
Potent CYP3A Inducers  
Rifampin 
Antibiotics 
Mitotane 
Other Antineoplastics 
Avasimibe 
Other Antilipemics 
Rifapentine 
Antibiotics 
Apalutamide 
Antiandrogens 
Phenytoin 
Anticonvulsants 
Carbamazepine 
Anticonvulsants 
Enzalutamide 
Antiandrogens 
St John's Wort extract 
Herbal medications 
Lumacaftor 
Cystic fibrosis treatments 
Rifabutin 
Antibiotics 
Phenobarbital 
Anticonvulsants 
Moderate CYP3A Inducers  
Ritonavir and St. John's wort 
None 
Semagacestat 
Alzheimer's treatments 
Efavirenz 
NNRTIs 
Tipranavir and ritonavir 
Protease inhibitors 
Dabrafenib 
Kinase inhibitors 
Lesinurad 
Antigout and uricosuric agents 
Bosentan 
Endothelin receptor antagonists 
Genistein 
Food products 
Thioridazine 
Antipsychotics 
Nafcillin 
Antibiotics 
Talviraline 
NNRTIs 
Lopinavir 
Protease inhibitors 
Modafinil 
Psychostimulants 
Pf-06282999 
Myeloperoxidase inactivators 
Etravirine 
NNRTIs 
Lersivirine 
NNRTIs 
Telotristat ethyl 
Antidiarrheals 


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CYP3A Inhibitors 
Inhibitor 
Therapeutic Class 
Potent CYP3A Inhibitors  
VIEKIRA PAK 
Antivirals 
Indinavir/RIT 
Protease inhibitors 
Tipranavir/RIT 
Protease inhibitors 
Ritonavir 
Protease inhibitors 
Cobicistat (GS-9350) 
None 
Ketoconazole 
Antifungals 
Indinavir 
Protease inhibitors 
Troleandomycin 
Antibiotics 
Telaprevir 
Antivirals 
Danoprevir/RIT 
Antivirals 
Elvitegravir/RIT 
Treatments of AIDS 
Saquinavir/RIT 
Protease inhibitors 
Lopinavir/RIT 
Protease inhibitors 
Itraconazole 
Antifungals 
Voriconazole 
Antifungals 
Mibefradil 
Calcium channel blockers 
LCL161 
Cancer treatments 
Clarithromycin 
Antibiotics 
Posaconazole 
Antifungals 
Telithromycin 
Antibiotics 
Grapefruit juice DS 
Food products 
Conivaptan 
Diuretics 
Nefazodone 
Antidepressants 
Nelfinavir 
Protease inhibitors 
Saquinavir 
Protease inhibitors 
Ribociclib 
Kinase inhibitors 
Idelalisib 
Kinase inhibitors 
Boceprevir 
Antivirals 


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Inhibitor 
Therapeutic Class 
Moderate CYP3A Inhibitors  
Erythromycin 
Antibiotics 
Fluconazole 
Antifungals 
Atazanavir/RIT 
Protease inhibitors 
Darunavir 
Protease inhibitors 
Diltiazem 
Calcium channel blockers 
Darunavir/RIT 
Protease inhibitors 
Dronedarone 
Antiarrhythmics 
Crizotinib 
Kinase inhibitors 
Atazanavir 
Protease inhibitors 
Letermovir 
Antivirals 
GSK2647544 
Alzheimer's disease & dementia treatments 
Aprepitant 
Antiemetics 
Casopitant 
Antiemetics 
Amprenavir 
Protease inhibitors 
Faldaprevir 
Antivirals 
Imatinib 
Antineoplastic agents 
Verapamil 
Calcium channel blockers 
Netupitant 
Antiemetics 
Nilotinib 
Kinase inhibitors 
Grapefruit juice 
Food products 
Tofisopam 
Benzodiazepines 
Cyclosporine 
Immunosuppressants 
ACT-178882 
Renin inhibitors 
Ciprofloxacin 
Antibiotics 
Magnolia vine (Schisandra sphenanthera) 
Herbal medications 
Isavuconazole 
Antifungals 
Cimetidine 
H-2 receptor antagonists 
FK1706 
Central nervous system agents 


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APPENDIX E. FGFR3 GENE ALTERATIONS 
Please follow instructions outlined in the Investigator Site Files for screening/enrolling 
participants.  This list contains recurrent FGFR3 alterations that have been previously described 
or are present in somatic mutation databases and is not inclusive of all possible alterations.  For 
FGFR3 alterations not present on this list, please consult with the study sponsor. 
Alteration 
R248C 
K650M 
S249C 
K650E 
G370C 
K650Q 
S371C 
K650T 
Y373C 
K650N 
G380R 
Novel FGFR3 fusion (with partner specified) 
G380E 
FGFR3-BAIAP2L1 
A391E 
FGFR3-IGH 
R399C 
FGFR3-TACC3 
S433C 
FGFR3-WHSC1 
D641N 
 


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APPENDIX F. PROTOCOL AMENDMENT SUMMARY OF CHANGES 
Document 
Date 
Amendment 1 
17 APR 2020 
Amendment 1 (17 APR 2020) 
Overall Rationale for the Amendment:  Requests by Health Authorities for certain changes as 
well as feedback from Scientific Steering Committee to help with enrollment of participants.  
1. Section 1, Protocol Summary (Table 2: Key Study Design Elements; Table 3: 
Treatment Groups for Randomization); Section 2.2.2, Justification for Dose and 
Schedule; Section 4.1, Overall Design (Table 8: Treatment Groups for 
Randomization); Section 6.1, Study Treatments Administered (Table 10:  Study 
Treatment Information) 
Description of change:  Added duration of treatments for the study groups. 
Rationale for change:  Clarification requested by investigators. 
2. Section 1, Protocol Summary (Table 4:  Schedule of Activities) 
The following updates were made: 
a. Description of change: Revised QLQ-C30 and EQ-5D-5L assessments during the 
treatment period to every 3 cycles on Day 1 starting on Cycle 4.  
Rationale for change:  In order to eliminate the requirement that a participant be 
seen in the clinic to complete the QLQ-C30 and EQ-5D on the same days as imaging 
assessments, the schedule for collection of quality-of-life assessments has been 
updated and will be associated/completed at the time of already planned visits to the 
clinic.  This revision will ensure that the questionnaires are completed by participants 
at the required timepoints. 
b. Description of change:  Clarified that assessments for up-titration will be completed 
during Cycle 1 but the first opportunity to up-titrate a participant is at Cycle 2 Day 1. 
Rationale for change:  Requested by the Italian Health Authority. 
c. Description of change:  Added that IRT should be contacted during the patient 
prescreening and Cycle 1 Day 8. 
Rationale for change:  Administrative errors. 
3. Section 1, Protocol Summary (Table 4: Schedule of Activities); Section 4.1, Overall 
Design; Section 5.1, Inclusion Criteria (Criteria 6 and 7); Section 6.4.1.1, PD-L1 
CPS Results; 
 
Description of change:  Updated to indicate that participants can be randomized based 
on local genomics testing results for FGFR3 mutation or rearrangement and PD-L1 
status, but tissue will need to be sent for central laboratory confirmation.  Participants 
who have a documented FGFR3 mutation or rearrangement confirmed by Foundation 
Medicine do not need the FGFR status reconfirmed centrally if the report is within 


