Real-world Evaluation of Efficacy and Safety With Avelumab (BAVENCIO®) + Axitinib (INLYTA®) in Patients With aRCC in Multiple EU Countries (AVION)
Conditions: Carcinoma, Renal Cell
Sponsor: Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany

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Non-Interventional Study Protocol 
Study Protocol Number 
MS100070_0110 
 
Title 
Real-world evaluation of efficacy and safety with 
AVelumab (BAVENCIO®) + Axitinib (INLYTA®) in 
patients with Advanced Renal-Cell CarcinOma (RCC) in 
multiple EU couNtries 
 
Protocol Version Identifier 
4.0 
 
Protocol Date / Version 
24 April 2023 / Version 4.0 
 
Replaces Version 
21 December 2022 / Version 3.0 
 
Active Substance 
L01XC31: Avelumab, Axitinib 
 
Medicinal Product 
Avelumab injection, Axitinib tablet 
 
Sponsor 
Merck Healthcare Germany GmbH 
an affiliate of Merck KGaA, Darmstadt, Germany 
Waldstraße 3, 64331 Weiterstadt 
Germany 
 
Research Question and 
Objectives 
The aim of this study is to expand knowledge on the 
effectiveness of Avelumab 800 mg intravenous infusion 
flat-dose treatment in combination with Axitinib 5 mg 
orally twice per day as the first-line therapy in patients with 
advanced renal-cell carcinoma (RCC) in addition to the 
safety and tolerability under routine conditions of daily 
clinical practice. 
Primary objective: 
• To determine overall survival (OS) rate at 12 months 
after the index date (baseline visit) 
Secondary objectives: 
• To determine OS rate at 24 months after the index date 
• To assess duration of OS 
• To evaluate objective response rate (ORR) and disease 
control rate (DCR) up to 24 months after the index date 
• To assess duration of response (DoR) 
• To assess duration of progression-free survival (PFS) 
on Avelumab plus Axitinib therapy and progression-

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free survival 2 (PFS2) on Avelumab plus Axitinib 
therapy followed by the second-line treatment 
• To assess health-related quality of life (HRQoL) using 
the 
National 
Comprehensive 
Cancer 
Network/Functional Assessment of Cancer Therapy-
Kidney Symptom Index 19 (NCCN-FACT FKSI-19) 
at the index date and at every third cycle of Avelumab 
treatment (intervals of about 6 weeks) thereafter, until 
the end of treatment or end of 24 months of study 
follow-up period, whichever occurs first 
• To analyze the nature, severity, duration, frequency, 
and timing of adverse events (AEs) that occurred from 
the index date up to 90 days post discontinuation of 
Avelumab plus Axitinib or completion of the 24 
months (i.e., end of the study) follow-up from the index 
date, whichever occurs first 
• To assess time to therapy discontinuation due to AE 
≥ Grade 3 
• To assess therapy modifications due to AE related to 
Avelumab plus Axitinib therapy and management of 
AE related to Avelumab plus Axitinib therapy 
• To determine percentage of patients receiving later-
line therapy and frequency distribution of later-line 
therapy regimes among patients progressing on 
Avelumab plus Axitinib 
• To assess time to second-line therapy initiation 
• To assess patient-reported potential signs and 
symptoms of immune-related AEs 
 
Countries of Study 
European countries 
 
Author 
 
 
 
 
 
 
 
 
 
 
 

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- Confidential – 
This document is the property of Merck KGaA, Darmstadt, Germany, or one of its subsidiaries. It is intended for 
restricted use only and may not – in full or part – be passed on, reproduced, published or used without express 
permission of Merck KGaA, Darmstadt, Germany, or its subsidiary. Copyright © 2023 by Merck KGaA, Darmstadt, 
Germany, or its subsidiary. All rights reserved. 

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1 
Table of Contents 
1 
Table of Contents ..................................................................................4 
2 
List of Abbreviations ............................................................................6 
3 
Responsible Parties ...............................................................................8 
3.1 
Responsibilities of the Investigator ......................................................9 
4 
Abstract ...............................................................................................10 
5 
Amendments and Updates ..................................................................17 
6 
Milestones ...........................................................................................20 
7 
Rationale and Background ..................................................................21 
8 
Research Question and Objectives .....................................................23 
8.1 
Primary Objective ...............................................................................23 
8.2 
Secondary Objectives .........................................................................23 
9 
Research Methods ...............................................................................24 
9.1 
Study Design .......................................................................................24 
9.1.1 
Design Overview ................................................................................24 
9.1.2 
Outcomes ............................................................................................25 
9.2 
Setting .................................................................................................27 
9.2.1 
Study Population .................................................................................27 
9.2.2 
Definition of Study Cohorts and Description of Treatments ..............28 
9.2.3 
Observation Period .............................................................................28 
9.2.4 
Frequency of Assessments ..................................................................28 
9.2.5 
Withdrawal from the Study ................................................................30 
9.3 
Variables .............................................................................................30 
9.4 
Data Source .........................................................................................30 
9.5 
Study Size ...........................................................................................31 
9.6 
Data Management ...............................................................................31 
9.7 
Data Analysis ......................................................................................31 
9.7.1 
Analysis Sets .......................................................................................32 
9.7.2 
Derived and Transformed Data ..........................................................32 
9.7.3 
Statistical Methods ..............................................................................33 
9.7.4 
Sequence of Analyses .........................................................................36 
9.8 
Quality Control ...................................................................................36 

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9.9 
Limitations of the Research Methods .................................................36 
9.10 
Other Aspects ......................................................................................37 
9.10.1 
Independent Ethics Committee or Institutional Review Board ..........37 
9.10.2 
Monitoring ..........................................................................................37 
9.10.3 
Health Authorities ...............................................................................38 
9.10.4 
Quality Assurance ...............................................................................38 
9.10.5 
Archiving ............................................................................................38 
10 
Protection of Human Subjects ............................................................38 
10.1 
Subject Information and Informed Consent .......................................38 
10.2 
Subject Identification and Privacy ......................................................39 
11 
Management and Reporting of Adverse Events .................................39 
11.1 
Adverse Events ...................................................................................39 
11.2 
Severity of Adverse Events ................................................................41 
11.3 
Causality Assessment .........................................................................42 
11.4 
Collection and Recording of Adverse Events .....................................42 
11.5 
Safety Data Reporting .........................................................................43 
11.6 
Regulatory Submission to the Health Authorities ..............................46 
12 
Plans for Disseminating and Communicating Study Results .............46 
12.1 
Study Report .......................................................................................46 
12.2 
Publication ..........................................................................................46 
13 
References ...........................................................................................47 
14 
Appendices .........................................................................................49 
14.1 
Signature Pages and Responsible Persons for the Study ....................50 
Signature Page – Protocol Lead .........................................................................................51 
Signature Page – Coordinating Investigator ......................................................................52 
Signature Page – Principal Investigator .............................................................................53 
Sponsor Responsible Persons Not Named on the Cover Page ..........................................54 
 
