Retrospective Analysis of Clinical Factors Associated With Greater Benefit of Axitinib in Metastatic Renal Cancer (AXILONG Study)
Conditions: Carcinoma, Renal Cell
Sponsor: Pfizer

 
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NON-INTERVENTIONAL STUDY (NIS) PROTOCOL  
Study Information 
Title 
Retrospective analysis of clinical factors 
associated with greater benefit of Axitinib in 
metastatic renal cancer (AXILONG Study) 
Protocol Code 
A4061089 /PFI-AXI-2017-01 
Protocol Version 
V 1.2_Admin changes 
Date of the latest Protocol version 
21 March 2018 
Active substance 
Therapeutic group/ATC code: L01XE17  
Active substance: Axitinib (A4061089) 
Drug 
Inlyta (axitinib) 
Hypothesis and objectives 
To describe the clinical characteristics of a 
population of patients with a long-term 
response to axitinib and to identify and 
analyse clinical factors which could be 
related to the long-term response to axitinib, 
through the comparison between two groups 
of patients with an extreme response to the 
drug. 
Author 
 
Pfizer España 
Avda. de Europa, 20B 
Parque Empresarial la Moraleja 
28108 Alcobendas (Madrid) 
 
CONTENTS 
PPD

 
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CONTENTS .....................................................................................................................................1 
1. LIST OF ABBREVIATIONS ......................................................................................................4 
2. PERSONS RESPONSIBLE FOR THE STUDY .........................................................................6 
3. ABSTRACT .................................................................................................................................7 
4. AMENDMENTS AND UPDATES ...........................................................................................11 
5. MILESTONES ...........................................................................................................................12 
6. STUDY RATIONALE ..............................................................................................................14 
6.1. Literature review ...........................................................................................................14 
6.1.1. Epidemiology of kidney cancer ........................................................................14 
6.1.2. Therapeutic approach ........................................................................................16 
6.1.3. Therapeutic Management of Metastatic Disease ..............................................17 
6.1.4. Axitinib in RCC ................................................................................................18 
6.1.5. Mechanism of action .........................................................................................18 
6.1.6. Efficacy data .....................................................................................................19 
6.1.7. Tolerability data ................................................................................................21 
6.1.8. Administration regimens ..................................................................................22 
6.2. Study rationale ...............................................................................................................23 
7. HYPOTHESIS AND OBJECTIVES .........................................................................................24 
7.1. Primary objective: .........................................................................................................24 
7.2. Secondary objectives: ....................................................................................................25 
8. METHODS OF INVESTIGATION ..........................................................................................27 
8.1. Study design ..................................................................................................................27 
8.2. Scope .............................................................................................................................27 
8.2.1. Inclusion Criteria ..............................................................................................28 
8.2.2. Exclusion Criteria .............................................................................................29 
8.3. Variables ........................................................................................................................29 
8.4. Source documents .........................................................................................................29 
8.5. Sample size ....................................................................................................................30 
8.6. Data processing .............................................................................................................30 

 
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8.7. Data Analysis ................................................................................................................30 
8.8. Quality control ...............................................................................................................31 
8.9. Limitations of the research methods .............................................................................31 
8.10. Further aspects .............................................................................................................32 
9. PROTECTION OF STUDY SUBJECTS ..................................................................................34 
9.1. Patient information and consent ....................................................................................34 
9.2. Withdrawal of patients ..................................................................................................35 
9.3. IEC ................................................................................................................................35 
9.4. Ethical considerations of the study ................................................................................35 
9.5. Interference with doctors’ prescribing patterns .............................................................36 
10. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/REACTIONS ..................38 
11. PUBLICATION OF RESULTS ..............................................................................................40 
12. REFERENCES ........................................................................................................................42 
13. LIST OF TABLES ...................................................................................................................45 
14. LIST OF CHARTS ..................................................................................................................46 
ANNEX 1. LIST OF INDEPENDENT DOCUMENTS ...............................................................47 
ANNEX 2. CASE REPORT FORM (VARIABLES)....................................................................48 
ANNEX 3: COORDINATING INVESTIGATOR’S STATEMENT OF COMMITMENT ........48 
ANNEX 4. IEC APPROVAL ........................................................................................................48 
ANNEX 5. PATIENT INFORMATION SHEET AND INFORMED CONSENT FORM ..........48 
ANNEX 6. FINANCIAL REPORT ...............................................................................................48 
ANNEX 7. SUMMARY OF PRODUCT CHARACTERISTICS FOR STUDY 
MEDICATION. ....................................................................................................................48 
ANNEX 8. AE REPORT FORM...................................................................................................48 
ANNEX 9. LIST OF PLANNED SITES AND PIS IN THE STUDY ..........................................48 
 

 
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1. LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AEMPS 
Agencia Española del Medicamento y Productos 
Sanitarios (Spanish Agency of Medicines and 
Medical Devices) 
AEs 
Adverse Events  
AR 
Autonomous Regions 
CR 
Complete Response 
CRF 
Case Report Form  
CRO 
Contract Research Organisation 
CT 
Computed Tomography 
CTC 
Circulating Tumour Cells 
DFS 
Disease-Free Survival 
DMBS 
Data Management & Biostatistics 
EMA 
European Medicines Agency 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice  
HBP 
High Blood Pressure 
Hgb 
Haemoglobin 
HIF 
Hypoxia-inducible Factor 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 

 
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IHC 
Immunohistochemistry 
IMDC 
International Metastatic Database Consortium 
LDH 
Lactate Dehydrogenase 
MedDRA 
Medical Dictionary for Regulatory Activities 
MSKCC 
Memorial Sloan Kettering Cancer Center 
NR 
No Response 
OS 
Overall Survival 
PD 
Progressive-Disease 
PFS 
Progression-Free Survival 
PR 
Partial Response 
RCC 
Renal Cell Carcinoma 
RTK 
Receptor Tyrosine Kinase 
SD 
Stable Disease 
SOPs 
Standard Operating Procedures 
TMAs 
Tissue Microarrays 
VEGFR 
Vascular Endothelial Growth Factor Receptor 
VHL 
Von Hippel–Lindau 
 
 

 
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2. PERSONS RESPONSIBLE FOR THE STUDY 
Name 
Title 
Affiliation 
Address 
Dr 
 
Coordinating 
Investigator  
 
 
 (Spain) 
 
Medical Advisor  
Pfizer Oncology 
Pfizer España 
Avda. de Europa, 20B 
Parque Empresarial la 
Moraleja 
28108 Alcobendas (Madrid) 
 
Medical & Scientific 
Relations  
Pfizer Oncology 
Pfizer España 
Avda. de Europa, 20B 
Parque Empresarial la 
Moraleja 
28108 Alcobendas (Madrid) 
 
 
 
PPD
PPD
PPD
PPD
PPD

 
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3. ABSTRACT 
SPONSOR:  
Laboratorios Pfizer 
Avenida de Europa, 20 – B 
Parque Empresarial La Moraleja  
28108 Alcobendas (Madrid) 
 
Contact person: 
 
 
STUDY TITLE: Retrospective analysis of clinical factors associated with greater benefit of 
Axitinib in metastatic renal cancer (AXILONG Study) 
 
PROTOCOL CODE: A4061089/PFI-AXI-2017-01 
 
COORDINATING INVESTIGATOR: 
The scientific coordinator will be responsible for maintaining the methodological rigour of the 
study, both in the design phase and in the evaluation of results and writing of the final report. 
He/she will guarantee the ethical conduct of the study, maintaining the scientific support for all 
participating doctors until the publication of the study results: 
 
Study coordinator: 
Dr
 
  
 Madrid 
 
STUDY SITES: 
It has initially been considered optimal to include patients in the Medical Oncology Departments 
of approximately thirty to forty Spanish sites. 
 
IEC ASSESSING THE STUDY 
This protocol will be submitted to the IEC: 
 
 
 
 
 Madrid 
 
PPD
PPD
PPD

 
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PRIMARY OBJECTIVE 
The primary objective of the study is: 
• To describe the baseline clinical characteristics of the population of patients with a long-
term response to axitinib and to identify clinical factors which could be related to the 
long-term response to axitinib (defined as progression-free survival after taking the drug 
of at least 9 months), through the comparison of two groups of patients with an extreme 
response to the drug: one group of patients who are progression-free of at least 9 months 
compared to a group of patients who are shown to have disease progression before the 
first response assessment. 
• To analyse the association of some clinical factors with greater benefit from the drug. 
 
