POST MARKETING SURVEILLANCE STUDY TO OBSERVE SAFETY AND EFFICACY OF INLYTA (REGISTERED)
Conditions: Advanced Renal Cell Carcinoma
Sponsor: Pfizer

INLYTA® (Axitinib) 
A4061075  NON-INTERVENTIONAL STUDY PROTOCOL 
Amendment 8, 19 Feb 2020 
 
  
 
 
 
NON-INTERVENTIONAL (NI) STUDY PROTOCOL 
 
POST MARKETING SURVEILLANCE STUDY TO OBSERVE  
SAFETY AND EFFICACY OF INLYTA®  
 
Compound Number: 
AG-013,736  
Compound Name: 
INLYTA® capsules 1mg, 5mg (Axitinib) 
Study Number: 
A4061075 
Version and Date: 
Final                       04 September 2012 
Amendment 1         02 January 2017 
Amendment 2         03 January 2018 
Amendment 3         19 March 2018 
Amendment 4         20 April 2018 
Amendment 5         16 May 2018 
Amendment 6         15 June 2018 
Amendment 7          30 January 2019 
Amendment 8          19 February 2020 
 
 
 

INLYTA® (Axitinib) 
A4061075  NON-INTERVENTIONAL STUDY PROTOCOL 
Amendment 8, 19 Feb 2020 
 
  
This document contains confidential information belonging to Pfizer.  Except as otherwise agreed to in writing, by 
accepting or reviewing this document, you agree to hold this information in confidence and not copy or disclose it to others 
(except where required by applicable law) or use it for unauthorized purposes.  In the event of any actual or suspected 
breach of this obligation, Pfizer must be promptly notified. 
 
ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Definition 
ADL 
Activities of Daily Living 
AE 
Adverse Event 
SAE 
Serious Adverse Event 
CRF 
Case Report Form 
eCRF 
Electronic Case Report Form 
CTCAE 
Common Terminology Criteria for Adverse Events 
CR 
Complete Response 
PR 
Partial Response 
SD 
Stable Disease 
PD 
Progressive Disease 
EIU 
Exposure in Utero 
FGF 
Fibroblast Growth Factor 
IRB/IEC 
Institutional Review Board/Independent Ethics Committee 
MFDS 
Ministry of Food and Drug Safety 
LPD 
Local Product Document 
LSLV 
Last Subject Last Visit 
NCI CTC 
National Cancer Institute Common. Terminology Criteria  
ODC 
Obvious Data Correction 
ORR 
Objective Response Rate 
PCD 
Primary Completion Date 
PDGF 
Platelet-derived Growth Factor 

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PFS 
Progression-free survival 
PV 
Pharmacovigilance 
RCC 
Renal Cell Carcinoma 
RECIST 
Response Evaluation Criteria In Solid Tumors 
SAP 
Statistical Analysis Plan 
SOP 
Standard Operating System 
SRSD 
Single Reference Single Document 
TTP 
Time to progression 
VEGF 
Vascular Endothelial Growth Factor 

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TABLE OF CONTENT 
1. RATIONALE AND BACKGROUND ........................................................................ 6 
2. RESEARCH QUESTION AND OBJECTIVES ......................................................... 7 
3. RESEARCH METHODS ............................................................................................ 7 
3.1. Study design ............................................................................................................ 7 
3.2. Study population ..................................................................................................... 7 
3.2.1. Inclusion criteria ..................................................................................................7 
3.2.2. Exclusion criteria .................................................................................................8 
3.3. Data sources ............................................................................................................ 8 
3.4. Variables ................................................................................................................. 8 
3.5. Study procedures ..................................................................................................... 9 
3.5.1. Study Duration .....................................................................................................9 
3.5.2. Study Treatment ...................................................................................................9 
3.5.3. Endpoints .............................................................................................................9 
3.5.4. Investigating Matters ...........................................................................................9 
3.6. Power and sample size .......................................................................................... 18 
3.7. Data sources .......................................................................................................... 18 
3.7.1. Case report forms ...............................................................................................18 
3.7.2. Record retention .................................................................................................19 
3.8. Data management.................................................................................................. 19 
3.9. Data analysis ......................................................................................................... 22 
3.9.1. Assessment Parameters ......................................................................................22 
3.9.2. Interim Analysis .................................................................................................23 
3.10. Quality control .................................................................................................... 23 
3.11. Strengths of the research methods ...................................................................... 24 
3.12. Limitations of the research methods ................................................................... 24 
4. PROTECTION OF HUMAN SUBJECTS ................................................................ 24 
4.1. Subject Information .............................................................................................. 24 
4.3. Subject withdrawal................................................................................................ 26 
4.4. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) ............ 26 
4.5. Ethical Conduct of the Study ................................................................................ 26 
5. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS ............................................................................................................. 27 

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5.1. Requirements for the study ................................................................................ 27 
5.1.1. REQUIREMENTS ........................................................................................... 27 
5.1.2. Reporting period ..............................................................................................28 
5.1.3. Causality assessment ........................................................................................29 
5.2. DEFINITIONS OF SAFETY EVENTS ............................................................ 29 
5.2.1. Adverse events ..................................................................................................29 
5.2.2. Serious adverse events .....................................................................................31 
5.2.3. Scenarios necessitating reporting to Pfizer Safety within 24 hours ............33 
5.3. COMMUNICATION OF ISSUES ....................................................................... 36 
5.4. SINGLE REFERENCE SAFETY DOCUMENT ................................................. 36 
6. STUDY DISCLOSURE............................................................................................. 37 
7. LIST OF FIGURES ................................................................................................... 38 
8. REFERENCES .......................................................................................................... 38 
APPENDIX 1. RESPONSIBLE PARTIES ................................................................... 39 
APPENDIX 3. MILESTONES ...................................................................................... 41 
APPENDIX 4. RECIST 1.1 TUMOR ASSESSMENT CRITERIA 1.1 ....................... 43 
 
 

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1. RATIONALE AND BACKGROUND  
Renal cell carcinoma (RCC) accounts for 85% of kidney cancers, and is a collection of 
different types of tumors that arise from the renal epithelium. Renal cell carcinoma (RCC) 
is diagnosed in approximately 170,000 patients worldwide annually, resulting in 82,000 
deaths. 
Early stage disease does not typically produce significant clinical signs or symptoms, 
consequently 25-30% of newly diagnosed patients present with advanced (including locally 
invasive or advanced) or unresectable disease. The 5-year survival rate for advanced RCC is 
estimated to be ≤10%. 
 
Most RCCs are highly vascularised tumors that over-express a number of growth factors, 
including VEGF (Vascular endothelial growth factor), PDGF (Platelet-derived growth factor) 
and fibroblast growth factor (FGF). The clear cell RCC subtype represents approximately 
85% of the RCC population and frequently displays allelic loss on chromosome 3p, 
accompanied by mutational inactivation of the von Hippel-Lindau (VHL) tumor suppressor 
gene. VHL-associated RCC are known for their vascularity and these tumors produce high 
levels of vascular endothelial growth factor (VEGF). In addition, recent studies suggest that 
in sporadic clear cell RCC, increased expression of VEGF is closely correlated with 
neovascularization, which is a prerequisite of tumor growth and metastasis. 
 
INLYTA®, a substituted indazole derivative, is an oral, potent, and selective inhibitor that 
blocks signal transmission via vascular endothelial growth factor receptor (VEGFR-1, -2 and 
-3) which is related to vascularization of tumors and tumor proliferation.  
 
INLYTA® was first approved as new medicine on 22 Aug 2012. As required for any new 
medication approved by Ministry of Food and Drug Safety (MFDS), safety and efficacy 
information of new medication should be provided at minimum 3000 subjects administered in 
the setting of routine practice during the initial 6 years after the approval. However, based on 
MFDS’s review upon Pfizer Korea’s request, additional 3 years of study period has been 
granted to collect safety and efficacy information of minimum of 100 subjects. 

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2. RESEARCH QUESTION AND OBJECTIVES 
The objective of this study is to monitor usage of INLYTA® in real practice including adverse 
events on INLYTA®.  
 