 
 

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2 
List of Abbreviations 
 
ADL 
activities of daily living 
AE 
adverse event 
AR 
adverse reaction 
ATC 
anatomical therapeutic chemical 
CI 
confidence interval 
CR 
complete response 
CTCAE 
common terminology criteria for adverse events 
DCR 
disease control rate 
DoR 
duration of response  
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form  
EDC 
electronic data capture 
EMA 
European Medicines Agency 
ePRO 
electronic patient-reported outcomes 
FWB 
functional and well-being 
GPP 
good pharmaco-epidemiology practices 
GPS 
Global Patient Safety   
HA 
Health Authorities 
HR 
hazard ratio 
HRQoL 
health-related quality of life  
IAP 
Integrated Analysis Plan 
ICF 
informed consent form 
IEC 
independent ethics committee 
IMDC 
International Metastatic RCC Database Consortium 
IME 
important medical event 
IRB 
institutional review board 
KPS 
Karnofsky performance status 
MedDRA 
medical dictionary for regulatory activities 
MSKCC 
Memorial Sloan–Kettering Cancer Center 
NCCN-FACT 
FKSI-19 
National Comprehensive Cancer Network/Functional Assessment of 
Cancer Therapy-Kidney Symptom Index 19  
NCI-CTCAE 
National Cancer Institute - Common Terminology Criteria for Adverse 
Events 
ORR 
objective response rate 
OS 
overall survival 
PD 
progressive disease 
PD1 
programmed cell death protein 1 

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PD-L1 
programmed death ligand 1 
PFS 
progression-free survival  
PFS2 
progression-free survival 2  
PR 
partial response 
PT 
preferred term  
RCC 
renal-cell carcinoma 
RECIST 
Response Evaluation Criteria in Solid Tumours 
SAE 
serious adverse event 
SAR 
serious adverse reaction 
SAS 
statistical analysis system 
SD 
stable disease 
SmPC 
summary of product characteristics 
SOC 
system organ class 
TNM 
tumor, node, metastasis 
TRAE 
treatment-related adverse events 
VEGF 
vascular endothelial growth factor 
WHO-DD 
World Health Organization Drug Dictionary 

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3 
Responsible Parties 
 
Responsible Parties 
 
Contact Details 
Coordinating Investigator 
 
 
 
 
  
 
 

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3.1 
Responsibilities of the Investigator 
The investigator is responsible for the conduct of the study at his/her site. He/she will ensure that 
the study is performed in accordance with the protocol and will ensure the quality and integrity of 
data, following all applicable international and national guidelines. 
This non-interventional study will not interfere with treatment prescription by investigators. 
Accordingly, the investigator will decide in advance the best therapeutic strategy for each patient 
according to current practice, regardless of the potential participation of this patient in the study. 
Subsequently, if the prescribed treatment is in line with the study protocol, the investigator will 
consider the possibility of including the patient in the study. 
The investigator is responsible for recording of all adverse events (AEs) and reporting of adverse 
reactions (ARs) and/or laboratory abnormalities, as specified in Section 11. 
 

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4 
Abstract 
Title 
Real-world evaluation of efficacy and safety with AVelumab 
(BAVENCIO®) + Axitinib (INLYTA®) in patients with Advanced Renal-
Cell CarcinOma (RCC) in multiple EU couNtries  
 
AVION 
 
24 April 2023 / Version 4.0 
 
 
 
Rationale and 
Background 
Approval of Avelumab plus Axitinib and other combined therapies by 
European Medicines Agency (EMA) in 2019 triggered a paradigm shift in 
the management of treatment-naïve patients with advanced renal-cell 
carcinoma (RCC). However, available data for Avelumab plus Axitinib 
therapy in advanced RCC are derived primarily from clinical development 
programs and thus, these data may not reflect the current clinical practice. 
Particularly, the extent of benefit in terms of improved clinical and patient-
reported outcomes, therapy tolerability, and management of toxicities in 
patients with advanced RCC treated with Avelumab plus Axitinib therapy 
under routine clinical conditions remain unknown. There is an urgent need 
to address this knowledge gap. 
Research Question 
and Objectives 
The aim of this study is to expand knowledge on the effectiveness of 
Avelumab 800 mg intravenous infusion flat-dose treatment in combination 
with Axitinib 5 mg orally twice per day as the first-line therapy in patients 
with advanced RCC in addition to the safety and tolerability under routine 
conditions of daily clinical practice. 
Primary objective: 
• To determine overall survival (OS) rate at 12 months after the index 
date (baseline visit) 
Secondary objectives: 
• To determine OS rate at 24 months after the index date 
• To assess duration of OS 
• To evaluate objective response rate (ORR) and disease control rate 
(DCR) up to 24 months after the index date  
• To assess duration of response (DoR) 
• To assess duration of progression-free survival (PFS) on Avelumab 
plus Axitinib therapy and progression-free survival 2 (PFS2) on 
Avelumab plus Axitinib therapy followed by the second-line treatment 