SECONDARY OBJECTIVE 
The secondary objectives of the study are: 
• To describe the response to treatment with axitinib in the group of patients with a long-
term response. 
• To describe the efficacy per treatment line (second line of treatment and subsequent lines)  
- 
Best response to treatment (CR, PR, SD) 
- 
Progression-free Survival 
- 
Objective response rate (ORR) and clinical benefit (sum of CR, PR and SD) 
- 
Time to progression 
- 
Overall Survival 
• To describe the duration of treatment with axitinib  
• To describe the percentage of patients who titrated doses of axitinib of more than 5 mg 
twice daily 
• To describe the percentage of patients who reduced doses of axitinib of less than 5 mg 
twice daily 
• To describe the tolerability of axitinib 
• To describe the treatments received at progression  
• To describe the response to the treatments received at progression  
 
DESIGN 
Post-authorisation, multicentre, observational study with retrospective follow-up.  
 
STUDY CONDITION 
Advanced renal cancer. 
 
STUDY POPULATION AND TOTAL NUMBER OF SUBJECTS 

 
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Patients of both sexes with advanced renal cell carcinoma will be included, who have received 
axitinib as second line or subsequent lines in accordance with the conditions approved for use in 
this disease.  
The aim is to include two groups of patients: one with a long-term response to the drug (a group 
of patients progression-free for at least 9 months) compared to a group of patients who are 
refractory to the treatment (group of patients who show disease progression at the first assessment 
after the initiation of treatment). 
The maximum possible number of patients will be included, progression-free at 9 months after the 
initiation of treatment. The ratio of long-term responders (PFS ≥9 months) and primary refractory 
patients (PFS ≤3 months) is estimated to be around 2:1. 
During the study recruitment period, the participating sites may include all patients who meet the 
study’s inclusion criteria and who do not meet the study exclusion criteria. Given that this is an 
observational and exploratory study, no hypotheses have been established and the sample size will 
not be pre-determined. 
In this study, the treatment with axitinib will have started before the enrolment of the patient, so 
the decision to treat and enrol these patients will be independent of the decision to carry out this 
study, and will depend exclusively on the clinical judgement of the responsible doctor.  
 
SCHEDULE 
The administrative procedures of the study are expected to begin with the central IEC and the 
AEMPS in September/October 2017, with the first sites expected to open in the first quarter of 
2018. 
Patient recruitment will be carried out competitively for a maximum period of three months 
following the opening of the last participating study site. No follow-up of patients will be carried 
out after their inclusion in the study.  
Regarding the observation period—given that it is an observational, retrospective study—this will 
always be prior to the inclusion of the patient in the study, with this starting at the time of diagnosis 
of the study condition (renal cell carcinoma) and ending at the time of inclusion in the study, or 
the death of the patient if this occurs first. 
The study is expected to end when the data of all enrolled patients have been collected and 
analysed, which is estimated for 2019.  
 
SOURCE OF FUNDING 
Pfizer España, as Sponsor, is responsible for funding the study. This funding includes all the 
research materials, the cost of recording and controlling processes for the Committee and 
healthcare authorities, the design, maintenance and management of the database, the cost of the 

 
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statistical analysis of the information and reports generated and the fees of the professionals 
involved in the collection and analysis of the data. 
Pfizer SLU, as Sponsor of the study, shall provide financial compensation to the sites/investigators 
participating in the study. Such compensation will be explicit and transparent, without prejudice 
to the internal rules of their employing agencies and in accordance with specific regulations in the 
ARs and at the sites where the study is conducted. 
 

 
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4.  AMENDMENTS AND UPDATES 
 
Amendme
nt No. 
Date 
Substantial or 
administrative 
amendment 
Amended protocol 
section(s) 
Summary of change(s) 
Reason 
1 
20 October 2017 
Administrative. 
Schedule/Milestones 
Add clarification on patient 
observation period 
Request from the AEMPS at the 
time of classification, to emphasise 
the retrospective nature of the 
study. 
2 
21 March 2018 
Administrative. 
- Format of data 
collection tool (CRF) 
- Schedule/Milestones 
- Annex 9 “list of 
planned sites and PIs 
in the study” 
- Change in format of CRF 
(final CRF in paper format 
instead of electronic format) 
- Update of past or future 
expected dates in the 
schedule/milestones 
- Amendment of Annex 9 
“list of planned sites and PIs 
in the study”, to include two 
new sites and to change the 
name of the PI of one of 
them. 
A decision has been made that the 
CRF format to be used in the study 
will be on paper because, with this 
being a retrospective study, it will 
be quicker and easier to use, and 
avoids delays in the start of the 
study caused by the scheduling and 
management thereof. 
Two new sites interested in 
participating in the study are also 
included, as well as the correction 
of the PI in one of the sites, 
following the request of his/her site. 
 
 

 
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5. MILESTONES  
In order to obtain enough information to perform a proper analysis of the data, the proposed 
work plan is as follows: 
Once the study is approved by the competent authorities and the contracts have been signed at 
each site, each study site will be opened and the investigator may start recording the requested 
data in the electronic case report form. 
Before including the patient in the study, the investigator should review and verify the 
inclusion/exclusion criteria. 
The observation period—given that it is an observational, retrospective study—will always be 
prior to the inclusion of the patient in the study, with this starting at the time of diagnosis of the 
study condition (renal cell carcinoma) and ending at the time of inclusion in the study, or the 
death of the patient if this occurs first. 
The person appointed by the sponsor to monitor the study may request a face-to-face or remote 
visit from the site for the review of the data reported in the eCRF at any time after the first 
patient is included. 
The site undertakes to fill in the data in the CRFs, and to resolve any discrepancies that may arise 
in them, on a regular basis and without interfering with the study’s planned schedule. 
The study sponsor will regularly inform the investigators involved in the study on its status by 
sending electronic monitoring reports. 
The administrative procedures for the study with the central IEC and the AEMPS are expected to 
start in September/October 2017, so the following schedule is being considered:  
Milestone 
Expected date 
Date of approval from the central IEC  
 7 NOVEMBER 2017 
Start of data collection  
Date of opening of the first site and start of study recruitment 
15 MARCH 2018 
End of recruitment period 
Expected date of study recruitment closure 
30 SEPTEMBER 2018 
End of data collection  
30 DECEMBER 2018 

 
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Expected date of closing of study data collection 
Final results report 
Expected date for the final results of the study 
31 MARCH 2019 
 

 
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6. STUDY RATIONALE 
6.1. Literature review 
6.1.1. Epidemiology of kidney cancer 
Kidney cancer accounts for approximately 5% and 3% of all new cases of cancer in men and 
women, respectively. This makes it the seventh most common cancer in men, and the tenth in 
women.1 Metastatic disease is found in 20-30% of patients at diagnosis and the main sites of 
metastasis are: lung (50-60%), bone (30-40%), liver (30-40%), and CNS (5%), with a median 
survival before and after the introduction of targeted therapies of approximately 13 months and 29 
months, respectively. In 2006, it was estimated that there were 63,300 new cases of kidney cancer 
and 26,400 deaths related to kidney cancer in the European Union, with 6,474 new cases being 
diagnosed in Spain in 2012.2 
However, these data not only include renal parenchyma tumours, but also urothelial cancer of the 
renal pelvis. More specifically, renal cell carcinoma (RCC) is the most common solid lesion in the 
kidney, representing around 90% of all malignant renal tumours, with approximately 80% of these 
being clear cell RCC. Other less common cell types include papillary, chromophobe and Bellini 
duct tumours. It is most common in men (with a male/female ratio of 1.5:1), with the median age 
at diagnosis being 64. 
Smoking and obesity are fully established risk factors for the development of kidney cancer, as 
well as several types of hereditary kidney cancer, with von Hippel-Lindau (VHL) disease—caused 
by an autosomal dominant mutation in the VHL gene which predisposes for renal carcinoma and 
other proliferative vascular lesions—being the most common. 
Due to the more regular performance of imaging tests such as ultrasound and computed 
tomography (CT) scans, the number of incidentally-diagnosed cases of kidney cancer has 
increased, with incidence rates increasing by an average of around 1.1% each year, although death 
rates have fallen, by an average of 0.7% from 2004 to 2013.3 Furthermore, the 5-year survival for 
localised cancer has increased from 88.4% (1992-1995) to 92.5% (2006-2012). In the case of 
advanced disease, this increase was from 7.3% (1992-1995) to 11.6% (2006-2012).3 