3. RESEARCH METHODS  
3.1. Study design  
Observational, non-interventional drug and multi-center study in which subjects will be 
administered as part of routine practice at Korean health care centers by accredited physicians. 
At least 3000 subjects should be enrolled in this study based on the Article 6 of “Basic 
Standards for the Re-examination of New Medicines” notified by MFDS. However, with 
additional 3 years of study period,at least 100 subjects who are being treated with Inlyta within 
the approved indication will be studied for total of 9 years according to the review result by 
the MFDS per Pfizer’s request to adjust the number of subjects. The study can be performed 
in Korean health care centers where INLYTA® is prescribed for advanced renal cell carcinoma 
(aRCC) after failure of one prior systemic therapy which is the indication for INLYTA® and 
where post-marketing study is allowed by institutions. 
To achieve the target sample size, the study is being conducted in prospective study design 
and retrospective study design.  
Patients to whom INLYTA® is first administered or patients who are already on INLYTA® 
during the study period should be enrolled in the study. Observation should be done from 
treatment initiation of INLYTA® for at least 28 calendar days. There are no visits or activities 
mandated by this study and routine observation will be done during INLYTA® treatment. 
3.2. Study population 
All subjects enrolled should meet the usual prescribing criteria for INLYTA® as per the Local 
Product Document (LPD) and should be entered into the study at the physician’s discretion. 
3.2.1. Inclusion criteria 
Subjects must meet all of the following inclusion criteria to be eligible for inclusion in the 
study: 

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1. Patients diagnosed as advanced renal cell carcinoma (aRCC) after failure of one prior 
systemic therapy. 
2. Patients to whom INLYTA® is first administered or patients who are already on 
INLYTA® during the study period 
3. Evidence of a personally signed and dated informed consent document indicating that 
the patient (or a legally acceptable representative) has been informed of all pertinent 
aspects of the study. 
3.2.2. Exclusion criteria 
Subjects meeting any of the following criteria will not be included in the study: 
1. Any patient who does not agree that Pfizer and companies working with Pfizer use his/her 
information  
2. Patients with hypersensitivity to axitinib or to any other component of INLYTA®  
3. Patients under 18 
4. Pregnant women 
 
3.3. Data sources  
The followings are data sources for the study: 
 
1. Medical records 
2. Laboratory test results 
 
3.4. Variables  
 
Variable 
Role 
Data source(s) 
Operational definition 
Demographic 
Characteristics  
Baseline characteristics 
Medical records 
* 
Basic Laboratory data 
Baseline characteristics 
Laboratory test results 
* 
Concomitant medication  
Baseline characteristics 
Medical records  
* 
Efficacy result by physician 
outcome 
Medical record  
* 

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AE events 
outcome 
Medical record  
* 
*Refer to 3.5.4.Investigating Matters 
Detail instruction of variable will be included Statistical Analysis Plan (SAP) and CRF. 
 
3.5. Study procedures 
3.5.1. Study Duration 
As specified in the product license given by MFDS, this study was to be conducted for 6 
years from the approval date of 22 Aug 2012 to 21 Aug 2018. On May 2018, MFDS has 
granted 3 additional years for the study, for total of 9 years for the study period. 
 
3.5.2. Study Treatment 
The use and dosage recommendations for INLYTA® will take place on the basis of the 
approved LPD and will be adjusted solely according to medical and therapeutic necessity. 
 
3.5.3. Endpoints 
3.5.3.1. Safety Endpoints 
The clinical nature, incidence, duration, and severity of adverse events; discontinuation 
due to adverse events; outcome and possible causality will be monitored in this study. 
 
3.5.3.2. Efficacy Endpoints 
- Tumor response based on RECIST 1.1 
- ORR 
- PFS within limited follow-up period 
- TTP 
 
3.5.4. Investigating Matters 
This means that the physician should enroll all subjects to whom INLYTA®  is prescribed for 
the first time after contract is executed and who agree that Pfizer Korea and companies 
working with Pfizer Korea use his/her information by signing the ‘data privacy statement’. 

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Data for patients who are currently on INLYTA® will be collected as much as possible 
following the categories for patients who are prescribed with INLYTA® for the first time. 
 
3.5.4.1. Reporting of the study 
Final study report will include analysis for patients prescribed with INLYTA® for the first 
time, for patients who are already on INLYTA® at the time of enrollment, and for all enrolled 
patients.  
3.5.4.2. Demographic Information 
- Name of Institution: Record the name of institution. 
- Name of Physician: Record the name of physician engaged into this study. 
- Department: Record the medical department, practicing the study. 
- Subject ID: Record 4 digit number per subject registration sequence. 
- Confirmation of Data Privacy Statement:  If all agreement for using subject’s personal 
and medical information, signature and date are obtained by subject or legally 
authorized representative, then check the box of ‘yes’. If not, check  ‘no’ which means 
that case is excluded from this study. 
3.5.4.3. Subject Status 
- Initial of Subject: Record the name of subject with English initials.  
- Date of birth: Record the date of birth of the subject. 
- Sex: Check either ‘male’ or ‘female’. 
- Classification: Check either ‘outpatient’ or ‘inpatient’. 
- Height/Weight: Record by cm / kg unit. 
- Allergic history: Check either ‘yes’ or ‘no’. If ‘yes’, then record the allergen and the 
according symptom.  
 
3.5.4.4. Diagnosis 
- Diagnosis: check the aRCC and classify cell component, ‘clear cell’ or ‘other’.  
- Date of diagnosis: Record the date the subject was initially diagnosed as advanced RCC  
- Metastasis: Check either ‘yes’ or ‘no’. If ‘yes’, check the metastasis site. If ‘other’, specify. 
- Primary lesion surgery: Check whether the subject had prior cancer surgery (nephrectomy) 

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or not. If the subject had the surgical procedure, record the surgical  date. 
- Prognostic criteria: Record the value of all risk factors for MSKCC and  Heng criteria and 
record the value of serum LDH both at diagnosis and at initiation of treatment of INLYTA 
1), 2), 3). 
• 
MSKCC risk factors 
Karnofsky performance status < 80% 
< 1 y between diagnosis and start of first systemic therapy 
Corrected serum calcium > 10 mg/dL 
Hemoglobin < lower limit of normal 
LDH > 1.5 times upper limit of normal 
• 
Heng risk factors 
Karnofsky performance status < 80% 
< 1 y between diagnosis and start of first systemic therapy 
Corrected serum calcium > 10 mg/dL 
Hemoglobin < lower limit of normal 
Neutrophils > upper limit of normal 
Platelets > upper limit of normal 
 
3.5.4.5. Medical History 
Check the box next to ‘yes’ or ‘no’ for past/present disease. If ‘yes’, record the full name of 
the disease as appears in the medical terminology dictionary (written by the Korean Medical 
Science Association). then select the box next to ‘past’ or ‘present’ in the line of according 
disease category. If the disease does not exist in the form, record the full name of the disease 
in the ‘others’ category as appears in the medical terminology dictionary (written by the 
Korean Medical Science Association).  
 
3.5.4.6. Prior Chemotherapy/Immunotherapy and Radiation Therapy 
Prior to administrating INLYTA®, if the subject received other chemotherapy / 
immunotherapy or received radiation therapy to treat, advanced RCC, record them. First, 
check among ‘yes’, ‘no’ or ‘unknown’. If ‘yes’, record the followings. 
 
<Chemotherapy/Immunotherapy> 
- Name of chemotherapy/immunotherapy drug: Record generic name. 
- Duration of administration: Record the start date and stop date of the chemotherapy/ 
immunotherapy. 
 

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<Radiation therapy> 
- Site of radiation therapy: Record the site of radiotherapy.  
- Duration of radiation therapy : Record the start date and stop date of the radiation therapy. 
 
3.5.4.7. Concomitant Medication  
The physician records the medication especially all anti-hypertensive drugs and any drug 
related to CYP3A4/5(including transfusion) which has been administered at the point of 
being enrolled in this study or which are administered newly after being enrolled. Check 
either ‘yes’ or ‘no’, if ‘yes’, record in detail. 
 
- Name of drug: Record the name of drug. 
- Total daily dose: Record the total daily dose. 
- Duration of administration: Record the start date and stop date of the concomitant 
medication (year/ month / day). If the medication is being continued at the completion of 
the study, record the start date only. 
- Purpose of administration: Record the purpose in detail. 
 
3.5.4.8. Administrative Status for Study Drug 
INLYTA® is provided by the physician’s prescription and Pfizer Korea will not provide 
drug for this study. 
Record the following with regard to administrative status for the study drug. 
- Duration of administration: Record the start date and stop date of the medicated drug (year 
/ month / day). If the medication is being continued at the completion of the study, check 
the box next to ‘ongoing’. 
- A single dose: Record the dose (in mg) of study drug. In case of dose titration up or down, 
record each dose with the periods respectively. 
- Daily dosing frequency: Record dosing frequency per day. 
- Reason for dose adjustment:  Record any remarks if applicable 
Refer to LPD for posology and method of administration. 
 