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• To assess health-related quality of life (HRQoL) using the National 
Comprehensive Cancer Network/Functional Assessment of Cancer 
Therapy-Kidney Symptom Index 19 (NCCN-FACT FKSI-19) at the 
index date and at every third cycle of Avelumab treatment (intervals of 
about 6 weeks) thereafter, until the end of treatment or end of 24 months 
of study follow-up period, whichever occurs first 
• To analyze the nature, severity, duration, frequency, and timing of 
adverse events (AEs) that occurred from the index date up to 90 days 
post discontinuation of Avelumab plus Axitinib or completion of the 
24 months (i.e., end of the study) follow-up from the index date, 
whichever occurs first 
• To assess time to therapy discontinuation due to AE ≥ Grade 3 
• To assess therapy modifications due to AE related to Avelumab plus 
Axitinib therapy and management of AE related to Avelumab plus 
Axitinib therapy 
• To determine percentage of patients receiving later-line therapy and 
frequency distribution of later-line therapy regimes among patients 
progressing on Avelumab plus Axitinib 
• To assess time to second-line therapy initiation 
• To assess patient-reported potential signs and symptoms of immune-
related AEs 
Study Design 
This study is a prospective, international, single-arm, observational real-
world study in patients with advanced RCC. This multicenter study will be 
conducted in various European countries. Patients, who are currently 
receiving Avelumab (800 mg intravenously every 2 weeks) plus Axitinib 
(5 mg orally twice per day) in accordance with the terms of the marketing 
authorization for the first-line therapy, will be selected. Patient assignment 
to Avelumab plus Axitinib therapy should be decided in advance by the 
treating physician and fall within current clinical practice prior to study 
enrollment.  
The index date (baseline visit) is defined as the first administration date, 
after informed consent, of Avelumab plus Axitinib therapy to patients with 
advanced RCC. Patients will be recruited over a period of approximately 
24 months and will be followed up for 24 months from the index date, 
irrespective of whether they continue or discontinue the study treatment. 
Study visits will be scheduled according to routine clinical practice in terms 
of visit frequency and types of performed treatments and assessments.  
Population 
Inclusion criteria: 
• Adult patient, age ≥ 18 years 

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• Patient with the Eastern Cooperative Oncology Group (ECOG) 
performance status 0, 1, or 2  
• Patient with a histologically confirmed diagnosis of RCC with any 
histological origin  
• Patient with a locally advanced/metastatic disease (i.e., newly 
diagnosed Stage IV RCC per American Joint Committee on Cancer) or 
has recurrent disease 
• Patient has received 1 or 2 cycles of Avelumab plus Axitinib treatment 
as a first-line therapy according to the approved Summary of Product 
Characteristics (SmPC)  
• Patient willing to sign the written informed consent form (ICF) to 
participate in this study 
Exclusion criteria: 
• Patient with contraindications for Avelumab or Axitinib according to 
the approved SmPC 
• Patient who has participated in any interventional clinical trial of a drug 
or device within 28 days prior to the start of Avelumab plus Axitinib 
Outcomes 
Primary outcome: 
• OS rate at 12 months after the index date 
• Percentage of patients who are still alive at 12 months after the index 
date 
Key secondary outcomes: 
• OS rate at 24 months after the index date 
• Percentage of patients who are still alive at 24 months after the index 
date 
• OS 
• Time interval from the index date to the date of death from any cause 
• ORR up to 24 months after the index date 
• Percentage of patients with complete response (CR) or partial 
response (PR), as best overall response up to 24 months after the 
index date according to the investigator assessment 
• DCR up to 24 months after the index date 
• Percentage of patients with CR, PR, or stable disease (SD), as best 
overall response up to 24 months after the index date according to the 
investigator assessment 

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• DoR 
• DoR is defined as the time from the first CR or PR criteria met, 
whichever was reported earlier, until the date of documented overall 
disease progression 
• PFS 
• Time interval from the index date to the date of disease progression 
or death from any cause, whichever comes first 
• PFS2  
• Time interval from the index date to the date of disease progression 
on second-line treatment or death from any cause, whichever comes 
first 
• HRQoL using the NCCN-FACT FKSI-19 at the index date and at every 
third cycle of Avelumab treatment (intervals of about 6 weeks) 
thereafter until the end of treatment or end of 24 months of study 
follow-up period, whichever occurs first 
• Frequency and nature of all-cause AEs according to Medical Dictionary 
for Regulatory Activities (MedDRA) system organ class (SOC) and 
preferred term (PT) that occurred from the index date up to 90 days post 
discontinuation of Avelumab plus Axitinib or completion of the 
24 months (i.e., end of the study) follow-up from the index date, 
whichever occurs first 
• Duration of Avelumab plus Axitinib therapy among patients who 
discontinued the study drugs due to all-cause AEs ≥ Grade 3 
• Percentage of patients with therapy modifications due to AE related to 
Avelumab plus Axitinib therapy  
• Frequency and type of medical intervention or medications used for the 
management of AE related to Avelumab plus Axitinib therapy  
• Percentage of patients receiving later-line therapy and frequency 
distribution of later-line therapy regimes among patients progressing on 
Avelumab plus Axitinib including the names of medications of 
monotherapy/combination treatment used in second-line and third-line 
therapy 
• Time to second-line therapy initiation  
• Frequency of patient-reported potential signs and symptoms of 
immune-related AEs 
Variables 
In addition to the outcomes data, data will be collected on: 
• Patient demographics (year of birth, gender) 
• Physical examination and vital signs 

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• Body weight 
• Concomitant diseases (e.g., autoimmune disease, cardiovascular 
disease, hypertension, renal failure, and liver disease) 
• Concomitant medications including the use of corticosteroids, 
anticoagulants, and antibiotics 
• Cancer history (age at diagnosis, tumor, node, metastasis (TNM) stage, 
location of metastases, received nephrectomy, other prior cancer 
therapies and procedures, and expression of the programmed death 
ligand 1 [PD-L1])  
• ECOG performance status 
• Memorial Sloan–Kettering Cancer Center (MSKCC) risk group 
• International Metastatic RCC Database Consortium (IMDC) risk group 
Data Sources 
Medical records collected during routine clinical care will be used as data 
source. Data relevant for the study (baseline and prospective data) will be 
documented in the electronic case report form (eCRF) by the investigator 
or designated study site personnel. Patient-reported HRQoL data will be 
automatically captured by eCRF from electronic patient-reported outcomes 
(ePRO). 
In exceptional 
cases, 
when paper questionnaires for 
patient-reported HRQoL data will be completed, those signed and dated 
paper questionnaires will be considered as source documents. 
Study Size 
 
 
 
 
 
 
 