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24 months  In addition, participants whose PD-L1 status is not evaluable will not be 
eligible. 
Rationale for change:  Concordance rates with local genomics assay compared to the 
central laboratory have been very high on other studies in the program. The Scientific 
Steering Committee and numerous sites have voiced their concerns about the turnaround 
time for the central testing as a barrier to recruitment.  MHRA recommended that if a 
PD-L1 sample is not evaluable, it is not acceptable to assign an arbitrary positive score. 
4. Section 1, Protocol Summary (Table 3: Treatment Groups for Randomization; 
Figure 1, Study Design Schema); Section 4.1, Overall Design (Table 8: Treatment 
Groups for Randomization); Section 5.1, Inclusion Criteria (Criterion 5); Section 
6.4.1.1, PD-L1 CPS Results 
Description of change:  Note added to indicate that in certain regions, pembrolizumab 
monotherapy will be administered only to participants who are not eligible for cisplatin-
containing chemotherapy regardless of PD-L1 status. 
Rationale for change:  MHRA recommended as this wording is consistent with the 
licensed indication included in the pembrolizumab SmPC.  The pembrolizumab SmPC 
does not contain any indication for treatment of patients with locally advanced or 
metastatic urothelial carcinoma who are not eligible to receive any platinum-containing 
chemotherapy regardless of PD-L1 expression status. 
5. Section 1, Protocol Summary (Table 4: Schedule of Activities); Section 8.2.1, Tumor 
Imaging; Section 8.2.1.1, Initial Tumor Imaging; Section 8.2.2, Tumor Imaging 
During the Study 
Description of change:  Updated to indicate that brain imaging and bone scans only need 
to be done at baseline if participants are symptomatic.  Removed notes requiring that 
bone scans and brain imaging need to be completed to confirm CR if positive at baseline.  
Clarified that bone scans and brain imaging need to be repeated with other imaging 
assessments while a participant is on study if they were positive at baseline.  Added that 
all imaging must be sent to central vendor as soon as possible after completion.  
Rationale for change:  For clarification.  The notes regarding imaging requirements to 
confirm CR were removed as all imaging requirements are noted in Table 4.  
6. Section 1, Protocol Summary (Table 4:  Schedule of Activities); Section 8.5.5, 
Comprehensive Eye Examination; Section 6.6.1, Criteria and Procedures for Dose 
Interruptions and Adjustments of Pemigatinib 
Description of change:  Updated to indicate that OCT is mandatory at baseline, every 
3 cycles, and at EOT as part of the comprehensive eye examination and to include 
guidelines for treatment associated with SRD/RPED. 
Rationale for change:  For consistency with other protocols in the INCB054828 
program. 




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13. Section 5.2, Exclusion Criteria 
The following updates were made: 
a. Description of change:  Exclusion criterion 2 updated to indicate that prior receipt of 
an anti–PD-1, anti–PD-L1, or anti–PD-L2 agent, or an agent directed to another 
co-inhibitory T-cell receptor, is allowed , but the last treatment must have been 
completed at least 18 months before enrollment in this study. 
Rationale for change:  After discussion with numerous investigators and the Scientific 
Steering Committee, it was determined that a large number of patients are now being 
treated with checkpoint inhibitors for urothelial carcinoma in early-stage disease.  
Excluding these patients will further limit the number of participants eligible for this 
study. 
b. Description of change:  Exclusion criterion 8 was updated to specify radiation to the 
primary tumor site for the sole purpose of sensitizing the tumor to local radiation can 
be done if there is a 3-week washout period prior to the first dose of study drug. 
Rationale for change:  For consistency between inclusion criterion 8 and exclusion 
criterion 8. 
c. Description of change:  In exclusion criterion 17, removed the note stating that no 
testing for HBV or HCV is required unless mandated by local health authority. 
Rationale for change:  The ICF and Protocol Section 8.5.6.2 state that HBV and 
HCV testing will be done at screening. 
d. Description of change:  In exclusion criterion 11 (Table 9: Exclusionary Laboratory 
Values), the hemoglobin units corrected to g/dL. Direct bilirubin value corrected to 
≤ ULN.  
Rationale for change:  Administrative error/incorrect unit of measure. 
14. Section 6.1, Study Treatments Administered (Table 10: Study Treatment 
Information) 
Description of change:  Added temperature range and language for room temperature. 
Rationale for change:  Japanese requirement. 
15. Section 6.2, Phosphate Binders in Japan (Table 11: Study Treatment 2 [Phosphate 
Binders for Japan]); Section 6.3, Preparation, Handling, and Accountability; 
Section 6.6.2, Management of Hyperphosphatemia 
Description of change:  Added phosphate binder information for Japan and clarification 
that phosphate binders for treatment of hyperphosphatemia for Japanese participants are 
provided by the sponsor and that the required documentation for binders is the same as 
for study drug. 
Rationale for change:  To clarify the tested binders in Japan for the management of 
hyperphosphatemia, which the sponsor provided with study-specific label, and to meet 
Japanese requirements. 


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16. Section 6.7.1, Restricted Medications and Procedures 
Description of change:  Updated to state that calcium-based phosphate binders may be 
used with appropriate clinical monitoring if other types of phosphate binders are not 
available in certain regions. 
Rationale for change:  Clarification that calcium-based phosphate binders can be used 
with appropriate clinical monitoring if this is the only option in certain regions. 
17. Section 7.1.1, Reasons for Discontinuation 
Description of change:  Clarified that participants in Treatment Group A (pemigatinib + 
pembrolizumab) need to discontinue pembrolizumab after 35 cycles of treatment but can 
continue pemigatinib until progression. 
Rationale for change:  For clarification. 
18. Section 8.5.1, Adverse Events 
Description of change:  Language was added to indicate that, for Japanese participants, 
the relationship with phosphate binders should also be collected on the Adverse Events 
Form in the eCRF. 
Rationale for change:  Japanese requirement. 
19. Section 8.5.4, Electrocardiograms 
Description of change:  Clarified that in the event that a single QTc is > 480 ms at 
screening, the participant may enroll if three ECGs are completed and the average QTc 
for the 3 ECGs is < 480 ms or with approval from the medical monitor. 
Rationale for change:  To avoid artifact measurements of a single ECG. 
20. Section 8.5.6, Laboratory Assessments 
Description of change:  Updated to indicate that the site's local laboratory will complete 
all safety assessments but will not analyze 
.  The site's 
laboratory will draw the blood for these tests, but the analyses will be conducted by 
Incyte. 
Rationale for change:  Administrative error. 
21. Section 8.7.1.3, Assessment on Tumor Samples 
Description of change:  Figure 2 was updated to indicate that an archival tumor tissue 
sample is required from < 24 months prior to screening as stated in Section 8.7.1.  
Rationale for change:  Administrative error/incorrect unit of time. 
22. Section 9.2, Definition of Serious Adverse Event 
Description of change:  Added language about AEs that may lead to disability. 
Rationale for change:  Japanese requirement. 


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23. Section 9.4, Reporting of Serious Adverse Events 
Description of change:  Language was added to indicate that in Japan, SAEs must be 
reported to the head of the study site; suspected expected deaths and life-threatening 
events will be reported to the PMDA; and events related to phosphate binder use for the 
treatment of hyperphosphatemia will be reported as SAEs. 
Rationale for change:  Japanese requirement. 
24. Section 9.9, Product Complaints 
Description of change:  Language added for medical devices. 
Rationale for change:  Japanese requirement. 
25. Section 10.4.1, Primary Analysis 
Description of change:  Clarified that patients with FGFR3 mutation or rearrangement 
confirmed by the central laboratory will be included in the primary analysis. 
Rationale for change:  The introduction of local testing for FGFR3 in this amendment 
required that the primary analysis population be defined in this way. 
26. Section 11.1, Investigator Responsibilities 
Description of change:  Added record retention requirements for Japan. 
Rationale for change:  Japanese requirement. 
27. Section 11.6, Study and Site Closure 
Description of change:  Language was added to reflect the responsibility of investigator 
and head of study site (Japan) upon study completion. 
Rationale for change:  Japanese requirement. 
28. Appendix A, Information Regarding the Effectiveness of Contraceptive Methods  
Description of change: Updated to indicate that partners of male participants should use 
contraception during the study and through 120 days after the last dose of pemigatinib 
and/or pembrolizumab or 180 days after the last dose of chemotherapy. 
Rationale for change:  Requested by the Belgian Health Authority. 
29. Appendix B, Pembrolizumab Dose Modifications (Table B1:  Dose Modification and 
Toxicity Management Guidelines for Immune-Related Adverse Events Associated 
With Pembrolizumab) 
Description of change:  Description of change:  Added irAEs of skin reactions to the 
table. 
Rationale for change:  Italian requirement. 
30. Incorporation of administrative changes.  Other minor, administrative changes have 
been incorporated throughout the Protocol and are noted in the redline version of the 
amendment. 