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3.5.4.9. Safety 
3.5.4.9.1. Adverse Event  
Every observed and reported adverse event, regardless of the causal relationship with the 
study drug, must be recorded on an adverse event section in case report forms. The query 
pattern of experience of adverse event to the subjects is as follow; 
Patients who are prescribed with INLYTA® for the first time during the study period: 
“Have you had any health problem since last visit?” 
Patients who are already on INLYTA® at the time of enrollment: all safety information will 
be collected from medical chart since the date of treatment initiation. 
For adverse events repeating before and after administrating the study drug, record the the 
date adverse event was first experienced and the date adverse event resolved. Background 
information on INLYTA® can be obtained from the current version of the local product 
document, which is the single reference safety document (SRSD) for information relating 
to INLYTA®. 
Check either ‘yes’ or ‘no’ in adverse event section. If ‘yes’, record in detail. 
- Adverse events: Record the name of adverse event. If possible, specify diagnosis, not 
individual symptoms. Record the name according to National Cancer Institute Common 
Terminology Criteria for Adverse Events (CTCAE) Version 5.0. 
- Date of onset: Record the date of onset. Record approximate date if an actual date is 
unknown. 
- Date of resolution: Record the date of resolution. Record approximate date if an actual 
date is unknown. 
 
- Severity: Severity evaluation of adverse event must be done according to the NCI CTC 
grade.          
 The physician will use the following definitions of severity in accordance with the 
National Cancer Institute Common Terminology Criteria for Adverse Events 
(CTCAE) Version 5.0 to describe the maximum intensity of the adverse event: 
 

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Grade 
Definition 
Grade 1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated.  
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental ADL*.  
Grade 3 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self care ADL**.  
Grade 4 
Life-threatening consequences; urgent intervention indicated.  
Grade 5 
Death related to AE.  
Activities of Daily Living (ADL) 
*Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, 
managing money, etc. 
**Self care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, 
and not bedridden. 
 
If the severity of an adverse event changed, the adverse event must be entered separately. 
Record stop date of previous severity and onset date of new severity – along with 
completion of all other items. 
 
- Seriousness: Check either ‘yes’ or ‘no’. If ‘yes’, record the appropriate number for the 
category of seriousness. 
A serious adverse event is any untoward medical occurrence in a subject administered 
a medicinal or nutritional product (including pediatric formulas) at any dose that: 
(1)  results in death; 
(2)  is life-threatening; 
(3)  requires inpatient hospitalization or prolongation of hospitalization; 
(4)  results in persistent or significant disability/incapacity(substantial disruption of the 
ability to conduct normal life functions); 
(5)  results in congenital anomaly/birth defect. 
Progression of the malignancy under study (including signs and symptoms of 
progression) should not be reported as a serious adverse event unless the outcome is 
fatal within the safety reporting period.  Hospitalization due to signs and symptoms of 
disease progression should not be reported as a serious adverse event.  If the 
malignancy has a fatal outcome during the study or within the safety reporting period, 
then the event leading to death must be recorded as an adverse event and as a serious 
adverse event with severity Grade 5.  

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Lack of efficacy should be reported as an adverse event when it is associated with a 
serious adverse event. 
Medical and scientific judgment is exercised in determining whether an event is an 
important medical event.  An important medical event may not be immediately life-
threatening and/or result in death or hospitalization.  However, if it is determined that 
the event may jeopardize the subject or may require intervention to prevent one of the 
other outcomes listed in the definition above, the important medical event should be 
reported as serious. 
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization; or development of drug dependency or drug abuse. 
Additionally, any suspected transmission via a Pfizer product of an infectious agent, 
pathogenic or non-pathogenic, is considered serious.  The event may be suspected from 
clinical symptoms or laboratory findings indicating an infection in a subject exposed to 
a Pfizer product.  The terms “suspected transmission” and “transmission” are 
considered synonymous.  These cases are considered unexpected and handled as 
serious expedited cases by PV personnel.  Such cases are also considered for reporting 
as product defects, if appropriate. 
 
In case of serious adverse event, Drug Safety Unit in Pfizer Pharmaceuticals Korea is 
to be notified promptly by the physician. 
 
Check the following at the end of the study or after the resolution of adverse event. 
- Outcome: The evaluation of outcome will include: Record the date of recovery in case of 
‘Recovered’ or ‘Recovered with sequelae’. 
• 
Recovered 
• 
Recovered with sequelae 
• 
Recovering 
• 
Not recovered 
• 
Unknown  

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- Causality of adverse event to the study drug: The causal relationship of adverse event to 
the study drug must be allocated by the physician according to the following criteria. 
(1) Certain 
- It follows a reasonable time sequence from administration of the drug (before and after 
the study medication). 
- It could not be explained by other drugs, chemical substance or accompanying diseases. 
- It has clinically reasonable reaction on cessation of the drug. 
- It has pharmacological or phenomenological reaction to re-administration of the drug, 
where necessary. 
(2) Probable/likely 
- It follows a reasonable time sequence from administration of the drug (before and after 
the study medication). 
- It could not be explained by other drugs, chemical substance or accompanying diseases. 
- It has clinically reasonable reaction on cessation of the drug. 
(No information on re-administration) 
(3) Possible 
- It follows a reasonable time sequence from administration of the drug. 
- It could also be explained by other drugs, chemical substance or accompanying 
diseases. 
- It lacks information or has unclear information on discontinuation of the drug. 
(4) Unlikely 
- It is not likely to have a reasonable causal relationship from administration of the drug. 
Rather, it seems to be temporary. 
- It could also be reasonably explained by other drugs, chemical substances or latent 
diseases. 
* Other causality of adverse event: If the adverse event is not related to the study drug, 
physicians should indicate the most appropriate cause from the followings and record in 
detail. 
1. Disease under the study 
2. Other disease (please specify) 
3. Concomitant treatment drug or non-drug (please specify) 
4. Others (please specify) 
(5) Conditional/unclassified 
- It needs more data to make an appropriate assessment or its additional data are being 
reviewed. 

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(6) Unaccessible/unclassifiable 
- Lack of sufficient information or conflicting information hampers accurate causality 
assessment or supplementation or confirmation. 
(7) Not applicable 
 
- Action: Check relevant action. 
A. Discontinuation (Permanently, Temporarily or delayed)  B. Dosage reduced   
C. Dosage increased   D. No Change  E. Unknown  F. Not Applicable 
 
3.5.4.9.2. Laboratory Test   
Laboratory test is not mandatory because this study is a non-interventional study. If 
physician performed a laboratory test (e.g. TSH, T4, CBC, LDH and corrected Calcium) 
under their usual practice, the results can be collected. 
- Name of laboratory test: Record the item of laboratory test. 
- Date for laboratory test: Record the date with year / month / day. 
- Test result before / after medication: Record the test result. 
 
If abnormal objective lab result is clinically significant related to adverse event, it has to 
be recorded in adverse event section of a case report form. 
3.5.4.10. Efficacy Assessment 
The determination of antitumor efficacy will be based on objective tumor assessments made 
according to the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 of 
unidimentional evaluation. Progression-free survival (PFS) is defined as the time from first 
dose of study medication to first documentation of objective tumor progression, or to death 
due to any cause, whichever occurs first. And Time To Progression(TTP) is defined as the 
time to progression is one way to see how well a new treatment works. PFS will be assessed 
using the Kaplan-Meier method. Estimate of the PFS curves from the Kaplan-Meier method 
will be presented.  
- Date of Tumor Assessment: Record the actual date that the scan was performed. 
- Overall response: Check in ONE box indicating the overall tumor assessment based on 
RECIST Tumor Assessment Criteria. 
 

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Refer to [Appendix 4] for RECIST 1.1 Tumor Assessment Criteria. 
 
3.6. Power and sample size  
Per MFDS regulation, at least 3000 subjects were required for the study initially. However, 
based on the decision from MFDS on April 26, 2018, at least 100 subjects who are eligible 
according to ‘3.2 Study population’ will be observed for total of 9 years 
3.7. Data sources  
3.7.1. Case report forms 
As used in this protocol,  the term CRF should be understood to refer to either a paper form 
or an electronic data record (eCRF; electronic case report form) or both, depending on the 
data collection method used in this study. 
A CRF is required and should be completed for each included subject. The completed 
original CRFs are the sole property of Pfizer and should not be made available in any form to 
third parties, except for authorized representatives of Pfizer or appropriate regulatory 
authorities, without written permission from Pfizer. The investigator shall ensure that the 
CRFs are securely stored at the study site in encrypted electronic form and will be password 
protected  to prevent access by unauthorized third parties. 
The investigator has ultimate responsibility for the collection and reporting of all clinical, 
safety and laboratory data entered on the CRFs and any other data collection forms (source 
documents) and ensuring that they are accurate, authentic / original, attributable, complete, 
consistent, legible, timely (contemporaneous), enduring and available when required.  The 
CRFs must be signed by the investigator or by an authorized staff member to attest that the 
data contained on the CRFs are correctly recorded.  Any corrections to entries made in the 
CRFs or source documents must be dated, initialed and explained (if necessary) and should 
not obscure the original entry. For studies using electronic data capture systems, an audit trail 
of any corrections to original data entry must be ensured.  
In many cases, the source document is the subject medical chart.  In these cases, data 
collected on the CRFs must match the data in the chart.  