 
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Moreover, the stratification of these patients based on prognostic models has helped the oncology 
community in the interpretation and identification of patient groups at the highest risk of relapse. 
These nomograms or algorithms integrate a certain number of prognostic factors (anatomical, 
clinical and histological), obtaining predictive results regarding the evolution of the disease. 
Motzer, et al. developed one of the most important models, deriving from the analysis of 463 
patients with advanced RCC treated with IFNα and with no previous systemic therapy, sequentially 
treated in clinical trials at the Memorial Sloan-Kettering Cancer Center (MSKCC) in New York 
between 1982 and 1996, including the number and site of metastases, performance status, previous 
radiotherapy, previous nephrectomy, diagnostic interval at the start of treatment and specific 
baseline laboratory data (haemoglobin, albumin, alkaline phosphatase and LDH) as clinical factors 
for the univariate analysis. Of the multivariate analysis, five of these criteria were the best 
predictors of survival, of which three groups or risk models were developed, in which survival and 
probability of being disease-free are predicted. In the development of this model, the median 
survival was 13 months, with 18%, 62%, and 20% of the 437 patients considering themselves as 
having a good, intermediate and poor prognosis, respectively. Since the clinical trials conducted 
over the course of these years were carried out using a drug with very little efficacy, the results 
represent the natural history of patients previously treated for advanced RCC. 
With the widespread use of new targeted therapies, it was necessary to develop prognostic models 
in patients reflecting the use thereof. Heng, et al. published a new prognostic model in 2009 based 
on the MSKCC model, with the addition of two additional factors, which was developed—thus 
proving useful—in patients treated with anti-VEGF targeted therapies. An important progression 
in this field was the development by the International Metastatic Renal Cell Carcinoma Database 
Consortium (IMDC) of a model, implemented in patients with metastatic RCC, treated with a 
following drug line with targeted therapies, in progression after a first-line with these targeted 
therapies.5, 6 

 
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6.1.2. Therapeutic approach 
Until a few years ago, the only active systemic treatment available for metastatic RCC was based 
on immunotherapy with cytokines, IL-2 and IFNα, associated with a modest impact on overall 
survival, with a 5-year survival rate of less than 10%. However, this has dramatically changed with 
the development and marketing of the new targeted therapies, which have substantially modified 
the therapeutic approach and prognosis for these patients, from the average OS of 9.4 months 
described in the Motzer, et al. study to an average OS of 35.5 months in patients with anti-VEGF 
therapies, in progression after a first line with these targeted therapies.4,6 
This substantial progress is based on the recent advances in the understanding of the genetics and 
biology of RCC, which has allowed the successful development of these targeted therapies aimed 
at VEGF and its receptors, and the target of the rapamycin pathway.7,8 Regarding VEGF, several 
research lines support a unique dependence of RCC, in particular those with clear-cell histology, 
on this growth factor for carcinogenesis and progression. 
Patients with a deletion in the VHL gene often develop multiple clear-cell tumours in their kidneys, 
at an early age. Similarly, the biallelic loss of the VHL gene occurs in the majority of patients who 
develop sporadic clear-cell RCC. This is because the VHL protein acts as a transcriptional activity 
regulator of the hypoxia-inducible factor (HIF), and its accumulation leads to the overexpression 
of multiple genes, including the gene that encodes for VEGF. VEGF binds to the receptor tyrosine 
kinases on the cell surface, located in the endothelial cells, to promote tumour angiogenesis and 
tumour proliferation.9 
Thus, seven molecules designed to act against specific targets and angiogenic signalling pathways 
have been approved in Europe and the USA, five of which target the VEGF pathway, with two 
targeting the rapamycin (mTOR) pathways. 
In addition to these molecules, there has been the recent approval from the European Medicines 
Agency (EMA) and the Food and Drug Administration (FDA) of nivolumab, a human-IgG4 
monoclonal antibody which binds to the PD-1 receptor and blocks its interaction with PD-L1 and 
PD-L2, thus releasing the PD-1 pathway that mediates the inhibition of immune response, 

 
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including anti-tumour immune response; cabozantinib, a small molecule that inhibits multiple 
receptor tyrosine kinases (RTKs) involved in tumour growth and angiogenesis; and lenvatinib, a 
selective RTK inhibitor of VEGF receptor kinase activity, approved in combination with 
everolimus, for the treatment of patients with RCC. 
 
6.1.3. Therapeutic Management of Metastatic Disease 
Angiogenesis is the key factor for the development and progression of RCC, given the high degree 
of vascularisation of these tumours, which is why it is considered to be a disease targeted by the 
VEGF pathway.9 Both bevacizumab, a monoclonal antibody inhibitor of the VEGF receptor, and 
the TKIs sunitinib, sorafenib, pazopanib and axitinib have shown significant clinical benefits in 
patients with mRCC, thanks to their mechanism of action on the molecular target responsible for 
the development of the disease, vascular endothelial growth factors (VEGF) and their receptors. 
For the treatment of the metastatic disease in first-line bevacizumab (in combination with 
interferon), sunitinib and pazopanib have been approved by the FDA and the EMA based on the 
improvement in PFS times, whether for interferon or placebo. Bevacizumab reported a PFS that 
was higher than the control group (10.2 m vs 5.4 m, HR 0.63 [95% CI: 0.52-0.75]; p=0.0001), 
independent of the risk group.10 The sunitinib study, meanwhile, showed a statistically significant 
improvement in PFS compared to IFα (11 m vs 5 m; HR 0.42 [95% CI: 0.32-0.54; p<0.001).11 
Lastly, pazopanib demonstrated a statistically significant improvement in PFS, compared to the 
placebo control group, of 9.2 months in the overall population (HR: 0.48; 95% CI: 0.34-0.62; p 
<0.0001).12 
In addition to axitinib, as second-line treatment, another three VEGFR inhibitors are authorised 
for use in the clinic, although none of them are authorised for the treatment of patients after failure 
of a previous line with a TKI: sunitinib, sorafenib, pazopanib. In two single-arm studies, sunitinib 
demonstrated an OS and PFS of 34-40% and 8.3-8.7 m, respectively.13 Sorafenib (5.5 m vs 2.8 m) 
and pazopanib (7.4 m vs 4.2 m) showed improvements in the median PFS versus placebo.12, 14  

 
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In the group of mTOR inhibitors, temsirolimus and everolimus (authorised after TKI) are currently 
available in the therapeutic arsenal. Temsirolimus was approved in first line, based on the positive 
OS results versus placebo (10.9 vs 7.3 m).8 Everolimus demonstrated an improvement in PFS 
compared with placebo (4.9 m vs 1.9 m), in patients who had progressed to a prior therapy that 
included sunitinib or sorafenib.15 
Furthermore, indication of advanced RCC after treatment with a prior VEGF therapy has recently 
been authorised by the EMA for cabozantinib and lenvatinib, with the latter being in association 
with everolimus. Cabozantinib (7.4 m vs 3.8 m) and lenvatinib in combination with everolimus 
(14.6 m vs 5.5 m) showed a statistically significant improvement in PFS compared to the 
everolimus active comparator.16, 17 
 
6.1.4. Axitinib in RCC 
Axitinib was also evaluated in advanced renal cell cancer in a pivotal phase III study, with which 
it received approval for the treatment of advanced renal cell carcinoma after the failure of previous 
systemic therapy from the FDA (Federal Drug Agency) on 27 January 2012. Subsequently, on 3 
September 2012, it was authorised by the EMA for the treatment of adult patients with advanced 
renal cell carcinoma after failure of a previous treatment with sunitinib or cytokines. On 1 June 
2014, after evaluating the data of axitinib in kidney cancer, the AEMPS (Spanish Agency of 
Medicines and Medical Devices) issued a favourable opinion for the authorisation of axitinib in 
the treatment of adult patients with advanced renal cell carcinoma after failure of a previous 
treatment with sunitinib or cytokines (authorised on 01/06/2014). 
6.1.5. Mechanism of action 
Axitinib is a potent and selective second-generation tyrosine kinase inhibitor (TKI) of vascular 
endothelial growth factor receptors VEGFR-1, VEGFR-2 and VEGFR-3, which are located on the 
surface of the endothelial cells and are involved in pathological angiogenesis, tumour growth and 
the metastatic progression of cancer.7, 9 Axitinib has a unique binding pattern and is more potent 
and selective against VEGF 1-3 than other multi-target TKIs such as sunitinib or sorafenib, and 