SAP_001.pdf: 
Official Title: 
NCT Number: 
Document Date: 
A Phase 2, Open-Label, Randomized, Multicenter Study to Evaluate the Efficacy and 
Safety of Pemigatinib Plus Pembrolizumab Versus Pemigatinib Alone Versus 
Standard of Care as First-Line Treatment for Metastatic or Unresectable Urothelial 
Carcinoma in Cisplatin-Ineligible Participants Whose Tumors Express FGFR3 
Mutation or Rearrangement (FIGHT-205)
NCT04003610
Statistical Analysis Plan: 23 February 2021


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Statistical Analysis Plan 
 
 
 
 
INCB 54828-205 
A Phase 2, Open-Label, Randomized, Multicenter Study to Evaluate the 
Efficacy and Safety of Pemigatinib Plus Pembrolizumab Versus 
Pemigatinib Alone Versus Standard of Care as First-Line Treatment for 
Metastatic or Unresectable Urothelial Carcinoma in Cisplatin-Ineligible 
Participants Whose Tumors Express FGFR3 Mutation or Rearrangement 
(FIGHT-205) 
 
 
 
IND Number: 
124,358 
EudraCT Number: 
2019‐000721-50 
Sponsor: 
Incyte Corporation 
1801 Augustine Cut-Off 
Wilmington, DE 19803 
United States 
Protocol Version: 
Protocol Amendment 1 dated 17 APR 2020 
CRF Approval Date: 
22 MAY 2020 
SAP Version: 
Original 
SAP Author:  
 
, Biostatistics 
Date of Plan: 
23 FEB 2021 
 
 
This study is being conducted in compliance with Good Clinical Practice, 
including the archiving of essential documents. 


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TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
TABLE OF CONTENTS .................................................................................................................2 
LIST OF ABBREVIATIONS ..........................................................................................................5 
1. 
INTRODUCTION ........................................................................................................7 
2. 
STUDY INFORMATION, OBJECTIVES, AND ENDPOINTS.................................7 
2.1. 
Protocol and Case Report Form Version ......................................................................7 
2.2. 
Study Objectives and Endpoints ...................................................................................7 
3. 
STUDY DESIGN .........................................................................................................9 
3.1. 
Randomization ............................................................................................................10 
3.2. 
Control of Type I Error ...............................................................................................10 
3.3. 
Sample Size Considerations .......................................................................................11 
3.4. 
Schedule of Assessments ............................................................................................12 
4. 
DATA HANDLING DEFINITIONS AND CONVENTIONS ..................................12 
4.1. 
Scheduled Study Evaluations and Study Periods .......................................................12 
4.1.1. 
Day 1 ...........................................................................................................................12 
4.1.2. 
Study Day ...................................................................................................................12 
4.1.3. 
Baseline Value ............................................................................................................13 
4.1.4. 
Handling of Missing and Incomplete Dates ...............................................................13 
4.1.5. 
Cycle Length and Duration .........................................................................................14 
4.2. 
Variable Definitions ....................................................................................................14 
4.2.1. 
Body Mass Index ........................................................................................................14 
4.2.2. 
Body Surface Area ......................................................................................................14 
4.2.3. 
Prior and Concomitant Medication .............................................................................14 
5. 
STATISTICAL METHODOLOGY ...........................................................................15 
5.1. 
General Methodology .................................................................................................15 
5.2. 
Treatment Groups .......................................................................................................15 
5.3. 
Analysis Populations ..................................................................................................15 
5.3.1. 
Intent-to-Treat Population ..........................................................................................15 
5.3.2. 
Per Protocol Population ..............................................................................................15 
5.3.3. 
Safety Population ........................................................................................................15 
6. 
BASELINE, EXPOSURE, AND DISPOSITION ......................................................16 


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6.1. 
Demographics, Baseline Characteristics, and Disease History ..................................16 
6.1.1. 
Demographics and Baseline Characteristics ...............................................................16 
6.1.2. 
Baseline Disease Characteristics ................................................................................16 
6.1.3. 
Disease History ...........................................................................................................16 
6.1.4. 
Prior Therapy ..............................................................................................................16 
6.1.5. 
Medical History ..........................................................................................................16 
6.2. 
Disposition of Participant ...........................................................................................17 
6.3. 
Protocol Deviations ....................................................................................................17 
6.4. 
Exposure .....................................................................................................................17 
6.5. 
Study Drug Compliance .............................................................................................18 
6.6. 
Prior and Concomitant Medication .............................................................................18 
7. 
EFFICACY .................................................................................................................18 
7.1. 
Efficacy Hypotheses ...................................................................................................18 
7.2. 
Analysis of the Primary Efficacy Parameter ..............................................................18 
7.2.1. 
Primary Efficacy Analysis ..........................................................................................18 
7.2.2. 
Sensitivity and Supportive Analyses for Primary Endpoint .......................................19 
7.3. 
Analysis of the Secondary Efficacy Parameter ..........................................................19 
7.3.1. 
Overall Survival ..........................................................................................................19 
7.3.2. 
Best Overall Response and Duration of Response .....................................................19 
7.3.3. 
Quality-of-Life Questionnaires ...................................................................................20 
7.3.3.1. 
EORTC QLQ-C30 ......................................................................................................20 
7.3.3.2. 
EQ-5D-5L ...................................................................................................................21 
 
21 
 
21 
 
21 
 
22 
8. 
SAFETY AND TOLERABILITY ..............................................................................22 
8.1. 
Adverse Events ...........................................................................................................22 
8.1.1. 
Adverse Event Definitions ..........................................................................................22 
8.1.2. 
Adverse Event Listings ...............................................................................................22 
8.2. 
Clinical Laboratory Tests ...........................................................................................22 
8.2.1. 
Laboratory Value Definitions .....................................................................................22 
8.2.2. 
Potential Hy's Law Events ..........................................................................................23 


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8.3. 
Vital Signs ..................................................................................................................23 
8.4. 
Electrocardiograms .....................................................................................................23 
9. 
INTERIM ANALYSES ..............................................................................................24 
10. 
CHANGES AND MODIFICATIONS TO THE ANALYSIS PLAN ........................24 
10.1. 
Changes to Protocol-Defined Analyses ......................................................................24 
10.2. 
Changes to the Statistical Analysis Plan .....................................................................24 
11. 
REFERENCES ...........................................................................................................25 
APPENDIX A. PLANNED LISTINGS ......................................................................................26 
 
LIST OF TABLES 
Table 1: 
Objectives and Endpoints .............................................................................................8 
Table 2: 
Treatment Groups for Randomization ........................................................................10 
Table 3: 
Median Progression-Free Survival Assumptions for Standard of Care 
Treatments ..................................................................................................................11 
Table 4: 
Evaluation and Censoring of Progression-Free Survival ............................................19 
Table 5: 
European Organization for Research and Treatment of Cancer Quality of 
Life Questionnaire-C30 Scales ...................................................................................20 
Table 6: 
Criteria for Clinically Notable Vital Sign Abnormalities ...........................................23 
Table 7: 
Criteria for Clinically Notable Electrocardiogram Abnormalities .............................24 
Table 8: 
Statistical Analysis Plan Versions ..............................................................................24 
 