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In some cases (e.g., subject interview), the CRF, or part of the CRF, may also serve as source 
documents.  In these cases, a document should be available at the investigator’s site as well 
as at Pfizer and clearly identify those data that will be recorded in the CRF, and for which the 
CRF will stand as the source document. 
3.7.2. Record retention 
To enable evaluations and/or inspections audits from regulatory authorities or Pfizer, the 
investigator agrees to keep records, including the identity of all participating patients 
(sufficient information to link records, eg, CRFs and hospital records), all original signed 
informed consent documents copies of all CRFs,  safety reporting forms source documents, 
and detailed records of treatment disposition, and adequate documentation of relevant 
correspondence (eg, letters, meeting minutes, telephone calls reports).  The records should be 
retained by the investigator according to local regulations, or as specified in the Clinical 
Study Agreement, whichever is longer. The investigator must ensure that the records 
continue to be stored securely for so long as they are retained. 
If the investigator becomes unable for any reason to continue to retain study records for the 
required period (eg, retirement, relocation), Pfizer should be prospectively notified.  The 
study records must be transferred to a designee acceptable to Pfizer, such as another 
investigator, another institution, or to an independent third party arranged by Pfizer.  
Investigator records must be kept for a minimum of 15 years after completion or 
discontinuation of the study or for longer if required by applicable local regulations.  
The investigator must obtain Pfizer’s written permission before disposing of any records, 
even if retention requirements have been met. 
 
3.8. Data management 
CRF data collected by the investigator will be entered into the clinical database. AEs and 
Medical history will be coded using World Health Organization - Adverse Reaction 
Terminology. Concomitant medication will be coded via ATC code. Statistical analysis will 
be carried out with SAS software version 9.4 or a more recent version. 
 
 
 
 
 
 
 
 
 
  
Preparation & Planning 
  
 
 
  
 
 
 

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Development of EDC 
Setup Document 
 
 
 
EDC Setup 
  
  
 
 
 
  
 
  
  
 
 
 
  
 
EDC Screen Design  
 
 
 
  
 
 
 
 
  
 
  
  
 
 
 
  
 
EDC DVS Programming 
 
 
 
  
 
 
 
 
  
 
  
  
 
 
 
  
 
EDC Validation & UAT 
 
 
 
  
 
 
 
 
  
 
  
  
 
 
 
  
 
EDC Approval 
 
 
 
  
  
 
 
 
 
 
  
  
 
 
 
 
 
EDC Open 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
Data Entry 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
  
  
 
 
 
 
 
 
Entry Finalization 
 
 
 
  
  
  
 
 
  
  
 
  
 
 
 
Data Validation 
 
  
 
Data Validation 
Incl. SAE Reconciliation 
  
 
  
 
 
  
  
 
  
 
 
Query Generation 
 
  
 
 
 
  
  
 
  
  
 
Medical Coding 
 
Query Resolution 
 
 
 
  
  
 
  
  
 
  
 
 
Is there any unresolved 
Query? 
 
  
 
 
 
  
 
  
  
  
  
  
 

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Yes 
 
  
No 
 
 
 
 
 
 
Database Lock  
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
Data Transfer/Archive 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
<figure1> Data management flow chart 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Data Validation 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
  
 
 
 
 
 
  
  
  
  
  
  
 
 
 
 
 
  
 
  
  
  
  
  
 
 
 
 
  
  
Programmed Check 
 
  
Manual Check 
 
 
 
 
  
 
  
 
 
 
 
 
 
  
  
 
  
 
 
 
 
 
 
 
  
Is it necessary that  
Query is generated? 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
Generate Query to EDC 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
Is it necessary data 
correction? 
  
Data Corretion by Site 
 
 
 
 
 
  
Yes 
 
 
 
 
 
 
  
No 
 
  
  
 
 
 
 
 
 
Answer to Query by Site 
 
  
  
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
  
  
 
  
  
 
 
  
  
  
  
is there any unresolved 
Query? 
  
  
  
 
 
 
  
Yes 
 
 
 
 
 
 
 
 
  
No 
 
 
 
 
 
 
 
 
Entry Finilization 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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<figure2> Data validation flow chart 
3.9.  Data analysis 
Analysis will be performed for the pooled data collected by each investigator during the re- 
examination period.  Total number of centers participating, total number of cases enrolled 
and retrieved, and total number of cases included in the analysis will be presented in 
summary tables.  Evaluation of data will primarily consist of summary displays (eg, 
descriptive statistics, tables, and graphs).   
Detailed methodology for summary and statistical analyses of data collected in this study will 
be documented in a Statistical Analysis Plan (SAP), which will be dated, filed and 
maintained by Pfizer.  The SAP may modify the plans outlined in the protocol; any major 
modifications of primary endpoint definitions or their analyses will be reflected in a protocol 
amendment. 
3.9.1. Assessment Parameters 
3.9.1.1. Parameters on Safety 
- Safety parameters will be evaluated. 
- Incidence of adverse events categorized according to physical organ and disease 
symptoms 
- Sub-analysis may be performed using factors considered to affect safety. If required, 
Chi-square test (X2 test) or Fisher’s exact test (if the expected frequency for each cells 
under 5 is more than 20%) will be used for subgroup analysis. 
- Clinically significant abnormalities from laboratory tests (if any). If data are applicable, 
paired t-test, descriptive analyses and other statistical methods will be used.  
 
3.9.1.2. Efficacy Parameters 
- The four *ORR categories (by RECIST) :  CR, PR, SD, PD 
- The two period scale: PFS, TTP 
- Efficacy parameters will be descriptively summarized. If necessary, For the ORR and 
PFS, sub-analysis may be performed using factors considered to affect efficacy. If 
required, Χ2-test or Fisher’s exact test (if the expected frequency for each cells under 5 

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is more that 20%) paired t-test, analysis by repeated measurement, Kaplan-Meier curve, 
Long-rank test and other statistical methods will be used. 
* ORR(Objective Response Rate) : the proportion of patients who have a partial or complete 
response to therapy 
3.9.2. Interim Analysis  
As required by MFDS regulations, the periodic report should be submitted to MFDS every 
6 months for the first two years and then annual report should be submitted to MFDS for the 
third, fourth and fifth year. The final report for the date collected until August 21, 2018 
should be submitted in the sixth year, by November 21, 2018. For the additional study 
period, periodic report should be submitted to MFDS every 6 months, and the final report of 
the entire study period should be submitted by November 21, 2021. Interim analysis will be 
performed in time for the report submission. 
 
Analysis will be performed for safety group and efficacy group for patients who are 
prescribed with INLYTA® for the first time and for patients who are already on INLYTA® 
separately, and for all enrolled patients. 
- Safety group: Subjects who have been administered INLYTA® at least once and 
evaluated with safety-related endpoints at least once. 
- Efficacy group:ITT (Intent-to-treat) group - subjects to whom INLYTA® is administered 
INLYTA®at least once.  
 
Detailed methodology for summary and statistical analyses of data collected in this study 
will be documented in a Statistical Analysis Plan (SAP), which will be dated, filed and 
maintained by the sponsor. The SAP may modify the plans outlined in the protocol; any 
major modifications of primary endpoint definitions or their analyses would be reflected in 
a protocol amendment. 
 
3.10. Quality control 
Quality assurance audits will be performed at study centers by Pfizer’s own independent 
quality assurance group or by the clinical research organization.  These audits will be 
conducted according to Pfizer’s procedures and the guidelines for Good 
Pharmacoepidemiology Practices (GPP). 
 

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3.11. Strengths of the research methods 
• Large scale non interventional real world study for evaluating efficacy and safety of 
investigational drug 
 
3.12. Limitations of the research methods 
• Regulatory- required study for maintaining license and exclusivity. 
• SAP and number of enrolled subjects are ruled by PMS guideline of MFDS, not 
specific to disease and/or drug characteristics.  
4. PROTECTION OF HUMAN SUBJECTS 
4.1. Subject Information  
 All parties will comply with all applicable laws, including laws regarding the 
implementation of organizational and technical measures to ensure protection of patient 
personal data.  Such measures will include omitting patient names or other directly 
identifiable data in any reports, publications, or other disclosures, except where required by 
applicable laws.  
 