In total, approximately 100 patients will be selected from approximately 30 
sites in different European countries. 
Data Analysis 
All eligible patients, who provided written informed consent and received 
1 or 2 cycles of Avelumab plus Axitinib treatment as a first-line therapy 
prior to informed consent, will be included in the analysis. All planned 
analyses will be descriptive, no formal statistical comparisons will be 
performed. 
Primary analysis:  
• OS rate (percentage of patients who are alive) at 12 months after the 
index date with the 95% CI 
Secondary analysis: 

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• OS rate (percentage of patients who are alive) at 24 months after the 
index date with the 95% CI 
• OS will be estimated by the Kaplan-Meier method 
• Summary of absolute and relative frequencies of ORR and DCR up to 
24 months after the index date together with the 95% CI 
• DoR, PFS, and PFS2 at 24 months after the index date will be estimated 
by the Kaplan-Meier method 
• There will be subgroup analyses for the primary outcome and selected 
secondary outcomes (OS, PFS, and PFS2 at 24 months and DCR up to 
24 months) based on: 
• ECOG performance status/IMDC risk group/MSKCC risk group 
• RCC histopathology (clear cell, sarcomatoid, others) 
• PD-L1 (±) status 
• Age group (< 65, 65-75, and > 75 years) 
• Concomitant autoimmune disease (yes, no) 
• Prior nephrectomy (yes, no) 
• No interim analyses are planned, but the primary outcome will be 
analyzed as soon as all evaluable patients complete 12 months of 
follow-up from the index date 
• The scores (total and subscales) of the HRQoL at the index date and at 
every third cycle of Avelumab treatment (intervals of about 6 weeks) 
will be summarized using descriptive statistics for continuous 
variables. Possible trend in HRQoL will be also analyzed by repeated 
measure analysis 
• Safety analysis will be performed on AEs incidence tables, presented 
by MedDRA SOC and PT, and the number and percentage of patients 
experiencing an event 
• Exposure among the patients who discontinued the study drug due to 
all-cause AEs ≥ Grade 3 will be summarized as per appropriate 
statistics 
• Percentage of patients with therapy modifications due to related AEs 
and frequency and type of medical intervention or medications used for 
the management of related AE will be presented 
• Time to onset and duration of AEs, time to Avelumab plus Axitinib 
discontinuation, and time to second-line therapy after study treatment 
discontinuation will be summarized by descriptive statistics for 
continuous variables 

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• Percentage of patients receiving later-line therapy (e.g., second-line 
therapy, third-line therapy) and frequency distribution of later-line 
therapy regimes among patients progressing on Avelumab plus 
Axitinib will be presented 
Milestones 
 
Start of data collection: July 2021 
Primary analysis: September 2024 
End of data collection: May 2025 
Final report of study results: August 2025 

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5 
Amendments and Updates 
Amendment # 1: 13 May 2022  
Sections modified 
Updates 
Reason(s) 
Throughout 
Protocol Lead: 
 
 
1. Administrative 
Cover Page 
Sponsor’s address was updated 
1. Administrative 
Throughout 
Time point to evaluate objective 
response rate (ORR) and disease 
control rate (DCR) was updated from 
‘at 24 months’ to ‘up to 24 months’. 
1. To remain consistent with 
the respective description in 
the IAP. 
Abstract – ‘Data 
Sources’ section 
 
9.4 Data Source 
Clarification 
regarding 
paper 
questionnaires 
for 
patient-reported 
HRQoL data as source documents was 
provided. 
1. To provide clarity on source 
documents pertaining to 
paper questionnaires when 
used. 
9.2.4 Frequency 
of Assessments 
Clarification 
regarding 
paper 
questionnaires 
for 
patient-reported 
HRQoL data was provided. 
1. To provide clarity on use of 
paper questionnaires in 
addition to ePRO. 
9.7 Data Analysis 
Integrated 
Analysis 
Plan 
(IAP) 
replaced Statistical Analysis Plan 
(SAP) 
1. Change in document name. 
Abstract – ‘Data 
Analysis’ section 
 
9.7.1 Analysis 
Sets 
Definition for the eligible patients for 
the analysis was updated. 
1. To remain consistent with 
the definition of the eligible 
patients mentioned in the 
IAP. 
11.4 Recording of 
Adverse Events 
All SARs/ARs due to Avelumab as 
well as Axitinib will be collected in the 
study database. 
1. To provide more clarity on 
recording of SARs/ARs due 
to Avelumab as well as 
Axitinib. 
11.5 Safety Data 
Collection for 
Reporting 
AE/SAE Observed in Association 
with Disease Progression 
Progression of the disease / disorder 
being studied assessed by measurement 
of lesions on radiographs or other 
methods as well as associated clinical 
signs 
or 
symptoms 
(including 
laboratory abnormalities) does not 
need to be reported as an (S)AE, unless 
the subject´s general condition is more 
severe than expected for the subject´s 
condition and / or unless the outcome is 
fatal within the AE reporting period, as 
defined in Section 11.4. 
1. To provide more clarity on 
AE/SAE observed in 
association with disease 
progression. 

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11.6 Regulatory 
Reporting to the 
Health 
Authorities 
Merck, as the marketing authorization 
holder of Avelumab, is only required to 
report SARs/ARs due to Avelumab to 
the Health Authorities. 
1. To provide more clarity on 
reporting of SARs/ARs due 
to Avelumab to the Health 
Authorities. 
14.1 Signature 
Pages and 
Responsible 
Persons for the 
Study 
Sponsor Responsible Persons Not 
Named on the Cover Page 
Function/title, Institution, and Address 
were updated. 
1. Administrative 
 
Amendment # 2: 21 December 2022 
Sections modified 
Updates 
Reason(s) 
Section 4; 
Section 9.1.1; 
Section 9.5; 
Figure 1 
Reduction of sample size from 400 to 
250 
1. Due to the change of 
disease landscape there is 
low probability that the 
study will be able to enroll 
400 patients within the 
study period. 
2. Investigators indicated that 
they will not be able to 
recruit the target number.  
3. Multiple closure of multiple 
sites, including several sites 
in Russia, exacerbates 
likelihood to recruit original 
target sample size. 
Section 4; 
Section 9.5 
Updated precision estimate 
1. Due to sample size 
reduction precision was 
recalculated 
Throughout the 
document 
Clarification on the wording for the 
frequency of visits 
1. The wording in current 
protocol version is not clear, 
thus the wording is updated 
to avoid misunderstanding 
and to align with the 
Clinical Trial Agreement 
(CTA) and real-world 
practice. 
Section 4;  
Section 9.1.1 
Clarification on the wording for the 
duration of recruitment period 
1. Planned recruitment should 
end March 2025, however, 
as the recruitment is 
competitive it may end 
sooner once 250 patients are 
enrolled 