LIST OF FIGURES 
Figure 1: 
Study Design Schema ...................................................................................................9 
 


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LIST OF ABBREVIATIONS 
Abbreviation 
Term 
AE 
adverse event 
AUC 
area under the plasma or serum concentration-time curve 
BICR 
blinded, independent, central review 
BMI 
body mass index 
BOR 
best overall response 
BSA 
body surface area 
CI 
confidence interval 
CPS 
combined positive score 
CR 
complete response 
CRF 
case report form 
CTCAE 
Common Terminology Criteria for Adverse Events 
DOR 
duration of response 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
FDA 
Food and Drug Administration 
FGFR 
fibroblast growth factor receptor 
HR 
hazard ratio 
ITT 
intent to treat 
IV 
intravenous(ly) 
MedDRA 
Medical Dictionary for Regulatory Activities  
NCI 
National Cancer Institute 
NE 
not evaluable 
OS 
overall survival 
PD 
progressive disease 
PD-L1 
programmed cell death protein 1 
PFS 
progression-free survival 
 
 
PO 
orally 
PP 
per protocol 
PR 
partial response 
PS 
performance status 
PT 
preferred term 
Q3W 
every 3 weeks 


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Abbreviation 
Term 
QD 
daily 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAP 
Statistical Analysis Plan 
SD 
stable disease 
SOC 
standard of care 
TEAE 
treatment-emergent adverse event 
TIL 
tumor-infiltrating lymphocytes 
TNM 
tumor, node, metastasis 
UC 
urothelial carcinoma 
ULN 
upper limit of normal 
WHO 
World Health Organization  


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1. 
INTRODUCTION 
This is a Phase 2, open-label, randomized, active-controlled study of pemigatinib plus 
pembrolizumab or pemigatinib alone versus SOC as first-line treatment for metastatic or 
unresectable UC in cisplatin-ineligible participants whose tumors express FGFR3 mutation or 
rearrangement.  Section 2 of the Protocol provides a detailed description of the investigational 
product, target patient population, rationale for doses to be examined, and potential risks and 
benefits of treatment with pemigatinib plus pembrolizumab and pemigatinib alone. 
The purpose of this SAP is to provide details of the statistical analyses that have been outlined in 
the INCB 54828-205 Protocol.  
 
 
  
 
 
2. 
STUDY INFORMATION, OBJECTIVES, AND ENDPOINTS 
2.1. 
Protocol and Case Report Form Version 
This SAP is based on INCB 54828-205 Protocol Amendment 1 dated 17 APR 2020 and CRFs 
approved 22 MAY 2020.  Unless superseded by an amendment, this SAP will be effective for all 
subsequent protocol amendments and eCRF versions. 
2.2. 
Study Objectives and Endpoints 
The objectives and endpoints apply to a study population of male or female participants at least 
18 years of age with a histologically confirmed diagnosis of metastatic or unresectable UC, 
whose tumors express an FGFR3 mutation or rearrangement and who are medically ineligible to 
receive cisplatin-based chemotherapy and have not received prior treatment. 
This study will be considered to have met its primary objective if pembrolizumab plus 
pemigatinib or pemigatinib alone is superior to SOC for the primary endpoint. 
Table 1 presents the objectives and endpoints. 


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Table 1: 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
To evaluate and compare PFS in participants treated 
with pemigatinib in combination with pembrolizumab 
(Treatment Group A) and pemigatinib alone 
(Treatment Group B) versus SOC (Treatment 
Group C). 
Differences in PFS will be evaluated hierarchically, 
and the comparison between pemigatinib in 
combination with pembrolizumab (Treatment 
Group A) and SOC (Treatment Group C) will be 
evaluated first, and if significant difference is detected, 
a second comparison will be made in PFS between 
pemigatinib alone (Treatment Group B) and SOC 
(Treatment Group C). 
Hypothesis:  The combination of pembrolizumab plus 
pemigatinib has superior PFS as compared with SOC.  
Contribution of pemigatinib alone to combination will 
be assessed by comparing Treatment Groups A and C 
and Treatment Groups B and C. 
Progression-free survival, defined as the time from 
randomization date until the date of disease 
progression (as measured by BICR per RECIST v1.1) 
or death due to any cause, whichever occurs first. 
Secondary 
To evaluate and compare the efficacy of the 
3 treatment groups with respect to OS. 
Overall survival, defined the time from the date of 
randomization until death due to any cause. 
To evaluate and compare the efficacy of the 
3 treatment groups with respect to overall tumor 
response and DOR. 
• Objective response rate, defined as the proportion of 
participants with BOR of CR or PR determined by 
BICR per RECIST v1.1. 
• Duration of response, defined as the time from the 
date of the first assessment of CR or PR until the 
date of the first disease progression per BICR per 
RECIST v1.1 or death, whichever occurs first. 
To evaluate the safety of the 3 treatment groups. 
Safety and tolerability of pemigatinib with or without 
pembrolizumab and SOC will be assessed by 
evaluating the frequency and severity of AEs, physical 
examination findings, vital sign changes, and clinical 
laboratory assessments. 
To evaluate changes from baseline in patient-reported 
outcomes. 
Patient-reported outcome scales (ie, EORTC 
QLQ-C30, EQ-5D-5L) at each timepoint and change 
from baseline to each timepoint. 




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3.1. 
Randomization 
Participants who are screened and found to have the FGFR3 mutation or rearrangement will be 
randomized 1:1:1 into 1 of the 3 treatment groups indicated in Table 2 and stratified by eligible 
to receive carboplatin versus not eligible to receive carboplatin, PD-L1 CPS ≥ 10 versus 
CPS < 10, and LN-only disease versus other metastatic disease. 
Table 2: 
Treatment Groups for Randomization 
Treatment Group 
Regimen 
A 
Pemigatinib 13.5 mg QD POa until PD + pembrolizumab 200 mg Q3W IV up to 
35 cycles (approximately 2 years) or PD, whichever occurs first 
B 
Pemigatinib 13.5 mg QD POa until PD 
C 
One of 2 SOC treatment options: 
1. Gemcitabine 1000 mg/m2 Q3W IV on Days 1 and 8 + carboplatin AUC 5 
(or AUC 4.5 if required per local guidelines) Q3W on Day 1 or 2 for 4 to 
6 cycles.  (Participants whose tumors express PD-L1 CPS < 10 who are 
eligible to receive carboplatin.) 
OR 
2. Pembrolizumab 200 mg Q3W IV up to 35 cycles (approximately 2 years).  
(Participants whose tumors express PD-L1 CPS ≥ 10 or participants who are 
not considered eligible to receive any platinum-containing chemotherapy 
regardless of PD-L1 expression status [only applicable in regions where 
pembrolizumab is used as SOC for participants who are not eligible for any 
platinum-containing chemotherapy regardless of PD-L1 status].)b 
a Participants not reaching the target serum phosphate during Cycle 1 will increase the daily dose to 18 mg starting 
at Cycle 2 as described in Section 6.6.2.1 of the Protocol. 
b Participants can be enrolled if regulatory authorities allow carboplatin-ineligible participants to receive 
pembrolizumab monotherapy. 
3.2. 
Control of Type I Error 
The overall level of significance is strongly controlled for primary and key secondary objectives 
at 1-sided 0.025 using a fixed sequential testing procedure.  The primary and key secondary 
efficacy endpoints at final analysis will be tested in the following order: 
1. PFS comparison for pemigatinib plus pembrolizumab versus SOC at 1-sided 0.025. 
2. OS comparison for pemigatinib plus pembrolizumab versus SOC at 1-sided 0.0147 at the 
time when primary analysis of PFS is conducted; OS comparison for pemigatinib plus 
pembrolizumab versus SOC at 1-sided 0.0103 at final OS analysis. 
3. PFS comparison for pemigatinib only versus SOC at 1-sided 0.025. 
4. OS comparison for pemigatinib only versus SOC at 1-sided 0.0147 at the time when 
primary analysis of PFS is conducted; OS comparison for pemigatinib only versus SOC 
at 1-sided 0.0103 at final OS analysis. 