The personal data will be stored at the study site in encrypted electronic form and will be 
password protected to ensure that only authorized study staffs have access.  The study site 
will implement appropriate technical and organizational measures to ensure that the personal 
data can be recovered in the event of disaster.  In the event of a potential personal data 
breach, the study site shall be responsible for determining whether a personal data breach has 
in fact occurred and, if so, providing breach notifications as required by law. 
To protect the rights and freedoms of natural persons with regard to the processing of 
personal data, when study data are compiled for transfer to Pfizer and other authorized 
parties, patient names will be removed and will be replaced by a single, specific, numerical 
code, based on a numbering system defined by Pfizer.  All other identifiable data transferred 

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to Pfizer or other authorized parties will be identified by this single, patient-specific code.  
The investigator site will maintain a confidential list of patients who participated in the study, 
linking each patient’s numerical code to his or her actual identity.  In case of data transfer, 
Pfizer will maintain high standards of confidentiality and protection of patients’ personal data 
consistent with the clinical study agreement and applicable privacy laws. 
4.2. Subject Consent 
The informed consent documents and any patient recruitment materials must be in 
compliance with local regulatory requirements and legal requirements, including applicable 
privacy laws. 
The informed consent documents used during the informed consent process and any patient 
recruitment materials must be reviewed and approved by Pfizer, approved by the institutional 
review board (IRB)/independent ethics committee (IEC) before use, and available for 
inspection. 
The investigator must ensure that each study patient, or his/her legally acceptable 
representative is fully informed about the nature and objectives of the study the sharing of 
data relating to the study and possible risks associated with participation, including the risks 
associated with the processing of the patient’s personal data.  The investigator, or a person 
designated by the investigator, will obtain the written data privacy statement from each 
patient or the patient’s legally acceptable representative before any study-specific activity is 
performed.  The investigator will retain the original of each patient’s signed data privacy 
statement. The investigator further must ensure that each study patient or his or her legally 
acceptable representative, or parent(s) is fully informed about his or her right to access and 
correct his or her personal data and to withdraw consent for the processing of his or her 
personal data. 
Whenever consent is obtained from a patient’s legally acceptable representative/parent(s), the 
patient’s assent (affirmative agreement) must subsequently be obtained when the patient has 
the capacity to provide assent, as determined by the IRB/IEC.  If the investigator determines 
that a patient’s decisional capacity is so limited that he or she cannot reasonably be 
consulted, then, as permitted by the IRB/IEC and consistent with local regulatory and legal 
requirements, the patient’s assent may be waived with source documentation of the reason 
assent was not obtained.  If the study patient does not provide his or her own consent, the 
source documents must record why the patient did not provide consent (e.g., minor, 

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decisionally impaired adult), how the investigator determined that the person signing the 
consent was the patient’s legally acceptable representative, the consent signer’s relationship 
to the study patient (e.g., parent, spouse), and that the patient’s assent was obtained or 
waived.  If assent is obtained verbally, it must be documented in the source documents. 
4.3. Subject withdrawal 
Subjects may withdraw from the study at any time at their own request, or they may be 
withdrawn at any time at the discretion of the physician or sponsor for safety, behavioral, or 
administrative reasons.  In any circumstance, every effort should be made to document 
subject outcome, if possible.  The physician should inquire about the reason for withdrawal 
and follow-up with the subject regarding any unresolved adverse events. 
If the subject withdraws from the study, and also withdraws consent for disclosure of future 
information, no further evaluations should be performed, and no additional data should be 
collected.  The sponsor may retain and continue to use any data collected before such 
withdrawal of consent. 
4.4. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
The study protocol will be submitted to MFDS prior to the study.  The ethical consideration 
on this study will be evaluated by the IRB/ IEC in each clinical site prior to the study, if the 
site has an approval process for this PMS study according to the local standard operation 
procedure of the site.  
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, and informed consent forms, and other relevant documents 
(e.g., recruitment advertisements), if applicable, from the IRB/IEC.  All correspondence with 
the IRB/IEC should be retained by the investigator.  Copies of IRB/IEC approvals should be 
forwarded to Pfizer.  
4.5. Ethical Conduct of the Study 
The study will be conducted in accordance with legal and regulatory requirements, as well as 
with scientific purpose, value and rigor and follow generally accepted research practices 
described in Good Pharmacoepidemiology Practices (GPP) issued by the International 
Society for Pharmacoepidemiology (ISPE), Pharmaceutical Research and Manufactures 
Association(PhRMA) guidelines and Korea PMS regulations and/or guidelines. 

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5. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS  
5.1. Requirements for the study 
5.1.1. REQUIREMENTS 
The table below summarizes the requirements for recording safety events on the case report 
form and for reporting safety events on the non-interventional study (NIS) adverse event 
monitoring (AEM) Report Form to Pfizer Safety.  These requirements are delineated for 
three types of events: (1) serious adverse events (SAEs); (2) non-serious AEs (as applicable); 
and (3) scenarios involving drug exposure, including exposure during pregnancy, exposure 
during breast feeding, medication error, overdose, misuse, extravasation, and occupational 
exposure.  These events are defined in the section “Definitions of safety events”.   
 
Safety event 
Recorded on the case report 
form  
Reported on the NIS AEM 
Report Form to Pfizer 
Safety within 24 hours of 
awareness 
SAE 
All 
All 
Non-serious AE 
All 
None 
Scenarios involving exposure 
to a drug under study, 
including exposure during 
pregnancy, exposure during 
breast feeding, medication 
error, overdose, misuse, 
extravasation; lack of efficacy; 
and occupational exposure 
All (regardless of whether 
associated with an AE), 
except occupational 
exposure  
All (regardless of whether 
associated with an AE) 
 
For each AE, the investigator must pursue and obtain information adequate both to determine 
the outcome of the adverse event and to assess whether it meets the criteria for classification 
as a SAE (see section "Serious Adverse Events” below).  
Safety events listed in the table above must be reported to Pfizer within 24 hours of 
awareness of the event by the investigator regardless of whether the event is determined 
by the investigator to be related to a drug under study. In particular, if the SAE is fatal or 

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life-threatening, notification to Pfizer must be made immediately, irrespective of the extent of 
available event information. This timeframe also applies to additional new (follow-up) 
information on previously forwarded safety event reports. In the rare situation that the 
investigator does not become immediately aware of the occurrence of a safety event, the 
investigator must report the event within 24 hours after learning of it and document the time 
of his/her first awareness of the events. 
For safety events that are considered serious or that are identified in the far right column of 
the table above that are reportable to Pfizer within 24 hours of awareness, the investigator is 
obligated to pursue and to provide any additional information to Pfizer in accordance with 
this 24-hour timeframe. In addition, an investigator may be requested by Pfizer to obtain 
specific follow-up information in an expedited fashion.  This information is more detailed 
than that recorded on the case report form. In general, this will include a description of the 
adverse event in sufficient detail to allow for a complete medical assessment of the case and 
independent determination of possible causality.  Any information relevant to the event, such 
as concomitant medications and illnesses must be provided.  In the case of a patient death, a 
summary of available autopsy findings must be submitted as soon as possible to Pfizer or its 
designated representative.  
 
5.1.2. Reporting period  
For each patient, the safety event reporting period begins at the time of  the patient’s first 
dose of Inlyta or the time of the patient’s informed consent if s/he is already exposed to 
Inlyta, and lasts through the end of the observation period of the study, which must include at 
least 28 calendar days following the last administration of a drug under study; a report must 
be submitted to Pfizer Safety (or its designated representative) for any of the types of safety 
events listed in the table above occurring during this period.  If a patient was administered a 
drug under study on the last day of the observation period, then the reporting period should 
be extended for 28 calendar days following the end of observation. Most often, the date of 
informed consent is the same as the date of enrollment. In some situations, there may be a lag 
between the dates of informed consent and enrollment.  In these instances, if a patient 
provides informed consent but is never enrolled in the study (e.g., patient changes his/her 
mind about participation, failed screening criteria), the reporting period ends on the date of 
the decision to not enroll the patient.   

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If the investigator becomes aware of a SAE occurring at any time after completion of the 
study and s/he considers the SAE to be related to Inlyta, the SAE also must be reported to 
Pfizer Safety.  
5.1.3. Causality assessment 
The investigator is required to assess and record the causal relationship.  For all AEs, 
sufficient information should be obtained by the investigator to determine the causality of 
each adverse event.  For AEs with a causal relationship to Inlyta, follow-up by the 
investigator is required until the event and/or its sequelae resolve or stabilize at a level 
acceptable to the investigator, and Pfizer concurs with that assessment. 
An investigator’s causality assessment is the determination of whether there exists a 
reasonable possibility that Inlyta caused or contributed to an adverse event. If the 
investigator’s final determination of causality is “unknown” and s/he cannot determine 
whether Inlyta caused the event, the safety event must be reported within 24 hours.   
If the investigator cannot determine the etiology of the event but s/he determines that Inlyta 
did not cause the event, this should be clearly documented on the case report form and the 
NIS AEM Report Form.  
5.2. DEFINITIONS OF SAFETY EVENTS 
5.2.1. Adverse events 
An AE is any untoward medical occurrence in a patient administered a medicinal product.  
The event need not necessarily have a causal relationship with the product treatment or 
usage. Examples of adverse events include but are not limited to:   
• 
Abnormal test findings (see below for circumstances in which an abnormal test 
finding constitutes an adverse event); 
• 
Clinically significant symptoms and signs; 
• 
Changes in physical examination findings; 
• 
Hypersensitivity; 
• 
Lack of efficacy;  

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• 
Drug abuse;  
• 
Drug dependency. 
Additionally, for medicinal products, they may include the signs or symptoms resulting from: 
• 
Drug overdose; 
• 
Drug withdrawal; 
• 
Drug misuse;  
• 
Off-label use;  
• 
Drug interactions; 
• 
Extravasation; 
• 
Exposure during pregnancy; 
• 
Exposure during breast feeding; 
• 
Medication error; 
• 
Occupational exposure. 
Abnormal test findings 
The criteria for determining whether an abnormal objective test finding should be reported as 
an adverse event are as follows:  
• 
Test result is associated with accompanying symptoms, and/or 
• 
Test result requires additional diagnostic testing or medical/surgical intervention, 
and/or 
• 
Test result leads to a change in study dosing or discontinuation from the study, 
significant additional concomitant drug treatment, or other therapy, and/or 
• 
Test result is considered to be an adverse event by the investigator or sponsor. 