 
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has been proven to potently inhibit the proliferation and cell survival of endothelial cells mediated 
by VEGF. The neutralisation of VEGF biological activity produces a regression of tumour 
vascularisation, normalises residual tumour vasculature and inhibits tumour neovascularisation, 
thereby inhibiting tumour growth.18  
6.1.6. Efficacy data 
Three prior phase II studies showed that axitinib had significant clinical activity in advanced RCC, 
both in patients refractory to cytokines (A4061012, A4061035 [only in Japanese patients], and 
those refractory to sorafenib (A4061023).19-21 
In the A4061012 study, which included 52 patients with metastatic RCC, the radiological objective 
response rate was 44.2% (95% CI: 30.5-58.7), with 4% achieving complete response. With a 
median follow-up of 5.9 years, the last analysis showed that 10 of the 52 patients were alive, with 
the 5-year OS rate being 20.6% (95% CI: 10.9%-32.4%), with a median OS of 29.9 months.19,20 
The A4061035 study was a phase II trial in 64 Japanese patients with metastatic RCC who were 
refractory to cytokines. An independent radiological review committee found that, in the intention-
to-treat population, axitinib reached a response rate of 50% and a median PFS of 11 months.21 
In the A4061023 study by Rini, et al., which included 62 patients with metastatic RCC, the median 
PFS was 7.4 months (95% CI: 6.7-11.0), and the median OS was 13.6 months (95% CI: 8.4-18.8). 
Most patients included in this study also received prior treatment with sunitinib or other agents 
such as bevacizumab and temsirolimus, with 75% of patients treated with at least two previous 
treatment lines.22 
Based on the results of these trials, a randomised (1:1), open-label pivotal phase III study compared 
axitinib with an active TKI—sorafenib—as a second line therapy (“Axitinib (AG 013736) As 
Second Line Therapy For Metastatic Renal Cell Cancer: Axis Trial”), and included 723 RCC 
patients with a clear-cell component, with progression to a treatment line based on sunitinib, 
bevacizumab plus interferon, temsirolimus or cytokine-based regimens.23 The patients were 
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treated until disease progression or unacceptable toxicity occurred. Nevertheless, after the disease 
progression defined by RECIST v.1.0 criteria, patients could continue with the treatment assigned 
at random at the discretion of the investigator. 
PFS—the primary study endpoint—was significantly greater in patients treated with axitinib 
(6.7 m vs 4.7 m; HR 0.665; [95% CI: 0.544-0.812], p<0.0001), and was also higher in the PFS 
analysis in the pre-specified groups, with all the HRs favouring axitinib, independent of the ECOG, 
performance status, previous therapies, race, gender, age, MSKCC status and geographic region. 
The benefit of axitinib in terms of PFS must also be pointed out in the subgroup of patients 
previously treated with cytokines (12.1 m vs 6.5 m; HR 0.484, [95% CI: 0.318-0.876], p<0.0001), 
and particularly in the subgroup who had progressed to one previous line with sunitinib (4.8 m vs 
3.4 m; HR 0.741 [95% CI: 0.573-0.958], p<0.0001). Likewise, the overall response rate favoured 
axitinib (19.4% vs 9.4%), with a median response duration of 11 m vs 10.6 m for axitinib and 
sorafenib, respectively. 
The median OS, the secondary study objective which had recently been updated, was similar in 
both groups (20.1 m vs 19.2 m (HR= 0.969, p= 0.374); although the study design did not take into 
account the collection of data on subsequent therapies after the first progression, in such a way 
that any possible effect of post-progression therapy on the OS could not be determined. When the 
patients previously treated with sunitinib were analysed, using the median duration of previous 
sunitinib treatment (9.7 months) as a cut-off point, axitinib was associated with a tendency towards 
greater OS in patients who received sunitinib for longer: 11.7 months vs 18.1 months, in the 
sunitinib group <9.7 months vs ≥9.7 months, respectively (HR: 1.24; 95% CI 0.88–1.75; p=0.220). 
24 
From a regulatory point of view, sorafenib was considered to be a reasonable choice for the 
comparator because it had shown activity in patients with RCC refractory to sunitinib, 
bevacizumab, and ≥1 previous antiangiogenic agent. During the start of the study, everolimus had 
still not been evaluated and was not approved as second line. 

 
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6.1.7. Tolerability data  
The overall safety profile of axitinib is similar to the profile of other drugs belonging to the same 
class of molecules that inhibit the VEGF pathway. However, the aforementioned greater selectivity 
of axitinib compared to other targeted therapies such as sorafenib gives it a better safety profile, 
with less toxicity caused by the off-target effect being seen with axitinib.23 These adverse events 
(AEs) include common events such as diarrhoea, nausea, high blood pressure (HBP), tiredness and 
dermatological events, as well as fewer common toxicities such as thromboembolic events, 
hypothyroidism and proteinuria. However, it should be noted that axitinib does not appear to have 
the same degree of elevated liver enzymes and potential for liver failure as described with certain 
other VEGF-pathway inhibiting molecules. In view of the above, the EMA recommends 
monitoring specific safety events such as heart failure, HBP, thyroid function, embolic and 
thrombotic events, arterial and venous events, erythrocytosis, proteinuria, etc., before starting 
treatment and regularly throughout treatment. In the pivotal study, the most common grade ≥3 AEs 
(≥10%) were HBP (17%), diarrhoea (11%) and fatigue (10%), whereas in patients receiving 
treatment with sorafenib palmar-plantar erythrodysesthesia and hypertension were reported in 17% 
and 11%, respectively.23 It should be pointed out that, in the axitinib arm, no deaths were reported 
that were related to the drug, while two deaths associated with sorafenib were reported: one case 
associated with retroperitoneal bleeding due to tumour necrosis and another associated with 
gastrointestinal bleeding, whereas the rate of withdrawals due to related AEs favoured axitinib 
(4% vs 8%).3 In the COMPARZ study, which directly compared pazopanib and sunitinib, the 
common toxicity profiles were reflected in: the median duration of treatment (8.0 m vs 7.6 m), 
number of dose reductions (44% vs 51%), and rate of discontinuation due to AEs (24% vs 19%), 
for pazopanib and sunitinib, respectively.25 By contrast, in the AXIS study, 31% of patients 
reduced their dose in the axitinib arm versus 52% in the sorafenib arm.23 
In accordance with their authorised indication, it is recommended to maintain axitinib until 
progression or unacceptable toxicity, with no cumulative toxicity apparently being observed using 
this therapeutic approach, as shown in the Rini, et al. study in a cumulative analysis of data in 672 

 
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patients with metastatic RCC previously treated with axitinib, 108 patients (16%) had received 
axitinib for ≥2 years, and most of the adverse events occurred during the first 6 months of 
treatment. The authors concluded that a stable or decreasing rate of AEs supported the concept of 
an acceptable safety profile for axitinib.26 
In summary, we can say that, although the safety profile of axitinib has a similarity to that of 
sorafenib and other approved agents targeting the VEGF pathway (based on indirect comparisons), 
some significant differences have been observed between axitinib and these other agents. Axitinib 
seems to be associated with a lower incidence of: skin reactions than those reported with sorafenib 
and sunitinib; myelosuppression than pazopanib and sunitinib; hypothyroidism than sorafenib and 
pazopanib; and changes in liver enzyme levels than with pazopanib and sunitinib. By contrast, 
axitinib appears to be associated with: a higher incidence of dysphonia than sorafenib and 
sunitinib; a higher incidence of hypothyroidism than sorafenib and pazopanib; and a higher 
incidence of HBP than sorafenib. These differences are partly derived from the higher specificity 
of axitinib, due to the inhibition of VEGFR, than other approved multi-target TKIs.  
6.1.8. Administration regimens 
The recommended starting dose of axitinib is 5 mg twice daily, every 12 hours, with or without 
food (with a glass of water), with dose increases or decreases being recommended in accordance 
with patient safety and tolerability. Patients who tolerate the starting dose of axitinib of 5 mg twice 
daily for two consecutive weeks, without presenting any serious adverse reactions, may increase 
the dose to 7 mg twice daily, unless the patient’s blood pressure is >150/90 mmHg or the patient 
is receiving antihypertensive treatment. Therefore, using the same criterion, patients who tolerate 
an axitinib dose of 7 mg twice daily may increase the dose to a maximum of 10 mg twice daily. 
Control of some adverse reactions may require a temporary or permanent suspension and/or a 
reduction in the dose of the treatment with axitinib. When the dose reduction is necessary, the dose 
of axitinib may be reduced to 3 mg twice daily or even 2 mg twice daily. 