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3.3. 
Sample Size Considerations 
The sample size calculation is based on the primary endpoint of PFS. 
The SOC treatment group in this study consists of participants who will receive pembrolizumab 
or chemotherapy depending on the participant carboplatin eligibility and PD-L1 CPS.  In 
KEYNOTE-052, a large, single-arm, Phase 2 study with pembrolizumab conducted in 
cisplatin-ineligible participants who had not been previously treated with systemic 
chemotherapy, the median PFS was 2.1 months (95% CI:  2, 3; Balar et al 2017a).  In 
EORTC 30968, a randomized, Phase 2/3 study comparing gemcitabine and carboplatin versus 
methotrexate/carboplatin/vinblastine, the median PFS was 5.8 months in the 
gemcitabine/carboplatin group as compared with 4.2 months in the other group(s) (De Santis 
et al 2012).  Based on available data from KEYNOTE-052 and EORTC 30968 and participants' 
distribution percentages (see Table 3), it is estimated that the median PFS in the SOC treatment 
group (pembrolizumab or gemcitabine/carboplatin) is expected to be 5 months based on 
simulation. 
Table 3: 
Median Progression-Free Survival Assumptions for Standard of Care 
Treatments 
Population 
Total (%) 
(N = 132) 
Median PFS 
Assumption 
Carboplatin-ineligible participants who will receive 
pembrolizumab 
26 (20%) 
2.1 months 
Carboplatin-eligible participants who will receive 
pembrolizumab (CPS ≥ 10) 
16 (12%) 
4.9 months 
Carboplatin-eligible participants who will receive 
gemcitabine/carboplatin (CPS < 10) 
90 (68%) 
5.8 months 
It is expected that treatment with pemigatinib plus pembrolizumab will result in an HR of 0.68 
for PFS compared to SOC, which corresponds to an increase in median PFS of 2.4 months under 
the exponential model assumption.  It is calculated that a total of 210 PFS events in the combined 
treatment groups of pemigatinib plus pembrolizumab and SOC need to be observed to ensure 
80% power to test the null hypothesis:  PFS HR = 1, versus the specific alternative hypothesis:  
PFS HR = 0.68 for pemigatinib plus pembrolizumab versus SOC.  This calculation assumes 
analysis using a 1-sided log-rank test at a 0.025 overall significance level and participants are 
randomized to the treatment groups in a 1:1 ratio. 
To keep a minimum meaningful hazard ratio of 0.68 for PFS in participants with pemigatinib 
alone versus SOC, a total of 210 PFS events in the combined treatment groups of pemigatinib 
alone and SOC need to be observed to achieve 80% power to test the null hypothesis:  PFS 
HR = 1, versus the specific alterative hypothesis:  PFS HR = 0.68 for pemigatinib alone versus 
SOC.  This calculation assumes analysis using a 1-sided log-rank test at a 0.025 overall 
significance level and participants are randomized to the treatment groups in a 1:1 ratio. 
Assuming uniform accrual of the participants over a 36-month period, an 8-month follow-up 
after the last participant is randomized, and a 5% lost to follow-up rate, a total of approximately 


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372 participants will need to be randomized to observe the targeted PFS events at approximately 
44 months after first participant is randomized. 
The median OS for the SOC group is about 10 months based on EORTC Study 30968 and 
KEYNOTE-052.  It is calculated that a total of 194 deaths in the combined treatment groups of 
pemigatinib plus pembrolizumab and SOC need to have been observed to achieve 76% power to 
detect an HR of 0.68 using a 1-sided log-rank test at a 0.025 overall significant level.  Final OS 
analysis is expected to occur at approximately 52 months after first participant is randomized.  
At the time when final PFS analysis is conducted, it is expected that about 169 deaths will be 
observed in the combined treatment groups of pemigatinib plus pembrolizumab and SOC.  
Overall survival comparison for pemigatinib plus pembrolizumab versus SOC will be conducted 
at nominal 1-sided alpha of 0.0147 according to the O'Brien-Fleming spending function.  Final 
OS analysis comparing pemigatinib plus pembrolizumab versus SOC will be conducted at 
nominal 1-sided alpha of 0.0103 when approximately 194 deaths are observed in the combined 
treatment groups of pemigatinib plus pembrolizumab and SOC.  The actual boundaries will be 
recalculated from the actual number of deaths at the time when final PFS analysis is conducted 
using the alpha- and beta-spending functions. 
3.4. 
Schedule of Assessments 
Refer to Protocol Amendment 1 dated 17 APR 2020 for a full description of all study procedures 
and assessment schedules for this study. 
4. 
DATA HANDLING DEFINITIONS AND CONVENTIONS 
4.1. 
Scheduled Study Evaluations and Study Periods 
4.1.1. 
Day 1 
For safety assessments, Day 1 is the date that the first dose of study drug (pemigatinib, 
pembrolizumab, gemcitabine, or cisplatin) is administered to the participants. 
For efficacy assessments, Day 1 is the randomization date. 
For randomized participants not treated with any study drug, Day 1 is defined as the date of 
randomization. 
4.1.2. 
Study Day 
If a visit/reporting date is on or after Day 1, then the study day at the visit/reporting date will be 
calculated as 
Day # = (visit/reporting date – Day 1 date + 1). 
If the visit/reporting date is before Day 1, then the study day at the visit/reporting date will be 
calculated as 
Day # = (visit/reporting date – Day 1 date). 
A study day of –1 indicates 1 day before Day 1. 


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4.1.3. 
Baseline Value 
Baseline is the last nonmissing measurement obtained before the first administration of study 
drug, unless otherwise defined. 
For randomized participants not treated with any study drug, baseline is defined as the last 
nonmissing assessment before randomization for all parameters. 
When scheduled assessments and unscheduled assessments occur on the same day and the time 
of the assessment or time of first dose is not available, use the following convention to determine 
baseline: 
• If both a scheduled and an unscheduled visit are available on the day of the first dose 
and the time is missing, use the scheduled assessment as baseline. 
• If all scheduled assessments are missing on the day of the first dose and an 
unscheduled assessment is available, use the unscheduled assessment as baseline. 
4.1.4. 
Handling of Missing and Incomplete Dates 
In general, values for missing dates will not be handled unless methods for handling missing 
dates are specified in this section or relevant sections.  The original reported dates collected on 
the eCRF should be used in all relevant listings.  The following rules will be used for handling 
partial dates for analyses requiring dates. 
When calculating the time since diagnosis of cancer, a partial cancer diagnosis date will be 
handled as follows in the calculation: 
• If only the day is missing, then the first day of the month will be used. 
• If both the month and day are missing, then 01 JAN of the year will be used. 
• If the diagnosis date is completely missing, then the time since diagnosis will not be 
calculated. 
When the date of the last dose is used in deriving variables such as duration of treatment or 
TEAE flag, a missing or partial date of the last dose will be handled as follows: 
• If only the day is missing, then the earlier date of the last day of the month or the date 
that the participant discontinued treatment will be used. 
• Otherwise, the date that the participant discontinued treatment will be used as the date 
of the last dose. 
For relevant efficacy endpoints, a partial date of the death date will be handled as follows in the 
calculation: 
• If mmyyyy for the last known alive date = mmyyyy for the death date, then the death 
date will be set to the day after the last known alive date. 
• If mmyyyy for the last known alive date < mmyyyy for the death date, then the death 
date will be set to the first day of the death month. 
• Otherwise, the partial death date will not be imputed. 