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Throughout the 
document 
The version number and date were 
updated 
1. Changes in protocol as 
outlined above required 
protocol amendment 
Section 4; Section 
6 
Planned dates updated. 
1. Related to the potential 
reduction of the recruitment 
period. Last Patient In 
changed so Last Patient Out 
changed as well impacting 
dates for milestones. 
Section 11.4;  
Section 11.5;  
Section 11.6 
Collection and reporting of AEs and 
ARs depending on their relation to 
each product were clearly defined 
1. All AE should be collected 
into Study Database, 
whereas only AR (serious 
and non-serious) related to 
Avelumab should be 
reported to Merck for entry 
into Safety Database and 
for regulatory reporting. 
2. The only SAR/AR related 
to Axitinib that need 
reporting to Merck are 
those that are also related to 
Avelumab. 
 
Amendment # 3: 24 April 2023 
Sections modified 
Updates 
Reason(s) 
Section 4 ; 
Section 9.1.1; 
Section 9.5; 
Figure 1 
Reduction of sample size from 250 to 
100 and updated precision estimate 
1. Due to the change of 
disease landscape there is 
low probability that the 
study will be able to enroll 
250 patients within the 
study period. 
2. Investigators indicated that 
they will not be able to 
recruit the target number.  
3. Multiple closure of multiple 
sites, including several sites 
in Russia, increases 
likelihood that the original 
target sample size cannot be 
reached. 
 
 
 
 
 
 

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Abstract – 
‘Milestones’ 
Planned dates updated. 
1. Recruitment period was 
reduced due to sample size 
reduction, impacting 
subsequent dates for 
milestones.  
1.1 
Collection 
and Recording of 
Adverse Events ; 
11.5 Safety Data 
Reporting; 
11.6 Regulatory 
Submission to the 
Health 
Authorities; 
Safety and regulatory submission 
updated 
1. There is a newly approved 
safety section for 
non-interventional study 
protocol, as a result these 
sections were updated to 
align with the new safety 
section.  
2. Direct transmission of 
non-serious adverse reaction 
to Global Patient Safety 
clarified.  
6 
Milestones 
 
Milestone 
Planned date 
Start of data collection  
July 2021 
Primary analysis 
September 2024 
End of data collection  
May 2025 
Final report of study results  
August 2025 
 

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7 
Rationale and Background 
Kidney cancer, including renal-cell carcinoma (RCC) accounts for 3.5% of all new cancer cases 
and for 2.8% of all cancer deaths in Europe (Ferlay 2018). RCC represents approximately 90% of 
all kidney malignancies, affecting men more frequently than women (Ferlay 2018, 
Ljungberg 2019). Since the early stage of RCC is often asymptomatic, most patients are diagnosed 
at an advanced stage of the disease when prognosis is poor. 
Tyrosine kinase inhibitors, immune checkpoint inhibitors, and immunotherapy are the mainstay 
treatments in advanced and metastatic RCC. Until recently, Sunitinib, an inhibitor of vascular 
endothelial growth factor (VEGF) receptor, was a standard-of-care, first-line treatment for patients 
with advanced RCC. However, in the last years, several phase III trials demonstrated superior 
efficacy of combined therapies involving immune checkpoint inhibitors over Sunitinib 
monotherapy. 
The CheckMate 214 study (NCT02231749) showed that therapy with Nivolumab (anti-
programmed cell death protein 1 [PD1] antibody) and Ipilimumab (anti-cytotoxic T-lymphocyte–
associated antigen 4 [CTLA4] antibody) resulted in a longer median progression-free survival 
(PFS) (11.6 months, 95% confidence interval [CI]: 8.7-15.5) compared with Sunitinib (8.4 months, 
95% CI: 7.0-10.8). The hazard ratio (HR) for disease progression or death was 0.82 (99.1% CI: 
0.64-1.05; p = 0.03). The objective response rate (ORR) was 42% (95% CI: 37%-47%) with 
Nivolumab plus Ipilimumab vs 27% (95% CI: 22%-31%) with Sunitinib (p < 0.001). The median 
overall survival (OS) was not reached in Nivolumab plus Ipilimumab group (95% CI: 28.2 to not 
estimable) vs 26.0 months (95% CI: 22.1 to not estimable) in Sunitinib group (HR for death, 0.63, 
p < 0.001) (Motzer 2018). 
Similarly, in the KEYNOTE-426 study (NCT02853331), Pembrolizumab (anti-PD1 antibody) 
combined with Axitinib (VEGF receptor inhibitor) increased median PFS to 15.1 months (95% 
CI: 12.6-17.7) compared to 11.1 months (95% CI: 8.7-12.5) in the Sunitinib group. The HR for 
disease progression or death was 0.69 (95% CI: 0.57-0.84; p < 0.001). The ORR was 59.3% (95% 
CI: 54.5%-63.9%) in the Pembrolizumab plus Axitinib arm and 35.7% (95% CI: 31.1%-40.4%) in 
the Sunitinib arm (p < 0.001). The OS rate at 1 year in the Pembrolizumab plus Axitinib group 
was 89.9% vs 78.3% in the Sunitinib group (HR: 0.53, 95% CI: 0.38-0.74; p < 0.0001) 
(Rini 2019a). 
The JAVELIN Renal 101 study (NCT02684006) evaluated the combination Avelumab (anti-
programmed death ligand 1 [PD-L1] antibody) and Axitinib (VEGF receptor inhibitor). In the 
overall population, patients receiving Avelumab plus Axitinib achieved longer median PFS (13.8 
months, 95% CI: 11.1 to not estimable) than those treated with Sunitinib (8.4 months, 95% CI: 
6.9-11.1). The HR for disease progression or death was 0.69 (95% CI: 0.56-0.84; p < 0.001). 
Furthermore, Avelumab plus Axitinib therapy increased ORR to 51.4% (95% CI: 46.6%-56.1%) 
compared to 25.7% (95% CI: 21.7%-30.0%) with Sunitinib therapy. Among the patients with 
PD-L1-positive tumors, PFS and ORR were similar to those observed in the overall population. 
The OS data were immature at the time of that analysis (Motzer 2019). 