 
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Treatment should be continued as long as clinical benefit is observed, or until an unacceptable 
toxicity occurs that cannot be managed with concomitant medication or dose adjustment.  
6.2. Study rationale 
 
The efficacy and safety profile of axitinib in patients with metastatic RCC is scientifically 
documented in the pivotal phase III “AXIS” study, with a subgroup of patients who benefited from 
a longer progression-free survival, called “long-term responders” with a survival of greater than 9 
months; however, due to the rigid inclusion criteria in a clinical trial, these data cannot be 
generalised to the population treated in normal clinical practice. Therefore, it is necessary to 
identify the clinical, tumour and response factors of these patients in “real” clinical practice 
compared to those patients with a below-average PFS.  
These concepts underline the need for observational studies that respond to unresolved questions 
and complete the information on clinical trials, helping to improve the knowledge on the real use 
of drugs after they have been marketed and to confirm and reaffirm the data obtained in the 
development phase. So much so that, in the last few years, the European and local health authorities 
have started to include in their guidelines the application for real-world studies with the authorised 
drugs that confirm these clinical data and allow for better patient screening.  
Furthermore, the studies carried out under routine clinical conditions allow us to establish whether 
the routine patterns used by the physician correspond with the authorisation, which is based on 
information obtained from clinical trials. 
 
 
 

 
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7. HYPOTHESIS AND OBJECTIVES 
7.1. Primary objective: 
 
- To describe the baseline clinical characteristics of the population of patients who are long-term 
responders to axitinib and to identify clinical factors associated with a long-term response to 
axitinib. 
 
For the study, “long-term responders to axitinib” has been defined as patients with progression-
free survival [PFS] of at least 9 months with the drug, and “patients refractory to axitinib” has 
been defined as patients with disease progression in the first assessment after the start of treatment 
[estimated PFS ≤3 months] 
 
To meet the study objective, two groups of patients with extreme response to the drug will be 
compared: a group of patients with long-term responses to the drug (group of long-term responders 
to axitinib) compared to a group of patients with disease progression in the first assessment after 
starting treatment (group of patients refractory to axitinib), in which the association of the 
following clinical factors will be analysed with the benefit of the treatment; 
- Age (≤65 years and >65 years) 
- Baseline ECOG/PS at the start of treatment for each line (0, 1 and ≥2) 
- Number of previous treatment lines (1, 2 and ≥3) 
- Previous nephrectomy (yes and no) 
- MSKCC risk group (favourable, intermediate and poor) 
- IMDC risk group (favourable, intermediate and poor) 
- Change in the MSKCC or the IMDC risk group with respect to the previous line (yes vs 
no);  
- Histology (100% clear cells, main component of clear cells, main component of non-clear 
cells, 100% non-clear cells). 

 
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- Duration of first-line with a TKI (≥12 months, ≤6 months; ≤3 months) 
- Better response with the TKI received in first-line (CR/PR, SD, DP) 
- Number of metastatic locations (1, 2 and ≥3); 
- Site of metastases (CNS metastases [yes vs no]; lymph nodes [yes vs no]; lung [yes vs 
no]; liver [yes vs no]; bone [yes vs no]) 
- Baseline LDH levels ≤1.5xULN (yes vs no) 
- Baseline Hgb levels >LLN (yes vs no) 
- Baseline corrected Ca++ levels ≤10 mg/dl (yes vs no) 
- Baseline neutrophil levels ≤ULN (yes vs no) 
- Baseline platelet levels ≤ULN (yes vs no) 
- Neutrophil/lymphocyte ratio ≤3 (yes vs no) 
- Smoking habits (smoker, non-smoker or ex-smoker) 
 
7.2. Secondary objectives: 
 
- To describe the response to treatment with axitinib in the long-term responder group (defined as 
a PFS of at least 9 months with the drug) 
- To describe the efficacy per treatment line (second line of treatment and subsequent) 
• Best response to treatment (CR, PR, SD) 
• Progression-free Survival 
• Objective response rate (ORR) and clinical benefit (sum of CR, PR and SD) 
 
• Time to progression 
• Overall Survival 
- To describe the duration of treatment with axitinib 
- To describe the percentage of patients who titrated doses of axitinib of more than 5 mg twice 
daily 

 
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- To describe the percentage of patients who have reduced doses of axitinib to below 5 mg twice 
daily 
- To describe the tolerability of axitinib 
- To describe the treatments received at progression 
- To describe the response to the treatments received at progression 
 
 
 

 
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8. METHODS OF INVESTIGATION 
The purpose of this study is to describe, in routine clinical practice, outside the context of a clinical 
trial, the clinical characteristics of patients with metastatic kidney cancer who have been treated 
with axitinib for at least 9 months and to identify clinical factors associated with a greater benefit 
from the drug. No hypotheses have been pre-specified, and all study data will be analysed using 
the statistical descriptive techniques. 
 
8.1. Study design  
Post-authorisation, multicentre, observational study with retrospective follow-up. 
 
In this study, the treatment with axitinib will have started before the enrolment of the patient, so 
the decision to treat and enrol these patients will be independent of the decision to carry out this 
study, and will depend exclusively on the clinical judgement of the responsible doctor. 
 
8.2. Scope 
The patient population eligible for this study includes any patient with advanced or metastatic 
kidney cancer who has been treated with axitinib for at least 9 months or who has had PD as the 
best response to this treatment. 
The requirements for a patient’s inclusion are that: 
1. 
These patients must have received axitinib as second-line treatment or later, in accordance 
with its Summary of Product Characteristics. Two groups presenting extreme responses 
to the drug will be compared: one group of patients showing no evidence of disease 
progression for at least 9 months after the start of treatment with axitinib versus a group 
of patients showing disease progression while taking the drug at the first response 
assessment. 
2. 
Collection of clinical, safety and response data in patients with advanced kidney cancer. 
The study is expected to be conducted in at least 30 sites distributed throughout Spain in order to 
reach the maximum number of study patients. 

 
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The study will start at each site after the contract with the site is signed and all study documentation 
and information on the procedures and objectives of the study are received by the person appointed 
by the sponsor.  
Recruitment will be competitive between all participating sites, and as many patients as there are 
at the site that meet the inclusion criteria during the recruitment period may be included.  
This is an observational study designed to reflect routine clinical practice; there will be no 
interference with the daily routine medical care of patients with kidney cancer. The data collected 
will be consistent with those normally collected from the patient’s medical record in routine 
clinical practice, including the patients’ demographic data, routine laboratory values required in 
the diagnosis and control of this condition, performance status, clinical condition, and the 
assessments carried out according to the site's routine clinical practice, use of medication, 
tolerability, adverse events and compliance with treatment.  
Given that this is an observational study, no additional material not included in routine practice 
will be required. 
Patients will be considered assessable if they meet the inclusion criteria and do not meet the 
exclusion criteria, and have received at least one dose of axitinib prior to their inclusion in the 
study. 
 