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4.1.5. 
Cycle Length and Duration 
Cycle 1 Day 1 is the day that the first dose of study drug is administered.  The scheduled cycle 
length is 21 days.  The actual Day 1 of subsequent cycles will correspond with the first day of 
administration of pemigatinib, pembrolizumab, or gemcitabine plus cisplatin in that cycle; thus, 
treatment cycles may become out of sync with the originally planned schedule, and the cycle 
length may be different from 21 days.  The date of the Day 1 of subsequent cycles recorded on 
the eCRF will be used as the Day 1 of the subsequent cycles. 
4.2. 
Variable Definitions 
The following variables will only be calculated if not reported on the eCRF. 
4.2.1. 
Body Mass Index 
Body mass index will be calculated as follows: 
BMI (kg/m2) = [weight (kg)] / [height (m)]2. 
4.2.2. 
Body Surface Area 
Body surface area will be calculated based on the Mosteller (1987) formula as follows: 
BSA (m2) = {[weight (kg)  height (cm)] / 3600}½. 
Sites will also record the BSA calculated per institutional standards. 
4.2.3. 
Prior and Concomitant Medication 
Prior medication is defined as any nonstudy medication started before the first dose of 
pemigatinib, pembrolizumab, or gemcitabine plus cisplatin. 
Concomitant medication is defined as any nonstudy medication that is started accordingly: 
• Before the date of first administration of pemigatinib, pembrolizumab, or gemcitabine 
plus cisplatin and is ongoing throughout the study or ends on/after the date of first 
study drug administration. 
• On/after the date of first administration of pemigatinib, pembrolizumab, or 
gemcitabine plus cisplatin and is ongoing or ends during the course of study. 
A prior medication could also be classified as "both prior and concomitant medication" if the end 
date is on or after first dose of pemigatinib, pembrolizumab, or gemcitabine plus cisplatin.  In the 
listing, it will be indicated whether a medication is only prior, only concomitant, or both prior 
and concomitant. 
For the purposes of analysis, all medications will be considered concomitant medications unless 
the medications can unequivocally be defined as not concomitant. 


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5. 
STATISTICAL METHODOLOGY 
5.1. 
General Methodology 
Unless otherwise noted, SAS® software (SAS Institute Inc, Cary, NC; v9 or later) will be used 
for the generation of all listings and statistical analyses. 
5.2. 
Treatment Groups 
This is a randomized, open-label, parallel treatment group design.  Participants will be 
summarized by treatment group. 
5.3. 
Analysis Populations 
5.3.1. 
Intent-to-Treat Population 
All participants who are randomized will constitute the ITT population.  Treatment groups for 
this population will be defined according to the treatment assignment at the time of 
randomization regardless of the actual study drug the participant might take during his/her 
participation in the study.   
The ITT population will be used for the listings of demographics, baseline characteristics, 
disease history, participant disposition, and analyses of all efficacy data. 
5.3.2. 
Per Protocol Population 
Participants in the ITT population who are considered to be sufficiently compliant with the 
Protocol will comprise the PP population.  This population includes all ITT participants who 
meet all major inclusion and no major exclusion criteria based on blinded review of clinical data. 
The following procedures will be performed to identify those participants who are to be excluded 
from the PP population: 
• Clinical review of Protocol deviations. 
• Clinical review of concomitant medications as defined in Section 6.7 of the Protocol. 
• Clinical review of the dose administration and drug accountability listing. 
The determination of participants being considered for exclusion from the PP population by the 
clinical team will be prepared and signed before database lock. 
The PP population will be used in the supportive sensitivity analyses for primary endpoints. 
5.3.3. 
Safety Population 
The safety population includes all randomized participants who received at least 1 dose of study 
treatment.  Treatment groups for this population will be determined according to the actual 
treatment the participant received regardless of assigned study drug treatment. 
All safety analyses will be conducted using the safety population. 


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6. 
BASELINE, EXPOSURE, AND DISPOSITION 
Appendix A provides a list of data displays. 
6.1. 
Demographics, Baseline Characteristics, and Disease History 
6.1.1. 
Demographics and Baseline Characteristics 
The following demographics will be listed for the ITT population:  age, sex, race, ethnicity, 
weight, height, BMI, BSA, eligibility to receive carboplatin, primary disease location, PD-L1 
CPS. 
6.1.2. 
Baseline Disease Characteristics 
The following baseline disease characteristics will be listed for the ITT population: baseline 
phosphate, ECOG PS, and tobacco history. 
In addition, start date and end date of tobacco consumption, average number of cigarettes 
consumed, average number of cigars consumed, average number of smokeless (pinches) tobacco 
consumed, and average number of pipefuls consumed will be listed. 
6.1.3. 
Disease History 
Time since initial diagnosis, histology at diagnosis, stage at diagnosis, TNM staging at diagnosis, 
TIL at diagnosis; time to diagnosis of advanced disease, current stage, current histology, current 
TNM stage, TIL currently reported, and current sites of disease will be listed for all participants 
in the ITT population.  
Time since diagnosis will be calculated as:  
time since diagnosis (years) = (date of randomization – date of diagnosis + 1) / 365.25. 
6.1.4. 
Prior Therapy 
Participants who received prior therapy regimens will be listed for the ITT population.  The 
component drugs of prior therapy regimens will be coded using the WHO Drug Dictionary.  
Regimen name, component drugs, start and stop date, route of the regimen taken, purpose of the 
regimen, best response, reason for discontinuation, and date of relapse/progression will be listed. 
Participants who received prior radiation will be listed for the ITT population, including 
radiotherapy type, anatomical location of the administration, start and stop date, number of 
fractions received, total dose, reason for regimen, and best response. 
Participants who had prior surgery or surgical procedure for the malignancies under study will be 
listed for the ITT population, including the date and description of the surgery/procedure. 
6.1.5. 
Medical History 
For participants in the ITT population, medical history will be listed. 


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6.2. 
Disposition of Participant 
Participants who were randomized, who were treated, who were ongoing with study treatment, 
who discontinued study treatment with a primary reason for discontinuation, who were still in 
the study, who completed the study, and who withdrew from the study with a primary reason for 
withdrawal will be listed for the ITT population. 
6.3. 
Protocol Deviations 
Protocol deviations recorded on the eCRF will be listed. 
6.4. 
Exposure 
For participants in the safety population, exposure to study drug will be listed as the following: 
• Number of cycles:  number of cycles with a nonzero dose of study drug 
(pemigatinib, pembrolizumab, or gemcitabine plus cisplatin). 
• Duration of treatment with study drug (days):   
For participants in Group A who take pemigatinib plus pembrolizumab: 
max (date of last dose of pembrolizumab + 20, date of last dose of pemigatinib) – 
date of first dose + 1 
For participants in Group B who take pemigatinib: 
date of last dose – date of first dose + 1 
For participants in Group C who take pembrolizumab: 
date of last dose + 20 – date of first dose + 1 
For participants in Group C who take gemcitabine plus cisplatin: 
date of last dose + 6 – date of first dose + 1 if last dose is on Day 1 of a cycle; 
date of last dose + 13 – date of first dose + 1 if last dose is on Day 8 of a cycle. 
• Dose modifications:  participants who had study drug dose reduction and 
interruption. 
• Average daily dose of pemigatinib (mg/day):  total actual pemigatinib dose taken 
(mg) / duration of treatment with pemigatinib (days). 
Total actual dose taken will be calculated based on the information entered on the 
Drug Accountability eCRF. 
For pembrolizumab, gemcitabine, and cisplatin, relative dose intensity will be listed: 
• Relative dose intensity (%):  100 × [total actual dose] / [total assigned dose] 
Total actual dose (mg) administered is the sum of the dose that has been administered 
to the participant.  Total assigned dose (mg) is the total dose expected if the 
participant had taken all doses as initially assigned. 