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The updated efficacy data from the JAVELIN Renal 101 study (NCT02684006) showed that after 
a follow-up of 13 months, PFS was significantly longer in the Avelumab plus Axitinib arm than 
in the Sunitinib arm as follow: (i) PD-L1+ population – HR: 0.62, 95% CI: 0.490-0.777, one-sided 
p < 0.0001, median: 13.8 months, 95% CI: 10.1-20.7 versus 7.0 months, 95% CI: 5.7-9.6; and (ii) 
overall population – HR: 0.69, 95% CI: 0.574-0.825, one-sided p < 0.0001, median: 13.3 months, 
95% CI: 11.1-15.3 versus 8.0 months, 95% CI: 6.7-9.8. The OS data were immature: (i) PD-L1+ 
population – HR: 0.828, 95% CI: 0.596-1.151, one-sided p = 0.1301; and (ii) overall population – 
HR: 0.796, 95% CI: 0.616-1.027, one-sided p = 0.0392 (Choueiri 2020). 
Importantly, these clinical trials demonstrated that increased efficacy offered by these treatments 
was paralleled by acceptable safety profile. Treatment-related adverse events (TRAEs) ≥ Grade 3 
occurred in 46% of patients treated with Nivolumab plus Ipilimumab, 62.9% of patients treated 
with Pembrolizumab plus Axitinib and in 56.7% of patients treated with Avelumab plus Axitinib 
compared to 55.4% to 63.0% of patients receiving Sunitinib. TRAEs ≥ Grade 3 occurred in ≥ 10% 
of patients were increased lipase levels among patients receiving Nivolumab plus Ipilimumab 
(10.0%), hypertension, and increased alanine aminotransferase levels in patients treated with 
Pembrolizumab plus Axitinib (22.1% and 13.3%, respectively), and hypertension in patients 
treated with Avelumab plus Axitinib (25.6%). Death due to toxicity of trial treatment was 
documented in 1.5% of patients treated with Nivolumab plus Ipilimumab, 0.9% of patients 
receiving Pembrolizumab plus Axitinib and 0.7% of patients treated with Avelumab plus Axitinib. 
About 22%, 10.7%, and 7.6% of patients treated with Nivolumab plus Ipilimumab, 
Pembrolizumab plus Axitinib, and Avelumab plus Axitinib, respectively, discontinued both study 
drugs due to TRAEs (Rini 2019b). 
Furthermore, therapy modifications were frequent across the studies. For instance, delays in 
administration of Nivolumab and Ipilimumab occurred in 58% and 27% of patients, respectively 
(Motzer 2018), while 69.9% of patients had interruption of either Pembrolizumab or Axitinib 
(Rini 2019a). Axitinib dose was reduced in 20.3% of patients co-treated with Pembrolizumab and 
in 42.2% of patients co-treated with Avelumab (Rini 2019a, Motzer 2019). High doses of 
glucocorticoids for management of immune-related adverse events (AEs) were required by 35% 
of patients on Nivolumab plus Ipilimumab and only by 11.1% of patients on Avelumab plus 
Axitinib therapy (Motzer 2018, Motzer 2019). Among patients treated with Avelumab plus 
Axitinib, 38.2% had any grade pre-specified immune-related AEs, which were most frequently 
immune-related thyroid disorders (24.7% of patients) (Motzer 2019). In 9.0% of patients, these 
immune-related AEs were of ≥ Grade 3 (Motzer 2019). 
Safety of Avelumab plus Axitinib was also investigated in an open-label, dose-finding phase 1b 
study JAVELIN Renal 100 (NCT02493751). About 58% of enrolled treatment-naïve advanced 
RCC patients experienced ≥ Grade 3 TRAEs, which were most frequently hypertension (29.0%) 
and increased concentrations of alanine aminotransferase, amylase, and lipase, and palmar-plantar 
erythrodysesthesia syndrome in 7.0% of patients each. About 2.0% of patients died due to 
treatment-related autoimmune myocarditis (Choueiri 2018). 
In general, the safety profile of combined Avelumab plus Axitinib therapy is in line with that of 
single agents. Recently, phase 1 JAVELIN Solid Tumor study (NCT01772004) provided further 
safety data for first-line Avelumab monotherapy in metastatic RCC. In this study, 12.9% of 

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patients had a ≥ Grade 3 TRAE, which was most frequently increased lipase levels 
(Vaishampayan 2019). About 3.2% of patients had serious TRAEs (colitis and hyperthermia). 
TRAEs led to drug discontinuation in 4.8% of patients (anaphylactic reaction, aspartate 
aminotransferase increase, and nephritis). Infusion-related reactions occurred in 35.5% of patients 
and 29.0% had immune-related AEs with thyroid disorders and immune-related rash documented 
in ≥ 10.0% of patients. Axitinib was compared against Sorafenib in phase III study in previously 
untreated metastatic RCC patients. Most frequent all-cause AEs ≥ Grade 3 in Axitinib arm were 
hypertension, asthenia, diarrhea, weight decrease, palmar-plantar erythrodysesthesia, and fatigue 
(Hutson 2013). About 5.0% of patients had serious TRAEs, including diarrhea, atrial flutter, 
cardiac arrest, myocardial infarction, gastric ulcer, gastrointestinal hemorrhage, melena, nausea, 
rectal hemorrhage, vomiting, retroperitoneal hematoma, asthenia, mucosal inflammation, 
dehydration, decreased appetite, aortoduodenal fistula, and hypertensive crisis. Compared to other 
VEGF receptor inhibitors, Axitinib causes less hepatic and hematologic toxicity and thus, it is 
considered a better partner for combined treatments with other anti-cancer agents such as 
Avelumab. 
Approval of Avelumab plus Axitinib and other combined therapies by the European Medicines 
Agency (EMA) in 2019 triggered a paradigm shift in the management of treatment-naïve patients 
with advanced RCC (BAVENCIO® Summary of Product Characteristics (SmPC), KEYTRUDA® 
SmPC, OPDIVO® SmPC). Nevertheless, available data for Avelumab plus Axitinib therapy in 
patients with advanced RCC are derived primarily from clinical development programs and thus, 
they may not fully reflect the current clinical practice. Particularly, the extent of benefit in terms 
of improved clinical and patient-reported outcomes, therapy tolerability, and management of 
toxicities in patients with advanced RCC treated with Avelumab plus Axitinib under routine 
clinical conditions remain unknown. Therefore, evidence on the real-world efficacy (i.e., 
effectiveness) and safety of Avelumab in combination with Axitinib therapy in advanced RCC is 
urgently needed to address this knowledge gap and can help bolster the value of using Avelumab 
plus Axitinib in first-line therapy in patients with advanced RCC. 
8 
Research Question and Objectives 
The aim of this study is to expand knowledge on the effectiveness of Avelumab 800 mg 
intravenous infusion flat-dose treatment in combination with Axitinib 5 mg orally twice per day 
as the first-line therapy in patients with advanced RCC in addition to safety and tolerability under 
routine conditions of daily clinical practice. 
8.1 
Primary Objective 
• To determine OS rate at 12 months after the index date (baseline visit) 
8.2 
Secondary Objectives 
• To determine OS rate at 24 months after the index date 
• To assess duration of OS 
• To evaluate ORR and disease control rate (DCR) up to 24 months after the index date 
• To assess duration of response (DoR) 