8.2.1. Inclusion Criteria 
Patients must meet all the inclusion criteria below to be eligible for inclusion in the study: 
1. Evidence of a personally signed and dated informed consent form indicating that the patient 
(or his/her legal representative) has been informed of all aspects relevant to the 
study.Informed consent will only be obtained from patients who are still alive.  
2. Aged 18 or over. 
3. Histologically confirmed diagnosis of advanced kidney cancer, with at least one radiological 
evaluation of the disease in accordance with RECIST 1.1 criteria 

 
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4. Treatment with axitinib as second-line or later with a PFS equal to or greater than 9 months, 
or with disease progression in the first response assessment 
8.2.2. Exclusion Criteria 
Patients who meet any of the following criteria will not be included in the study: 
1. Treatment with axitinib not accounted for in the Summary of Product Characteristics 
2. Non-compliance with any of the study inclusion criteria 
 
8.3. Variables 
For this observational study, the following variables will be recorded: demographic, medical 
history (including date and stage of disease at diagnosis and at progression), surgical treatment, 
histology, blood count and blood biochemistry, first-line treatments, associated adverse events, 
clinical efficacy and history of treatment with axitinib, including treatment line (second, third, 
etc.), dose, reason and date of start of treatment, disease risk criteria before onset, comorbidities, 
associated adverse events, concomitant medication and subsequent treatments, as well as the 
patient’s condition (alive, deceased) and the last date on which contact was made. 
A complete description of the variables, including the operational definitions, will be detailed in 
the Statistical Analysis Plan of the study.  
 
8.4. Source documents  
The investigator will, at all times, be fully responsible for the accuracy and authenticity of all 
clinical and laboratory data included in the CRFs. 
The source document for this study will be the medical records of the patient documented in his/her 
medical record, including his/her surgical records, which will be kept at the site where the study 
is conducted. All data will be captured in a case report form (CRF). For particular problems and/or 
questions or governmental requirements for an inspection, it will also be necessary to access a 
complete study file, provided that the patient’s right to anonymity is protected. 

 
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The information in the CRFs should be consistent with the data in the medical records. 
 
8.5. Sample size 
Given the low incidence of metastatic renal cell cancer, and thus the population to be included in 
the study, the number of patients expected to be included will be small, and it is expected that it 
will be around 60 patients. However, as it is an observational and exploratory study, no hypotheses 
were specified and, therefore, the calculations of the sample size are not applicable.  
 
8.6. Data processing  
The detailed software methodology for the handling of the data to be applied in this study will be 
documented in the Data Management Plan (DMP), which will be designed, filed and maintained 
by the sponsor. This document shall contain the details about which data (e.g. previous and 
concomitant medications, adverse events, etc.) will be encoded using the World Health 
Organization’s (WHO) Drug Reference List (DRL), which will use the Anatomical Therapeutic 
Chemical (ATC) classification system, or the Medical Dictionary for Regulatory Activities 
(MedDRA). The specific versions of the coding dictionaries used will be documented in the DMP. 
 
8.7. Data Analysis  
The data will be analysed using descriptive statistics. A statistical summary will be provided 
including sample size, mean, standard deviation, median and range for the continuous variables, 
when applicable; frequency and percentages for the categorical variables. Depending on the results 
of interest, a stratified data analysis may be conducted. Additional exploratory analyses will be 
conducted, if necessary. 
Details of the methodology for the summary and statistical analysis of the data collected in this 
study will be documented in the Statistical Analysis Plan (SAP), which will be prepared, filed and 
maintained by the sponsor. The SAP can modify the plans originally described in the protocol; any 
major change in the definitions of the study’s primary objective or analyses will be reflected as an 
amendment to the protocol. 

 
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8.8. Quality control 
As this is a post-authorisation study, the same procedures used in routine clinical practice will be 
followed by the investigator. 
  
However, the investigators are responsible for ensuring that the protocol and Good Clinical 
Practice (GCP) standards are complied with. 
 
Study sites might be subject to face-to-face or remote monitoring by the person appointed by the 
sponsor and a review by the Independent Ethics Committee (IEC) and/or quality assurance audits 
conducted by the relevant regulatory authorities and the study sponsor. 
 
During the conduct of this study, Pfizer (or its representative) will monitor the activities of the 
collection of data by the sites, and can also carry out periodic monitoring visits at the sites in order 
to ensure the correct progress of the study. During visits at the sites, the monitors may review the 
source documents to confirm that the data recorded in the CRF are correct. All the information 
recorded in the CRF for this study must be consistent with the patient’s source documentation (e.g. 
medical history). 
Data included in the database, and some integrated data from third parties (if applicable), will be 
verified/validated as documented in the components of the DMP, which will be prepared, stored 
and maintained by the sponsor. 
 
 
8.9. Limitations of the research methods 
Due to the low incidence of patients with advanced clear-cell kidney cancer undergoing treatment 
with axitinib, and especially patients with the required response characteristics, it is difficult to 
estimate the number of patients who could be included throughout the course of the study. 
 

 
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8.10. Further aspects 
- 
Study procedures: 
For the inclusion of patients in the study, the Investigator must review the inclusion/exclusion 
criteria and, in the case of including patients who are alive and being followed-up at the site, the 
patient will be required to sign the ICF before inclusion in the study, as per the model appended to 
the protocol. 
For patients who have already died at the time of inclusion in the study, the request for informed 
consent is not required, as is permitted in order SAS/3470/2009 of 16 December, on observational 
post-authorisation studies. 
 
With the data available in the medical record, the requested information will be recorded in the 
electronic case report form in order to analyse the study variables. Lists of these variables, such as 
Annex I, are attached to the protocol. 
 
- Review and confirmation of meeting the inclusion criteria and not meeting the exclusion criteria 
for the study.  
- In the case of living patients who are subject to follow-up at the site, the patient must receive an 
explanation of the procedures and purpose of the study, and be requested to sign the ICF if he/she 
wishes to participate in the study. 
 
- Data on demographic characteristics 
- Disease history:  
• Patient’s medical records  
• Data on the disease for which he/she is receiving treatment with axitinib 
• Data on previous treatments received for the disease. 
 
- Data on the treatment with axitinib 
• Information on the patient’s response to the treatment 

 
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• Information on the tolerability and management of treatment with axitinib  
• Information on survival and dates of progression (if any) 
- Information on subsequent treatment(s) received (if any). 
- Information on the patient’s vital signs in the last follow-up performed.  
  

 
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9. PROTECTION OF STUDY SUBJECTS 
The study will be conducted in accordance with routine clinical practice as described in the 
protocol, standards of Good Clinical Practice, the International Conference on Harmonisation and 
applicable local laws and requirements (Order SAS/3470/2009, of 16 December). The sponsor 
undertakes to abide by current legislation regarding post-authorisation studies and the associated 
commitments. 
 
9.1. Patient information and consent 
All parties will ensure that personal data are protected and will not include patients’ names on any 
of the sponsor’s forms, reports, publications or any other text for disclosure, unless so required by 
law. For data transfer, Pfizer will maintain a high level of confidentiality and protection of patients’ 
personal data. 
 
Since this study is retrospective, a large number of patients will probably have died by the time 
they are included. In this case, and in accordance with order SAS/3470/2009 of 16 December on 
observational post-authorisation studies in which it is established that “In studies that require 
subjects to be interviewed or in those in which, using other sources of data, it is not possible to use 
a safe dissociation procedure that ensures that the information contains no personal data, subjects 
must be asked to provide informed consent, which must be granted in writing in accordance with 
current regulations”, these patients will not be required to provide their signed informed consent.  
In the case of patients who are alive at the time of their inclusion in the study, the informed consent 
form must comply with the routine regulatory requirements, which should comply with ICH GCP, 
local administrative standards and legal requirements. 
 
The informed consent form used in this study and any changes made during the course of the study 
must be prospectively approved by the IEC and by Pfizer prior to implementation. 

 
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The investigator must ensure that each study patient or his/her legal representative is informed of 
the nature and objectives of the study and possible risks associated with his/her participation 
therein. The investigator, or a person appointed by the same, will obtain written informed consent 
from each patient or his/her legal representative before performing any study-specific procedure. 
The investigator will retain the original of each patient’s signed informed consent form. 
 
9.2. Withdrawal of patients 
Patients who are alive at the time of their enrolment in the study can withdraw at any time 
voluntarily, or may be withdrawn at the discretion of the investigator or the sponsor for safety, 
behaviour or administrative reasons. In any event, every effort should be made to document the 
results of any such patient. The investigator should inquire about the reason for the withdrawal 
and conduct follow-up on the patient in relation to any unresolved adverse event. 
If the patient leaves the study and also withdraws his/her consent for future disclosure of 
information, no further data evaluation or collection should be performed. The sponsor may retain 
and continue to use any data collected before the withdrawal of consent. 
9.3. IEC 
The sponsor is responsible for obtaining the prospective approval of the study protocol, 
amendments and informed consent forms, and other relevant documents, if necessary, from the 
IEC. All correspondence with the IEC should be kept in the Investigator’s File. Copies of the 
approvals from the IEC should be sent to Pfizer.  
 