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6.5. 
Study Drug Compliance 
For participants in the safety population, overall compliance (%) for pemigatinib will be listed 
and calculated as follows: 
compliance (%) = 100  [total dose actually taken] / [total prescribed dose]. 
The total prescribed dose is defined as the sum of the doses prescribed by the investigator 
accounting for dose modifications. 
The total actual dose taken will be calculated based on information entered on the Drug 
Accountability eCRF.  If there are dispensed drugs that have not been returned yet, the actual 
dose taken starting from the dispense date of the unreturned drugs will be imputed by the dose 
taken as reported on the Dosing eCRF. 
6.6. 
Prior and Concomitant Medication 
Prior medications and concomitant medications will be coded using the WHO Drug Dictionary.  
For participants in the ITT population, each prior and concomitant medication will be listed. 
7. 
EFFICACY 
Appendix A provides a list of data displays. 
7.1. 
Efficacy Hypotheses 
Not applicable. 
7.2. 
Analysis of the Primary Efficacy Parameter 
7.2.1. 
Primary Efficacy Analysis 
The primary endpoint of the study is PFS, defined as the time from the date of randomization to 
the earlier date of death due to any cause or PD as determined by BICR of objective radiographic 
disease assessments per RECIST v1.1.  Participants without a PFS event at the time of analysis 
will be censored.  Censoring for PFS will follow the algorithm outlined in Table 4, which is 
based on FDA guidance (2018).  Progression-free survival will be listed for each participant in 
ITT population. 


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Table 4: 
Evaluation and Censoring of Progression-Free Survival 
Situation 
Outcome 
Date of Progression or Censoring 
No baseline tumor assessments 
Censored 
Date of randomization  
No valid postbaseline response 
assessments 
Censored 
Date of randomization 
Progression documented between 
scheduled response assessments 
Progressed 
Date of first overall response of PD 
No progression 
Censored 
Date of last valid radiologic assessment 
(not NE and not missing) 
Study withdrawal for 
undocumented progression 
Censored 
Date of last valid radiologic assessment 
(not NE and not missing) 
Study withdrawal for toxicity or 
other reason 
Censored 
Date of last valid radiologic assessment 
(not NE and not missing) 
New anticancer treatment started 
Censored 
Date of last valid radiologic assessment 
(not NE and not missing) on/before starting a 
new anticancer treatment 
Death before first progressive 
response assessment 
Progressed 
Date of death 
Death between adequate response 
assessments 
Progressed 
Date of death 
Death or progression after 2 or 
more missed assessments 
Censored 
Date of last valid radiologic assessment 
(not NE and not missing) 
7.2.2. 
Sensitivity and Supportive Analyses for Primary Endpoint 
Not applicable. 
7.3. 
Analysis of the Secondary Efficacy Parameter 
Secondary efficacy parameters will be listed for the ITT population. 
7.3.1. 
Overall Survival 
Overall survival is defined as the interval between the randomization date and the date of death 
due to any cause.  Date of death will be determined using the Death Report eCRFs.  Participants 
who are lost to follow-up or still alive at the time of analysis will be right-censored at the earlier 
of the date the participant was last known alive and the clinical data cutoff date for the analysis.  
Partial death dates will be handled using the rules described in Section 4.1.4.   
7.3.2. 
Best Overall Response and Duration of Response 
In general, BOR is the best response recorded postbaseline prior to and including the first PD, in 
the order of CR, PR, SD, PD and NE.  In the case of SD, measurements must meet the SD 
criteria at least once after randomization date at a minimum interval of 49 days.  Participants 


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who fail to meet this criterion will have a BOR of PD if the next available assessment indicates 
PD or NE if there is no additional assessment available. 
Duration of response is defined as the time from the first assessment of CR or PR until the date 
of the first PD per RECIST v1.1 or death.  Participants who are still responding at the time of 
analysis will be censored.  Censoring of DOR will follow the same algorithm as the censoring of 
PFS. 
7.3.3. 
Quality-of-Life Questionnaires 
7.3.3.1. 
EORTC QLQ-C30 
The EORTC QLQ-C30 score for each of the 5 functional scales, 3 symptom scales, 1 global 
health status/QoL scale, and 6 single-item scales at each visit where the variable is measured, as 
well as change from baseline to each visit, will be listed by visit for each participant.  The scores 
for each scale will be calculated based on responses from the 30 questions using the mapping of 
questions to scales presented in Table 5. 
Table 5: 
European Organization for Research and Treatment of Cancer Quality of 
Life Questionnaire-C30 Scales 
Scale 
Question(s) 
Global health status/QoL 
29, 30 
Physical functioning 
1 to 5 
Role functioning 
6, 7 
Emotional functioning 
21 to 24 
Cognitive functioning 
20, 25 
Social functioning 
26, 27 
Fatigue 
10, 12, 18 
Nausea and vomiting 
14, 15 
Pain 
9, 19 
Dyspnea 
8 
Insomnia 
11 
Appetite loss 
13 
Constipation 
16 
Diarrhea 
17 
Financial difficulties 
28 
The raw score of each scale is the mean of the item values that contribute to the scale, and the 
standardized score is a linear transformation of the raw score so that the range is from 0 to 100.  
A higher standardized score represents a higher/better level of functioning/QoL or a 
higher/worse level of symptoms. 


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The raw score will be the mean of nonmissing item values if the number of missing item values 
is less than 50% of the items that contribute to the scale.  Otherwise, the raw score will be 
considered as missing. 
Let range be the difference between the possible maximum and minimum of a raw scale, which 
is 6 for Global Health Status/QoL and 3 for all other scales.  The standardized score for 
functional scale will be calculated by the following: 
100
)
1
1(

−
−
Range
RawScore
 
For all other scales (symptom scales, items and global health status, QoL), the standardized score 
will be calculated by the following: 
100
)
1
(

−
Range
RawScore
 
7.3.3.2. 
EQ-5D-5L 
The EQ-5D-5L essentially consists of 2 pages:  the EQ-5D descriptive system and the EQ VAS. 
The EQ-5D-5L descriptive system is composed of 5 dimensions (mobility, self-case, usual 
activities, pain/discomfort, and anxiety/depression).  Each dimension has 5 response levels, 
which are coded by single-digit numbers:  1 = no problems, 2 = slight problems, 3 = moderate 
problems, 4 = severe problems, 5 = unable to/extreme problems.  Answers for each of the 
5 dimensions at each visit where the variable is measured will be listed for each participant. 
The EQ VAS provides a quantitative measure of the participant's perception of their overall 
health.  The EQ VAS scales will be listed by visit. 


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8. 
SAFETY AND TOLERABILITY 
Appendix A provides a list of data displays. 
8.1. 
Adverse Events 
8.1.1. 
Adverse Event Definitions 
A TEAE is any AE either reported for the first time or worsening of a pre-existing event after the 
first dose of study drug until 30 days after the last dose of study drug.  Analysis of AEs (as 
discussed below) will be limited to TEAEs, but data listings will include all AEs regardless of 
their timing in relation to study drug administration.  For purposes of analysis, all AEs will be 
considered TEAEs unless the AE can unequivocally be defined as not treatment-emergent. 
Adverse events will be tabulated by MedDRA PT and system organ class.  Severity of AEs will 
be graded using the NCI CTCAE v5.0.  The CTCAE reporting guidelines and grading details are 
available on the Cancer Therapy Evaluation Program website. 
The subset of AEs considered by the investigator to be related to study drug will be considered to 
be treatment-related AEs.  If the investigator does not specify the relationship of the AE to study 
drug, the AE will be considered to be treatment-related. 
8.1.2. 
Adverse Event Listings 
The following listings will be produced: 
• AEs 
• Grade 3 or higher AEs 
• Serious AEs 
• Treatment-related AEs 
• AEs with a fatal outcome 
• AEs leading to study drug dose interruption, reduction, or discontinuation 
8.2. 
Clinical Laboratory Tests 
8.2.1. 
Laboratory Value Definitions 
Laboratory values will be listed by visit.  Baseline will be determined according to Section 4.1.3.  
If there are multiple values that meet the criteria for baseline, additional rules may be provided 
after consultation with the medical monitor to delineate which value will be defined as baseline. 