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• To assess duration of PFS on Avelumab plus Axitinib therapy and progression-free survival 2 
(PFS2) on Avelumab plus Axitinib therapy followed by the second-line treatment 
• To assess the health-related quality of life (HRQoL) using the National Comprehensive Cancer 
Network/Functional Assessment of Cancer Therapy-Kidney Symptom Index 19 (NCCN-
FACT FKSI-19) at the index date and at every third cycle of Avelumab treatment (intervals of 
about 6 weeks) thereafter, until the end of treatment or end of 24 months of study follow-up 
period, whichever occurs first 
• To analyze the nature, severity, duration, frequency, and timing of AEs that occurred from the 
index date up to 90 days post discontinuation of Avelumab plus Axitinib or completion of the 
24 months (i.e., end of the study) follow-up from the index date, whichever occurs first 
• To assess time to therapy discontinuation due to AE ≥ Grade 3 
• To assess therapy modifications due to AE related to Avelumab plus Axitinib therapy and 
management of AE related to Avelumab plus Axitinib therapy 
• To determine percentage of patients receiving later-line therapy and frequency distribution of 
later-line therapy regimes among patients progressing on Avelumab plus Axitinib 
• To assess time to second-line therapy initiation 
• To assess patient-reported potential signs and symptoms of immune-related AEs 
9 
Research Methods 
9.1 
Study Design 
9.1.1 
Design Overview 
This study is a prospective, international, single-arm, observational real-world study in patients 
with advanced RCC. This multicenter study will be conducted at approximately 30 centers in 
various European countries. A total of approximately 100 patients, who are currently receiving 
Avelumab (800 mg intravenously every 2 weeks) plus Axitinib (5 mg orally twice per day) in 
accordance with the terms of the marketing authorization for the first-line therapy, will be selected. 
Patient assignment to Avelumab plus Axitinib therapy should be decided in advance by the treating 
physician and fall within current clinical practice prior to study enrollment. There will not be any 
study-specific interventions in this study. The study size is further described in Section 9.5. 
The index date (baseline visit) is defined as the first administration date, after informed consent, 
of Avelumab plus Axitinib therapy to patients with advanced RCC. Patients will be recruited over 
a period of approximately 24 months and will be followed up for 24 months from the index date, 
irrespective of whether they continue or discontinue the study treatment. There will be a safety 
follow-up at 90 days post discontinuation of Avelumab plus Axitinib therapy. 
Study visits will be scheduled according to routine clinical practice in terms of visit frequency and 
types of performed treatments and assessments. Due to the observational nature of this study, 
planned assessments will be recorded as part of routine clinical practice, in line with the approved 
SmPC and as clinically indicated.  

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Figure 1 below provides a schematic overview of the study design. 
Figure 1 . Overview of the Study Design 
 
 
W=Week, HRQoL=Health-related quality of life, NCCN-FACT FKSI-19=National Comprehensive Cancer 
Network/Functional Assessment of Cancer Therapy-Kidney Symptom Index 19 
9.1.2 
Outcomes 
9.1.2.1 
Primary 
The primary effectiveness outcome is: 
• OS rate at 12 months after the index date 
• Percentage of patients who are still alive at 12 months after the index date 
9.1.2.2 
Secondary 
Secondary effectiveness outcomes:  
• OS rate at 24 months after the index date 
• Percentage of patients who are still alive at 24 months after the index date 
• OS 
• Time interval from the index date to the date of death from any cause 
• ORR up to 24 months after the index date 
• Percentage of patients with complete response (CR) or partial response (PR), as best overall 
response up to 24 months after the index date according to the investigator assessment 

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• DCR up to 24 months after the index date 
• Percentage of patients with CR, PR, or stable disease (SD), as best overall response up to 24 
months after the index date according to the investigator assessment 
• DoR 
• DoR is defined as the time from the first CR or PR criteria met, whichever was reported 
earlier, until the date of documented overall disease progression 
Note: CR, PR, SD, progressive disease (PD) will be defined as per Response Evaluation Criteria 
in Solid Tumours (RECIST) version 1.1 (Eisenhauer 2009) 
Progression-free survival: 
• PFS  
• Time interval from the index date to the date of disease progression or death from any cause, 
whichever comes first 
• PFS2 
• Time interval from the index date to the date of disease progression on second-line treatment 
or death from any cause, whichever comes first 
Patient-reported outcomes: 
• HRQoL using the NCCN-FACT FKSI-19 at the index date and at every third cycle of Avelumab 
treatment (intervals of about 6 weeks) thereafter until the end of treatment or end of 24 months 
of study follow-up, whichever occurs first 
• The NCCN-FACT FKSI-19 is a 19-item self-reported questionnaire that captures symptom 
severity and interference in activity and general health perceptions (Rothrock 2013, 
Rao 2009) 
• The NCCN-FACT FKSI-19 covers 4 subscales of the FKSI:  
1. DRS-P, disease-related symptoms subscale–physical 
2. DRS-E, disease-related symptoms subscale–emotional 
3. TSE, treatment side effects subscale 
4. Functional and well-being (FWB), function and well-being subscale (Rao 2009) 
• Each of the items is scored on a five-point scale from zero (not at all) to 4 (very much).  
Safety and tolerability: 
• Frequency and nature of all-cause AEs according to Medical Dictionary for Regulatory 
Activities (MedDRA) system organ class (SOC) and preferred term (PT) that occurred from the 
index date up to 90 days post discontinuation of Avelumab plus Axitinib or completion of the 
24 months (i.e., end of the study) follow-up from the index date, whichever occurs first 
• Frequency of all-cause AEs by maximum Common Terminology Criteria for Adverse Events 
(CTCAE) grade that occurred from the index date up to 90 days post discontinuation of 