The requirements of current local regulations will be followed for the submission and management 
of initial approvals or amendments to the protocol. 
 
9.4. Ethical considerations of the study 
The study will be conducted in accordance with legal and regulatory requirements and scientific 
rigour, respect and responsibility and will follow the generally accepted research practices 

 
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described in the Guidelines for Good Pharmacoepidemiology Practices (GPP) published by the 
International Society for Pharmacoepidemiology (ISPE), Good Epidemiological Practice (GEP) 
guidelines published by the International Epidemiological Association (IEA), Good Practices for 
Outcomes Research published by the International Society for Pharmacoeconomics and Outcomes 
Research (ISPOR), International Ethical Guidelines for Epidemiological Research published by 
the Council for International Organizations of Medical Sciences (CIOMS), European Medicines 
Agency (EMA) and the European Network of Centres for Pharmacoepidemiology and 
Pharmacovigilance (ENCePP) Guide on Methodological Standards in Pharmacoepidemiology. 
 
The study will be conducted in accordance with the protocol, Good Clinical Practice standards, 
the International Conference on Harmonisation and applicable local laws and requirements. 
 
Additionally, the study will be governed by the basic ethical principles contained in the Declaration 
of Helsinki. 
 
Data confidentiality 
 
The highest levels of professional conduct and confidentiality will be maintained at all times, 
following national data protection legislation. The patient’s right to confidentiality is fundamental. 
The patient’s identity in the study documents will be encoded and only authorised persons will 
have access to personal details that could identify the patient if so required by data verification 
procedures. Personal details that could identify the patient will be kept confidential. 
 
9.5. Interference with doctors’ prescribing patterns 
 
There will be no interference with the investigator’s decision on the most appropriate treatment 
for the patient. 

 
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It is a non-interventional, retrospective study, and therefore decisions on treatment indications and 
inclusion in the study will be independent, and always based on routine clinical practice. 
 
 

 
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10. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/REACTIONS  
REQUIREMENTS 
This study protocol requires a manual review of unstructured patient data. The term “unstructured 
data” refers to literal medical data, including descriptions based on texts and visual representations 
of medical information, such as medical records, images of medical notes, neurological images, 
X-rays, or database narrative fields. The reviewer must report adverse events (AEs) that are 
explicitly attributable to any Pfizer drug that appear in the reviewed information (defined 
according to the study population and the study period specified in the protocol). The explicit 
attribution should not be deduced by a temporal relationship between drug administration and an 
AE, but should be based on a definite statement of causality by a healthcare professional, which 
links the administration of the drug with the AE. 
The requirements for the reporting of safety events in the non-interventional study (NIS) adverse 
event monitoring (AEM) report form to Pfizer’s Drug Safety Department are the following: 
• All serious and non-serious AEs with explicit attribution to any Pfizer product that appear 
in the reviewed information should be recorded in the Case Report Form (CRF) and 
reported within 24 hours of knowledge thereof to Pfizer’s Drug Safety Department using 
the NIS AEM Report Form. 
• Situations involving exposure to a drug, including exposure during pregnancy, exposure 
during breast-feeding, medication errors, overdose, incorrect use of the drug, extravasation, 
lack of efficacy and occupational exposure associated with the use of a Pfizer product 
should be reported to Pfizer’s Drug Safety Department within 24 hours of knowledge 
thereof using the NIS AEM Report Form. 
Should these safety events be attributed explicitly or associated with the use of a Pfizer product, 
the data contained in the medical record will be all the known information regarding these adverse 
events. There will be no follow-up of these related adverse events. 
All research staff will have to undertake the compulsory training in: “Your Reporting 
Responsibilities: Monitoring the Safety, Performance and Quality of Pfizer Products (Multiple 

 
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Languages)” and any supplementary training of Your Reporting Responsibilities that is considered 
to be relevant. This training will be provided to the research staff before the start of the study. All 
training modules include a Confirmation of Training certificate (which must be signed by the 
person who has received the training) as a record that he/she has completed the training, and must 
be stored in a recoverable format. Copies of all signed training certificates will be submitted to 
Pfizer. 
Training must be completed annually, using the most recent version of: “Your Reporting 
Responsibilities”.  
 
  
 
 
 

 
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11. PUBLICATION OF RESULTS 
The investigator will send a written report of the study status to the sponsor, as described in the 
Study Agreement document. The investigator will also send regular interim progress reports to the 
sponsor, as required. A Clinical Study Report is also expected to be created. Periodic safety update 
reports will be provided on a yearly basis. 
All information obtained as a result of this study will be considered confidential. 
 
The Scientific Coordinator of the study, together with the sponsor, will undertake to disclose the 
results through the usual scientific means. 
The authors listed in the publication of the study results must meet the following requirements: 
 
•Substantial contribution to the proposal and design of the study or in the collection, analysis and 
interpretation of the study data AND 
•Involvement or contribution in writing and/or reviewing the publications with regard to the 
intellectual content AND 
•Contribution to the final approval of the published version AND 
•Agreement to act responsibly in all aspects of the publication of the data to ensure that issues 
relating to the accuracy or integrity of any part of the work are investigated and appropriately 
addressed. 
 
INCIDENT REPORTING 
In the event that a ban or restriction (e.g. temporary suspension) is imposed by a competent 
authority in any part of the world, or if the investigator is aware of any new information that might 
influence the evaluation of the benefits and risks of a Pfizer product, Pfizer must be immediately 
informed thereof. 
The investigator will also inform Pfizer immediately of any urgent safety measures taken to protect 
the study patients from any danger and any violation of the protocol of which he/she is aware. 

 
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RESOURCES FOR THE CONDUCT OF THE STUDY  
-Funding 
 
Pfizer SLU, as sponsor of the study, will provide financial compensation to the sites/investigators 
participating in the study. Such compensation will be explicit and transparent, without prejudice 
to the internal rules of their employing agencies and in accordance with specific regulations at the 
sites where the study is conducted. 
 
PRACTICAL CONSIDERATIONS 
-Monitoring  
 
There will be on-site monitoring at approximately 10% of sites with patients enrolled in the study. 
At the other sites, there will be telephone monitoring of the case report form. The sponsor will 
appoint the person in charge of monitoring the study. 
 
-Follow-up and final reports 
 
During the study and after its completion, the relevant reports will be sent to the Division of 
Pharmacoepidemiology and Pharmacovigilance of the Spanish Agency of Medicines and Medical 
Devices and the competent authorities for PASs under current regulations. 

 
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12. REFERENCES 
1. Siegel RL, Siegel RL, Miller KD, Jemal A. Cancer Statistics, 2017. CA Cancer J 
Clin. 2017 Jan;67(1):7-30. doi: 10.3322/caac.21387. Epub 2017 Jan 5. 
2. Incidencia del cáncer en España en 2012 y previsión para 2020: Sociedad Española de 
Oncología 
Médica 
(SEOM). 
http://www.seom.org/seomcms/images/stories/recursos/LAS_CIFRAS_DEL_CANCER_
EN_ESP_2016.pdf 
3. SEER Stat Facts Sheets: Kidney and Renal Pelvis Cancer. Available at: 
https://seer.cancer.gov/statfacts/html/kidrp.html 
4. Motzer, R.J., Bacik, J., Murphy, B.A. et al. Interferon-alfa as a comparative treatment for 
clinical trials of new therapies against advanced renal cell carcinoma. J Clin 
Oncol. 2002; 20: 289–296. 
5. Heng DY, Xie W, Regan MM, Warren MA, 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 Dec 
1;27(34):5794-9. doi: 10.1200/JCO.2008.21.4809. Epub 2009 Oct 13. 
6. Ko JJ, Xie W, Rini BI, Choueiri TK, Heng DY, et al. The International Metastatic Renal 
Cell Carcinoma Database Consortium model as a prognostic tool in patients with 
metastatic renal cell carcinoma previously treated with first-line targeted therapy: a 
population-based study. Lancet Oncol. 2015 Mar;16(3):293-300. doi: 10.1016/S1470-
2045(14)71222-7. Epub 2015 Feb 12. 
7. Rini BI, Vascular endothelial growth factor-targeted therapy in renal cell carcinoma: 
current status and future directions. Clin Cancer Res 2007;13:1098-106 
8. Hudes G, Carducci M, Tomczak P et al. Temsirolimus, interferon alfa, or both for advanced 
renal-cell carcinoma. N Engl J Med 2007;356(22):2271-81 
9. Rini BI, Rathnell WK. Biological aspects and binding strategies of vascular endothelial 
growth factor in renal cell carcinoma.  Clin Cancer Res 2007;13:741s–746s 
10. Escudier B, Pluzanska A, Koralewski P, et al. Bevacizumab plus interferon alfa-2a for 
treatment of metastatic renal cell carcinoma: a randomized, double-blind phase III trial. 
Lancet 370:2103-11, 2007 