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Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an adverse event.  Any abnormal test result that is determined to be an error does 
not require reporting as an adverse event. 
 
5.2.2. Serious adverse events 
A serious adverse event is any untoward medical occurrence in a patient administered a 
medicinal or nutritional product (including pediatric formulas) at any dose that: 
• 
Results in death; 
• 
Is life-threatening; 
• 
Requires inpatient hospitalization or prolongation of hospitalization (see below for 
circumstances that do not constitute adverse events); 
• 
Results in persistent or significant disability/incapacity (substantial disruption of the 
ability to conduct normal life functions); 
• 
Results in congenital anomaly/birth defect. 
Progression of the malignancy under study (including signs and symptoms of progression) 
should not be reported as a serious adverse event unless the outcome is fatal within the safety 
reporting period.  Hospitalization due to signs and symptoms of disease progression should 
not be reported as a serious adverse event.  If the malignancy has a fatal outcome during the 
study or within the safety reporting period, then the event leading to death must be recorded 
as an adverse event and as a serious adverse event with severity Grade 5. 
Medical and scientific judgment is exercised in determining whether an event is an important 
medical event.  An important medical event may not be immediately life-threatening and/or 
result in death or hospitalization.  However, if it is determined that the event may jeopardize 
the patient or may require intervention to prevent one of the other outcomes listed in the 
definition above, the important medical event should be reported as serious. 
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; 
or development of drug dependency or drug abuse. 

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Additionally, any suspected transmission via a Pfizer product of an infectious agent, 
pathogenic or non-pathogenic, is considered serious.  The event may be suspected from 
clinical symptoms or laboratory findings indicating an infection in a patient exposed to a 
Pfizer product.  The terms “suspected transmission” and “transmission” are considered 
synonymous.  These cases are considered unexpected and handled as serious expedited cases 
by PV personnel.  Such cases are also considered for reporting as product defects, if 
appropriate. 
 
Hospitalization 
Hospitalization is defined as any initial admission (even if less than 24 hours) to a hospital or 
equivalent healthcare facility or any prolongation to an existing admission.  Admission also 
includes transfer within the hospital to an acute/intensive care unit (e.g., from the psychiatric 
wing to a medical floor, medical floor to a coronary care unit, neurological floor to a 
tuberculosis unit). An emergency room visit does not necessarily constitute a hospitalization; 
however, an event leading to an emergency room visit should be assessed for medical 
importance.  
Hospitalization in the absence of a medical AE is not in itself an AE and is not reportable. 
For example, the following reports of hospitalization without a medical AE are not to be 
reported.  
• 
Social admission (e.g., patient has no place to sleep) 
• 
Administrative admission (e.g., for yearly exam) 
• 
Optional admission not associated with a precipitating medical AE (e.g., for 
elective cosmetic surgery) 
• 
Hospitalization for observation without a medical AE 
• 
Admission for treatment of a pre-existing condition not associated with the 
development of a new AE or with a worsening of the pre-existing condition 
(e.g., for work-up of persistent pre-treatment lab abnormality) 
• 
Protocol-specified admission during clinical study (e.g., for a procedure 
required by the study protocol) 

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5.2.3. Scenarios necessitating reporting to Pfizer Safety within 24 hours  
Scenarios involving exposure during pregnancy, exposure during breastfeeding, medication 
error, overdose, misuse, extravasation, lack of efficacy, and occupational exposure are 
described below. 
Exposure during pregnancy 
An exposure during pregnancy (EDP) occurs if: 
1. A female becomes, or is found to be, pregnant either while receiving or having been  
exposed to (e.g., environmental) Inlyta, or the female becomes, or is found to be, 
pregnant after discontinuing and/or being exposed to Inlyta (maternal exposure). 
An example of environmental exposure would be a case involving direct contact with 
a Pfizer product in a pregnant woman (e.g., a nurse reports that she is pregnant and 
has been exposed to chemotherapeutic products). 
2. A male has been exposed, either due to treatment or environmental exposure to Inlyta 
prior to or around the time of conception and/or is exposed during the partner 
pregnancy (paternal exposure). 
As a general rule, exposure during pregnancy reports from any source are reportable 
irrespective of the presence of an associated AE and  the procedures for SAE reporting 
should be followed. 
If a study participant or study participant’s partner becomes, or is found to be, pregnant 
during the study participant’s treatment with Inlyta, this information must be submitted to 
Pfizer, irrespective of whether an adverse event has occurred using the NIS AEM Report 
Form and the EDP Supplemental Form.  
In addition, the information regarding environmental exposure to Inlyta in a pregnant woman 
(e.g., a subject reports that she is pregnant and has been exposed to a cytotoxic product by 
inhalation or spillage) must be submitted using the NIS AEM Report Form and the EDP 
supplemental form. This must be done irrespective of whether an AE has occurred.   

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Information submitted should include the anticipated date of delivery (see below for 
information related to termination of pregnancy). 
Follow-up is conducted to obtain general information on the pregnancy; in addition, follow-
up is conducted to obtain information on EDP outcome for all EDP reports with pregnancy 
outcome unknown.  A pregnancy is followed until completion or until pregnancy termination 
(e.g., induced abortion) and Pfizer is notified of the outcome.  This information is provided 
as a follow up to the initial EDP report.  In the case of a live birth, the structural integrity of 
the neonate can be assessed at the time of birth.  In the event of a termination, the reason(s) 
for termination should be specified and, if clinically possible, the structural integrity of the 
terminated fetus should be assessed by gross visual inspection (unless pre-procedure test 
findings are conclusive for a congenital anomaly and the findings are reported). 
If the outcome of the pregnancy meets the criteria for an SAE (e.g., ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a 
live born, a terminated fetus, an intrauterine fetal demise, or a neonatal death]), the 
procedures for reporting SAEs should be followed. 
Additional information about pregnancy outcomes that are reported as SAEs follows:  
• 
Spontaneous abortion includes miscarriage and missed abortion; 
• 
Neonatal deaths that occur within 1 month of birth should be reported, without 
regard to causality, as SAEs.  In addition, infant deaths after 1 month should be 
reported as SAEs when the investigator assesses the infant death as related or 
possibly related to exposure to investigational product 
Additional information regarding the exposure during pregnancy may be requested.  Further 
follow-up of birth outcomes will be handled on a case-by-case basis (e.g., follow-up on 
preterm infants to identify developmental delays).   
In the case of paternal exposure, the study participant will be provided with the Pregnant 
Partner Release of Information Form to deliver to his partner.  It must be documented that the 
study participant was given this letter to provide to his partner. 
 
Exposure during breastfeeding 

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Scenarios of exposure during breastfeeding must be reported, irrespective of the presence of 
an associated AE. An exposure during breastfeeding report is not created when a Pfizer drug 
specifically approved for use in breastfeeding women (e.g., vitamins) is administered in 
accord with authorized use.  However, if the infant experiences an AE associated with such a 
drug’s administration, the AE is reported together with the exposure during breastfeeding. 
 
Medication error 
A medication error is any unintentional error in the prescribing, dispensing or administration 
of a medicinal product that may cause or lead to inappropriate medication use or patient harm 
while in the control of the health care professional, patient, or consumer.  Such events may 
be related to professional practice, health care products, procedures, and systems including: 
prescribing; order communication; product labeling, packaging, and nomenclature; 
compounding; dispensing; distribution; administration; education; monitoring; and use.   
Medication errors include: 
• 
Near misses, involving or not involving a patient directly (e.g., inadvertent/erroneous 
administration, which is the accidental use of a product outside of labeling or 
prescription on the part of the healthcare provider or the patient/consumer); 
• 
Confusion with regard to invented name (e.g., trade name, brand name). 
The investigator must submit the following medication errors to Pfizer, irrespective of the 
presence of an associated AE/SAE : 
• 
Medication errors involving patient exposure to the product, whether or not the 
medication error is accompanied by an AE. 
• 
Medication errors that do not involve a patient directly (e.g., potential medication 
errors or near misses).  When a medication error does not involve patient exposure to 
the product the following minimum criteria constitute a medication error report: 
− 
An identifiable reporter; 
− 
A suspect product; 
− 
The event medication error. 