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Any laboratory test results and associated normal ranges from local laboratories will be 
converted to SI units.  Laboratory test values will be assessed for severity based on the numerical 
component of CTCAE v5.0. 
8.2.2. 
Potential Hy's Law Events 
Participants with elevated alanine aminotransferase or aspartate aminotransferase > 3 × ULN 
range and alkaline phosphatase < 2 × ULN range accompanied by total bilirubin > 2 × ULN 
range at the same visit will be listed by treatment group. 
8.3. 
Vital Signs 
Values at each scheduled visit, change, and percentage change from baseline for vital signs, 
including systolic blood pressure, diastolic blood pressure, pulse, temperature, respiratory rate, 
and weight will be listed. 
Criteria for clinically notable vital sign abnormalities are defined in Table 6.  For participants 
exhibiting clinically notable vital sign abnormalities, the abnormal values will be listed along 
with their assigned treatment group.  Alert vital signs are defined as an absolute value outside the 
defined normal range and percentage change greater than 25%.  Note that the definition of alert 
vital signs does not apply for body temperature and weight.  The abnormal values for participants 
exhibiting alert vital sign abnormalities will be listed. 
Table 6: 
Criteria for Clinically Notable Vital Sign Abnormalities 
Parameter 
High Threshold 
Low Threshold 
Systolic blood pressure 
> 155 mmHg 
< 85 mmHg 
Diastolic blood pressure 
> 100 mmHg 
< 40 mmHg 
Pulse 
> 100 bpm 
< 45 bpm 
Temperature 
> 38°C 
< 35.5°C 
Respiratory rate 
> 24 breaths/min 
< 8 breaths/min 
8.4. 
Electrocardiograms 
Twelve-lead ECGs including heart rate, PR, QT, QRS, QTc intervals will be obtained for each 
participant during the study.  Values at each scheduled visit, change, and percentage change from 
baseline will be listed for each ECG parameter.  Baseline will be determined as the average of all 
nonmissing values before the first administration of pemigatinib or pembrolizumab, gemcitabine 
plus cisplatin. 
Criteria for clinically notable ECG abnormalities are defined in Table 7.  Participants exhibiting 
clinically notable ECG abnormalities will be listed with study visit and assigned treatment group.  
Alert ECG are defined as an absolute value outside the defined range and percentage change 
greater than 25% (QRS 30%).  The abnormal values for participants exhibiting alert ECG 
abnormalities will be listed.  Outliers of QT and QTc values, defined as absolute values 
> 450 milliseconds and > 500 milliseconds, or change from baseline > 30 milliseconds, will be 
summarized. 


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Table 7: 
Criteria for Clinically Notable Electrocardiogram Abnormalities 
Parameter 
High Threshold 
Low Threshold 
PR 
> 220 ms 
< 75 ms 
QT 
> 500 ms 
< 300 ms 
QRS 
> 120 ms 
< 50 ms 
QTc 
> 460 ms 
< 295 ms 
Heart rate 
> 100 beats/min 
< 45 beats/min 
9. 
INTERIM ANALYSES 
Not applicable. 
10. 
CHANGES AND MODIFICATIONS TO THE ANALYSIS PLAN 
All versions of the SAP are listed in Table 8. 
Table 8: 
Statistical Analysis Plan Versions 
SAP Version 
Date 
Original 
23 FEB 2021 
10.1. 
Changes to Protocol-Defined Analyses 
A decision was made to terminate enrollment, and fewer than 10 participants were enrolled into 
the study.  Therefore, an interim futility analysis will not be conducted, and only listings will be 
provided for the final analysis. 
10.2. 
Changes to the Statistical Analysis Plan 
Not applicable. 


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11. 
REFERENCES 
Balar AV, Castellano D, O'Donnell PH, et al. First-line pembrolizumab in cisplatin-ineligible 
patients with locally advanced and unresectable or metastatic urothelial cancer 
(KEYNOTE-052): a multicentre, single-arm, phase 2 study. Lancet Oncol 2017;18:1483-1492. 
De Santis M, Bellmunt J, Mead G, et al. Randomized phase II/III trial assessing 
gemcitabine/carboplatin and methotrexate/carboplatin/vinblastine in patients with advanced 
urothelial cancer who are unfit for cisplatin-based chemotherapy: EORTC study 30986. J Clin 
Oncol 2012;30:191-199. 
Food and Drug Administration. Guidance for Industry: Clinical Trial Endpoints for the Approval 
of Cancer Drugs and Biologics. 2018. 
Mosteller RD. Simplified calculation of body surface area. N Engl J Med 1987;317:1098. 


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APPENDIX A. PLANNED LISTINGS 
This appendix provides a list of the planned listings for the Clinical Study Report. 
The list of listings is to be used as a guideline.  Modifications of the list that do not otherwise 
affect the nature of the analysis will not warrant an amendment to the SAP. 
Listings 
Listing No. 
Title 
2.1.1 
Participant Enrollment and Disposition Status 
2.1.2 
Participant Inclusion and Exclusion Criteria Violations 
2.2.1 
Protocol Deviations 
2.3.1 
Analysis Population 
2.4.1 
Demographic and Baseline Characteristics 
2.4.2 
Disease History 
2.4.3 
Tobacco 
2.4.4 
Prior Radiation Treatment 
2.4.5 
Prior Systemic Therapy 
2.4.6 
Prior Surgery or Surgical Procedure 
2.4.8 
Medical History 
2.4.9 
Prior and Concomitant Medication 
2.4.10 
FGF/FGFR Alteration 
2.5.1 
Study Drug Compliance 
2.5.2 
Study Drug Administration 
2.6.1 
Deaths 
2.6.2 
Best Overall Response, Duration of Response, Progression-Free Survival, and Overall Survival 
2.6.3 
Overall Response Assessment by Visit 
2.6.4 
Response Assessment:  Target Lesions 
2.6.5 
Response Assessment:  Nontarget Lesions 
2.6.6 
Response Assessment:  New Lesions 
2.6.7 
EORTC QLQ-C30 Score 
2.6.8 
EQ-5D-5L Score 
2.6.9 
Tumor Tissue 
2.6.10 
ECOG Status 
2.7.1 
Adverse Events  
2.7.2 
Serious Adverse Events 
2.7.3 
Grade 3 and Higher Adverse Events 
2.7.4 
Fatal Adverse Events 
2.7.5 
Treatment-Related Adverse Events 
2.7.6 
Adverse Events Leading to Interruption, Reduction, or Discontinuation of Study Drug 
2.8.1 
Clinical Laboratory Values - Hematology 
2.8.2 
Clinical Laboratory Values - Chemistry 
2.8.3 
Clinical Laboratory Values - Coagulation 
2.8.4 
Clinical Laboratory Values - Urinalysis 
2.8.5 
Abnormal Clinical Laboratory Values - Hematology 
2.8.6 
Abnormal Clinical Laboratory Values - Chemistry 


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Listing No. 
Title 
2.8.7 
Abnormal Clinical Laboratory Values - Coagulation 
2.8.8 
Abnormal Clinical Laboratory Values - Urinalysis 
2.8.9 
Possible Hy's Law Cases 
 
 
 
 
2.9.1 
Vital Signs 
2.9.2 
Abnormal Vital Sign Values 
2.9.3 
Alert Vital Sign Values 
2.10.1 
12-Lead ECG Values 
2.10.2 
Abnormal 12-Lead ECG Values 
2.10.3 
Alert 12-Lead ECG Values 
2.11.1 
Eye Examination 
2.11.2 
Optical Coherence Tomography