 
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11. Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Oudard S, et al. 
Overall survival and updated results for sunitinib compared with interferon alfa in patients 
with metastatic renal cell carcinoma. J Clin Oncol. 2009 Aug 1;27(22):3584-90 
12. Sternberg CN, Davis ID, Mardiak J, Szczylik C, Lee E, Wagstaff J et al. Pazopanib in 
Locally Advanced or Metastatic Renal Cell Carcinoma: Results of a Randomized Phase III 
Trial JCO Feb 20, 2010:1061-1068 
13. Motzer RJ, Rini BI, Bukowski RM, et al. Sunitinib in patients with metastatic renal cell 
carcinoma. JAMA 2006; 295: 2516-2524. 
14. Escudier B, Eisen T, Stadler WM, et al. Sorafenib for treatment of renal cell carcinoma: 
Final efficacy and safety results of the phase III treatment approaches in renal cancer global 
evaluation trial. J Clin Oncol 2009; 27(20): 3312-33 
15. Motzer RJ, Escudier B, Oudard S et al. Efficacy of everolimus in advanced renal cell 
carcinoma:a double blind, randomized, placebo-controlled phase III trial. Lancet 
2008;372:449-456. 
16. Choueiri TK, Escudier B, Powles T, Mainwaring PN, Rini BI, et al; METEOR 
Investigators.. Cabozantinib versus Everolimus in Advanced Renal-Cell Carcinoma. N 
Engl J Med. 2015 Nov 5;373(19):1814-23. doi: 10.1056/NEJMoa1510016. Epub 2015 Sep 
25 
17. Motzer RJ, Hutson TE, Ren M, Dutcus C, Larkin J. Independent assessment of lenvatinib 
plus everolimus in patients with metastatic renal cell carcinoma. Lancet Oncol. 2016 
Jan;17(1):e4-5. doi: 10.1016/S1470-2045(15)00543-4. Epub 2015 Dec 23. 
18. Hu-Lowe DD, Zou HY, Grazzini ML, et al. Nonclinical antiangiogenesis and antitumor 
activities of axitinib (AG-013736), an oral, potent, and selective inhibitor of vascular 
endothelial growth factor receptor tyrosine kinases 1, 2, 3. Clin Cancer Res. 2008 Nov 
15;14(22):7272-83. doi: 10.1158/1078-0432.CCR-08-0652 
19. Rixe O, Bukowski RM, Michaelson MD, Rini BI, et al. Axitinib treatment in patients with 
cytokine-refractory metastatic renal-cell cancer: a phase II study. Lancet Oncol. 2007 
Nov;8(11):975-84. Epub 2007 Oct 2 
20. Rini BI, de La Motte Rouge T, Harzstark AL, et al. Five-year survival in patients with 
cytokine-refractory metastatic renal cell carcinoma treated with axitinib. Clin Genitourin 
Cancer. 2013 Jun;11(2):107-14. doi: 10.1016/j.clgc.2012.12.004. Epub 2013 Feb 4 
21. Tomita Y, Uemura H, Fujimoto H, Kanayama HO, et al; Japan Axitinib Phase II Study 
Group. Key predictive factors of axitinib (AG-013736)-induced proteinuria and efficacy: 

 
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a phase II study in Japanese patients with cytokine-refractory metastatic renal cell 
Carcinoma. Eur J Cancer. 2011 Nov;47(17):2592-602. doi: 10.1016/j.ejca.2011.07.014. 
Epub 2011 Aug 31. 
22. Rini BI, Wilding G, Hudes G, Stadler WM, et al. Phase II study of axitinib in sorafenib-
refractory metastatic renal cell carcinoma. J Clin Oncol. 2009 Sep 20;27(27):4462-8. doi: 
10.1200/JCO.2008.21.7034. Epub 2009 Aug 3. 
23. Rini BI, Escudier B, Tomczak P, et al. Comparative effectiveness of axitinib versus 
sorafenib in advanced renal cell carcinoma (AXIS): A randomised phase 3 
trial. Lancet 2011;378:1931-1939 
24. Escudier B, Michaelson MD, Motzer RJ, Hutson TE, Rini BI, et al. Axitinib versus 
sorafenib in advanced renal cell carcinoma: subanalyses by prior therapy from a 
randomised phase III trial Br J Cancer. 2014 Jun 10;110(12):2821-8. doi: 
10.1038/bjc.2014.244. Epub 2014 May 13 
25. Motzer R, Hutson TE, Reeves J, Hawkins R, Guo J, Nathan P et al. Randomized, open-
label, phase iii trial of pazopanib versus sunitinib in first-line treatment of patients with 
metastatic renal cell carcinoma (mrcc): results of the COMPARZ Trial. Proceedings of the 
European Society for Medical Oncology 2012 Congress LBA8 PR 
26. Rini BI, Escudier B, Motzer RJ, et al. Long-Term Safety With Axitinib in Previously 
Treated Patients With Metastatic Renal Cell Carcinoma. Clin Genitourin Cancer. 2015 
Dec;13(6):540-7.e1-7. doi: 10.1016/j.clgc.2015.07.001. Epub 2015 Jul 20. 
27. Puente 
J, 
Laínez 
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Dueñas 
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Méndez-Vidal 
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Novel potential predictive markers of sunitinib outcomes in long-term respondersversus 
primary refractory patients with metastatic clear-cell renal cell carcinoma. Oncotarget. 
2017 May 2;8(18):30410-30421. doi: 10.18632/oncotarget.16494 
28. Tam S, de Borja R, Tsao MS, McPherson JD. Robust global microRNA expression 
profiling using next-generation sequencing technologies. Lab Invest. 2014 Mar;94(3):350-
8. doi: 10.1038/labinvest.2013.157. Epub 2014 Jan 20. 
 

 
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13. LIST OF TABLES  
N/A 
 

 
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14. LIST OF CHARTS 
N/A 
 

 
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ANNEX 1. LIST OF INDEPENDENT DOCUMENTS 
 
List of Annexes to the Protocol: 
Number 
Date 
Title 
Annex 1 
N/A 
List of Annexes to the Protocol 
Annex 2 
N/A 
List of variables to be included in the CRF. 
Annex 3 
N/A 
 Coordinating investigator’s Statement of commitment 
Annex 4 
 
Agreement of the central IEC 
Annex 5 
Version 1.0 of 
5Sep2017 
Patient Information Sheet/Informed Consent Form 
Annex 6 
Version 1.0  
Schedule of Payments/Financial Report 
Annex 7 
N/A 
Summary of product characteristics 
Annex 8 
- 
AEs Report Form 
Annex 9 
Version 1.1 
List of planned Sites and PIs in the study 
 
 
 
 
 
 

 
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ANNEX 2. CASE REPORT FORM (VARIABLES) 
ANNEX 3: COORDINATING INVESTIGATOR’S STATEMENT OF COMMITMENT 
ANNEX 4. IEC APPROVAL 
ANNEX 5. PATIENT INFORMATION SHEET AND INFORMED CONSENT FORM 
ANNEX 6. FINANCIAL REPORT 
ANNEX 7. SUMMARY OF PRODUCT CHARACTERISTICS FOR STUDY 
MEDICATION.  
ANNEX 8. AE REPORT FORM 
ANNEX 9. LIST OF PLANNED SITES AND PIS IN THE STUDY