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Overdose, Misuse, Extravasation 
Reports of overdose, misuse, and extravasation associated with the use of a Pfizer product are 
reported to Pfizer by the investigator, irrespective of the presence of an associated AE/SAE.  
 
Lack of Efficacy 
Reports of lack of efficacy to a Pfizer product are reported to Pfizer by the investigator, 
irrespective of the presence of an associated AE/SAE or the indication for use of the Pfizer 
product. 
 
Occupational Exposure 
Reports of occupational exposure to a Pfizer product are reported to Pfizer by the 
investigator, irrespective of the presence of an associated AE/SAE. 
 
5.3. COMMUNICATION OF ISSUES 
In the event of any prohibition or restriction imposed (eg, clinical hold) by an applicable 
Competent Authority in any area of the world, or if the physician is aware of any new 
information which might influence the evaluation of the benefits and risks of INLYTA®, 
Pfizer should be informed immediately.   
In addition, the physician will inform Pfizer immediately of any urgent safety measures 
taken by the physician to protect the study subjects against any immediate hazard, and of 
any serious breaches of this NI study protocol that the physician becomes aware of. 
 
5.4. SINGLE REFERENCE SAFETY DOCUMENT 
Background information on INLYTA® can be obtained from the current version of the local 
product document, which is the single reference safety document (SRSD) for information 
relating to INLYTA®  in this study. 

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6. STUDY DISCLOSURE 
Pfizer fulfils its commitment to publicly disclose clinical trial results through posting the 
results of this study on www.clinicaltrials.gov.  Pfizer posts the results of all studies that is 
has registered on ClinicalTrials.gov regardless of the reason for registration. 
The results are posted in a tabular format called Basic Results. 
 
• For studies involving a Pfizer product, the timing of the posting depends on whether 
the Pfizer product is approved for marketing in any country at the time the study is 
completed: 
• For studies involving products applicable under the US Food and Drug 
Administration Amendments Act of 2007 (FDAAA), ie, FDA-approved products, 
Pfizer posts results within one year of the primary outcome completion date (PCD). 
For studies involving products approved in any country, but not FDA approved, 
Pfizer posts results one year from last subject, last visit (LSLV).  
• For studies involving products that are not yet approved in any country, Pfizer posts 
the results of already-completed studies within 30 days after US regulatory approval.  
or one year after the first ex-US regulatory approval of the product (if only submitted 
for approval ex-US); 
• For studies involving products whose drug development is discontinued before 
approval, Pfizer posts the results within one year after such discontinuation of the 
program (if there are no plans for outlicensing or within two years if outlicensing 
plans have not completed). 
• Primary Completion Date is defined as the date that the final subject was examined or 
received an intervention for the purposes of final collection of data for the primary 
outcome, whether the clinical trial concluded according to the pre-specified protocol 
or was terminated. 
 

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7. LIST OF FIGURES 
1. <Figure 1> Data Management Flow Chart 
2. <Figure 2> Data Validation Flow Chart 
 
8. REFERENCES 
1) Robert J. Motzer, Jennifer Bacik et al. Interferon-Alfa as a Comparative Treatment for 
Clinical Trials of New Therapies Against Advanced Renal Cell Carcinoma. J Clin Oncol 
2001, 20:289-296.  2001  
2) Tarek M. Mekhail, Rony M. et al.  Validation and Extension of the Memorial Sloan-
Kettering Prognostic Factors Model for Survival in Patients With Previously Untreated 
Metastatic Renal Cell Carcinoma. J Clin Oncol 2005, 23:832-841.  
3) Daniel Y.C. Heng, Wanling Xie, et al. Prognostic Factors for Overall Survival in Patients 
With Metastatic Renal Cell Carcinoma Treated With Vascular Endothelial Growth Factor–
Targeted Agents: Results From a Large, Multicenter Study. J Clin Oncol 2009, 27:5794-
5799.  
 
 
 

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APPENDIX 1. RESPONSIBLE PARTIES 
Protocol Contact 
Name, degree(s) 
Title 
Affiliation 
Address 
 
Korea Oncology 
Medical Lead 
 
 
 Korea 
 
Country Coordinating Physicians 
NA
PPD
PPD
PPD

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APPENDIX 2. AMENDMENTS 
 
Amendment 
number 
Date 
Country(ies) 
Site(s) 
Rationale for 
amendment 
Protocol section(s) 
changed  
1 
03 May 
2016 
South Korea 
 
-Sample 
size 
reduction 
-Safety 
reporting 
language 
Section 3.2 
Section 5 
Appendix 1 
2 
03 Jan 2018 
South Korea 
 
Adverse events 
reporting criteria 
change 
Section 3.5.4 
3 
19 Mar 2018 
South Korea 
 
Change in study 
design 
Section 3.1 
Setion 3.5 
Section 3.6 
Section 4 
Section 5 
4 
20 Apr 2018 
South Korea 
 
Change in study 
design 
Section 3.1 
Section 3.2. 
Section 3.5 
Section 3.6 
Section 5 
5 
16 May 
2018 
South Korea 
 
Change in study 
design and 
minimum number 
of cases 
Section 1 
Section 3.1 
Section 3.2. 
Section 3.5 
Section 3.6 
Section 3.7 
Section 3.8 
Section 3.10 
Section 4 

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6 
15 Jun 2018 
South Korea 
 
Change in study 
duration, sample 
size 
Section 1 
Section 3.1 
Section 3.2 
Section 3.5 
Section 3.6 
Section 3.7 
Section 3.8 
Section 3.10 
Section 4 
Section 5 
APPENDIX 3. MILESTONES  
  
Milestone 
Planned date 
Start of data collection 
Dec 2012 
End of data collection 
21 Aug 2018 
Interim reports 
21 Apr 2013 
21 Oct 2013 
21 Apr 2014 
21 Oct 2014 
21 Oct 2015 
21 Oct 2016 
21 Oct 2017 
21 Apr 2019 
21 Oct 2019 
21 Apr 2020 
21 Oct 2020 

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21 Apr 2021 
Study result report (initial 6years) 
Final study report (initial 6years + additional 3 years) 
21 Nov 2018 
21 Nov 2021 
 
 
 
 
 
 

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APPENDIX 4. RECIST 1.1 TUMOR ASSESSMENT CRITERIA 1.1 
At baseline, individual tumor lesions will be categorized by the physician as either 
measurable or not, according to the criteria summarized below: 
Measurable Lesions 
Lesions that can be accurately measured in at least one dimension (longest diameter in the 
plane of measurement is to be recorded) with a minimum size of:  
10 mm for lesions other than lymph nodes and assessed by CT scan (CT scan slice thickness no 
greater than 5 mm). 
10 mm for lesions assessed clinically by caliper measurement (lesions which cannot be accurately 
measured with calipers should be recorded as non-measurable). 
20 mm for lesions assessed by chest X-ray. 
15 mm in short axis for lymph nodes when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm).  
Non-measurable Lesions  
Non-measurable lesions include small lesions (longest diameter <10 mm or pathological 
lymph nodes with a ≥10 but <15 mm short axis) as well as truly non-measurable lesions.  
Truly non-measurable lesions include: leptomeningeal disease, ascites, pleural or pericardial 
effusion, inflammatory breast disease, lymphangitic involvement of skin or lung, abdominal 
masses identified by physical exam and not measurable by reproducible imaging techniques. 
Nodes that have a short axis <10 mm are considered non-pathological and should not be 
recorded or followed.  
Special Considerations Regarding Specific Lesions  
Bone lesions: 
Bone scan, PET scan or plain films are not considered adequate imaging techniques to 
measure bone lesions.  However, these techniques can be used to confirm the presence or 
disappearance of bone lesions. 

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Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, 
that can be evaluated by cross sectional imaging techniques such as CT or MRI can be 
considered as measurable lesions if the soft tissue component meets the definition of 
measurability described above. 
Blastic bone lesions are non-measurable.  
Cystic lesions: 
Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above.  However, if non-cystic 
lesions are present in the same patient, these are preferred for selection as target lesions. 
Lesions with prior local treatment: 
Tumor lesions situated in a previously irradiated area, or in an area subjected to other 
loco-regional therapy, are usually not considered measurable unless there has been 
demonstrated progression in the lesion. 
Solitary lesions: 
If a measurable disease is restricted to a solitary lesion, its neoplastic nature should be 
confirmed by cytology/histology.  
Recording Tumor Measurements 
All measurable lesions up to a maximum of 2 lesions per organ and up to 5 in total and 
representative of all involved organs should be identified as target lesions and measured and 
recorded at baseline and at the stipulated intervals during treatment.  Target lesions should be 
selected on the basis of their size (lesions with the longest diameters) and their suitability for 
accurate repetitive measurements (either by imaging techniques or clinically).  
The longest diameter will be recorded for each target lesion.  The sum of the longest 
diameter of all target lesions will be calculated and recorded as the baseline sum diameter to 

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be used as reference to further characterize the objective tumor response of the measurable 
dimension of the disease during treatment.  
One exception to the above described approach is related to pathological lymph nodes.  
Pathological lymph nodes are defined as measurable lesions and may be identified as target 
lesions if the criterion of a short axis of ≥15 mm by CT scan is met.  Only the short axis of 
these nodes will contribute to the baseline sum.  Nodal size is normally reported as two 
dimensions in the plane in which the image is obtained (for CT scan this is almost always the 
axial plane; for MRI the plane of acquisition may be axial, sagittal or coronal).  The smaller 
of these measures is the short axis.  
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all 
target lesions will be calculated and reported as the baseline sum diameters.  The baseline 
sum diameters will be used as reference to further characterize any objective tumor 
regression in the measurable dimension of the disease. 
All other lesions (or sites of disease) should be identified as non-target lesions and should 
also be recorded at baseline.  Measurements are not required and these lesions should be 
followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal progression’.  In addition, it is 
possible to record multiple non-target lesions involving the same organ as a single item on 
the case record form (eg, ‘multiple enlarged pelvic lymph nodes’ or ‘multiple liver 
metastases’). 
Definition of Tumor Response  
Target Lesions 
Response in target lesions is defined as follows: 
Complete Response (CR): disappearance of all target lesions.  
Partial Response (PR): at least a 30% decrease in the sum of diameters of target lesions, 
taking as reference the baseline sum diameters. 
Progressive Disease (PD): at least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study).  In addition to the relative increase of 20%, the sum must also 

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demonstrate an absolute increase of at least 5 mm.  The appearance of one or more new 
lesions is also considered a sign of progression. 
Stable Disease (SD): neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study. 
When nodal disease is included in the sum of target lesions and the nodes decrease to 
‘normal’ size (<10 mm), they may still have a measurement reported on scans.  This 
measurement should be recorded even though the nodes are normal in order not to overstate 
progression should it be based on increase in size of the nodes.  As noted earlier, this means 
that patients with CR may not have a total sum of ‘zero’ on the CRF. 
Non-Target Lesions 
While some non-target lesions may actually be measurable, they need not be measured and 
instead should be assessed only qualitatively at the time points specified in the protocol.  
Response in non-target lesions is defined as follows: 
Complete Response (CR): Disappearance of all non-target lesions and normalization of 
tumor marker level.  All lymph nodes must be non-pathological in size (<10 mm short axis). 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of 
tumor marker level above the normal limits.  
Progressive Disease (PD): Unequivocal progression of existing non-target lesions.  (Note: 
the appearance of one or more new lesions is also considered progression). 
Cytology, histology  
These techniques can be used to differentiate between PR and CR in rare cases if required by 
protocol (for example, residual lesions in germ cell tumors).  When effusions are known to 
be a potential adverse effect of treatment (eg, taxane compounds or angiogenesis inhibitors), 
the cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment can be considered if the measurable tumor has met criteria for response or 
stable disease in order to differentiate between response or stable disease and progressive 
disease. 

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For patients having effusions or ascites, only cases having cytological proof of malignancy 
should be recorded on the CRF.  Effusions that have not been evaluated using cytology or 
were found to be non-malignant should not be recorded on the CRF.  
New Lesions  
The appearance of new malignant lesions indicates PD.  New lesion should be unequivocal 
(eg, not attributable to differences in imaging technique, or change in imaging modality or 
findings not attributable to tumor).  If a new lesion is equivocal, for example due to its small 
size, continued therapy and follow-up assessment will clarify the etiology of the disease.  If 
repeat scans confirm there is definitely a new lesion, then progression should be declared 
using the date of the initial scan.  
The use of FDG-PET is sometimes reasonable to complement a CT scan assessment of a PD 
(particularly for possible ‘new’ disease).  New lesions on the basis of FDG-PET imaging can 
be identified according to the following algorithm:  
Negative FDG-PET at baseline, with a positive FDG-PET at follow-up;  
No FDG-PET at baseline and a positive FDG-PET at follow- up: if the positive FDG-PET at 
follow-up corresponds to a new site of disease confirmed by CT, this is PD. 
If the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT scans are needed to determine if there is truly progression occurring 
at that site (if so, the date of PD will be the date of the initial abnormal FDG-PET scan). 
If the positive FDG-PET at follow-up corresponds to a pre-existing site of disease on CT that 
is not progressing on the basis of the anatomic images, this is not PD. 
Confirmation of Tumor Response  
Confirmation of response is required for non-randomized trials with primary endpoint of 
response, but is not required in randomized studies since the control arm serves as 
appropriate means of interpretation of data. 
 
 

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Determination of Overall Response by the RECIST 1.1 Criteria 
When both target and non-target lesions are present, individual assessments will be recorded 
separately.  The overall assessment of response will involve all parameters as depicted in 
Table 1. 
Table 1. 
Response Evaluation Criteria in Solid Tumors 
Target lesions 
Non-target lesions 
New 
Lesions 
Overall 
response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or 
not all evaluated 
No 
PR 
SD 
 
Non-PD or 
not all evaluated 
No 
SD 
Not all 
Evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR = complete response, PR = partial response, SD = stable disease, 
PD = progressive disease, and NE = inevaluable. 
 
 

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Best overall response 
The best overall response is determined once all the data for the patient is known.  Best 
response in trials in which confirmation of complete or partial response is not required 
(ie, randomized trials) is defined as the best response across all time points (for example, a 
patient who has SD at first assessment, PR at second assessment, and PD on last assessment 
has a best overall response of PR).  When SD is believed to be the best response, it must also 
meet the protocol specified minimum time from baseline.  If the minimum time is not met 
when SD is otherwise the best time point response, the patient’s best response depends on the 
subsequent assessments.  For example, a patient who has SD at first assessment, PD at 
second and does not meet minimum duration for SD, will have a best response of PD.  The 
same patient lost to follow-up after the first SD assessment would be considered inevaluable.  
When confirmation of CR and PR is required (ie, non-randomized trials with primary 
endpoint of response), the best overall response is defined according to the tumor response 
along the study.  Complete or partial responses may be claimed only if the criteria for each 
are met at a following time point as specified in the protocol (generally 4 weeks later).  In 
this circumstance, the best overall response can be interpreted as in Table 2. 
Table 2. 
Best overall response when confirmation of CR and PR required 
Overall response  
First time point  
Overall response Subsequent 
time point 
BEST overall response 
CR 
CR 
CR 
CR 
PR 
SD, PD or PRa 
CR 
SD 
SD provided minimum criteria for SD 
duration met, otherwise, PD 
CR 
PD 
SD provided minimum criteria for SD 
duration met, otherwise, PD 
CR 
NE 
SD provided minimum criteria for SD 
duration met, otherwise NE 
PR 
CR 
PR 
PR 
PR 
PR 

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PR 
SD 
SD 
PR 
PD 
SD provided minimum criteria for SD 
duration met, otherwise, PD 
PR 
 
NE 
SD provided minimum criteria for SD 
duration met, otherwise NE 
NE 
NE 
NE 
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, and NE 
= inevaluable. 
a If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease 
meeting PR criteria relative to baseline, makes the disease PD at that point (since disease must have 
reappeared after CR).  Best response would depend on whether minimum duration for SD was met.  
However, sometimes ‘CR’ may be claimed when subsequent scans suggest small lesions were likely 
still present and in fact the patient had PR, not CR at the first time point.  Under these circumstances, 
the original CR should be changed to PR and the best response is PR. 
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
‘symptomatic deterioration’.  Every effort should be made to document objective progression 
even after discontinuation of treatment.  Symptomatic deterioration is not a descriptor of an 
objective response: it is a reason for stopping study therapy.  The objective response status of 
such patients is to be determined by evaluation of target and non-target lesions. 
In some circumstances it may be difficult to distinguish residual disease from normal tissue.  
When the evaluation of CR depends upon this determination, it is recommended that the 
residual lesion be investigated (fine needle aspirate/biopsy) before assigning a status of 
complete response.  FDG-PET may be used to upgrade a response to a CR in a manner 
similar to a biopsy in cases where a residual radiographic abnormality is thought to represent 
fibrosis or scarring.  The use of FDG-PET in this circumstance should be prospectively 
described in the protocol and supported by disease specific medical literature for the 
indication.  However, it must be acknowledged that both approaches may lead to false 
positive CR due to limitations of FDG-PET and biopsy resolution/ sensitivity.