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Avelumab plus Axitinib or completion of the 24 months (i.e., end of the study) follow-up from 
the index date, whichever occurs first 
• Frequency of all-cause AE ≥ Grade 3 leading to discontinuation of Avelumab plus Axitinib 
summarized by MedDRA SOC and PT 
• Duration of Avelumab plus Axitinib therapy among patients who discontinued the study drug 
due to all-cause AEs ≥ Grade 3 
• Time to onset of all-cause AEs defined as the time interval from the index date to the onset of 
AE  
• Duration of all-cause AEs defined as the time interval between the onset and resolution of AE 
• Outcome of all-cause AEs: resolved, resolving, not resolved, resolved with sequelae, fatal, 
unknown  
• Percentage of patients with therapy modifications due to AE related to Avelumab plus Axitinib 
therapy (e.g., therapy interruptions and reductions of infusion rate for Avelumab, therapy 
interruptions, and dose reductions for Axitinib) 
• Frequency and type of medical intervention or medications used for the management of AE 
related to Avelumab plus Axitinib therapy (e.g., use of corticosteroids, antihypertensive 
therapy, treatment for thyroid dysfunction, measures to decrease hemoglobin, and hematocrit) 
• Percentage of patients receiving later-line therapy and frequency distribution of later-line 
therapy regimes among patients progressing on Avelumab plus Axitinib including the names 
of medications of monotherapy/combination treatment used in second-line and third-line 
therapy 
• Time to second-line therapy initiation is defined as the time from Avelumab plus Axitinib 
therapy discontinuation to the initiation of second-line therapy 
• Frequency of patient-reported potential signs and symptoms of immune-related AEs (the 
investigator or the treating physician will explain signs and symptoms of potential 
immune-related AEs to patients; immune-related AEs may include immune-mediated 
pneumonitis, immune-mediated colitis, immune-mediated hepatitis, immune-mediated 
endocrinopathies, immune-mediated nephritis with renal dysfunction etc.) (BAVENCIO, 
SmPC) 
9.2 
Setting 
9.2.1 
Study Population 
The study population will be identified according to the below inclusion and exclusion criteria. 
For inclusion in the study, all of the following inclusion criteria must be fulfilled: 
1. Adult patient, age ≥ 18 years  
2. Patient with the Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 
2 (Oken 1982) 
3. Patient with a histologically confirmed diagnosis of RCC with any histological origin 

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4. Patient with a locally advanced/metastatic disease (i.e., newly diagnosed Stage IV RCC 
per American Joint Committee on Cancer) or has recurrent disease 
5. Patient has received 1 or 2 cycles of Avelumab plus Axitinib treatment as a first-line 
therapy according to the approved SmPC 
6. Patient willing to sign the written informed consent form (ICF) to participate in this study 
Patients are not eligible for this study if they fulfill any of the following exclusion criteria: 
1. Patient with contraindications for Avelumab or Axitinib according to the approved SmPC 
2. Patient who has participated in any interventional clinical trial of a drug or device within 
28 days prior to the start of Avelumab plus Axitinib 
9.2.2 
Definition of Study Cohorts and Description of Treatments 
This is a single cohort study enrolling patients with advanced RCC, who are currently receiving 
Avelumab plus Axitinib in accordance with the terms of the marketing authorization for the first-
line therapy. Patient assignment to Avelumab plus Axitinib therapy should have been decided in 
advance by the treating physician and fall within current clinical practice and prior to study 
enrollment. 
According to the approved SmPC, the recommended dose of Avelumab is 800 mg administered 
intravenously over 60 minutes every 2 weeks in combination with Axitinib 5 mg orally taken twice 
per day (12 hours apart) with or without food until disease progression or unacceptable toxicity. 
9.2.3 
Observation Period 
Each patient will be followed up from the date the ICF is signed until lost to follow-up, withdrawal 
of consent, death, or the end of the data collection period, whichever comes first. Patients will be 
followed up for 24 months from the index date, irrespective of whether they continue or 
discontinue the study treatment. 
9.2.4 
Frequency of Assessments 
The Table 1 provides the Schedule of Assessments for this study. Patients who sign the ICF and 
meet all eligibility criteria during the screening will be enrolled in this study. The baseline visit 
will be at the index date, which is defined as the first administration date, after informed consent, 
of Avelumab plus Axitinib therapy to patients with advanced RCC. Baseline data will be collected 
at the index date. The screening visit and the baseline visit may or may not be on the same day. 
Patients will attend the sites (hospitals) as per routine clinical practice at the discretion of the 
treating physician. Therefore, the timing of the visits may vary. Results from physical 
examinations, vital signs, and body weight will be collected upon availability. Data on treatment 
response will also be collected upon availability. Patients will be asked to provide HRQoL data 
using the NCCN-FACT FKSI-19 questionnaires available as electronic patient-reported outcomes 
(ePRO) questionnaires at the index date and at every third cycle of Avelumab treatment (intervals 
of about 6 weeks) thereafter, until the end of treatment or end of 24 months of study follow-up 
period, whichever occurs first. Patients can fill out HRQoL data (ePRO questionnaires) either at 
their homes or at sites (hospitals) during their scheduled visits as per their convenience. In 

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exceptional cases, the questionnaires on patient-reported HRQoL data can be completed on paper 
and transferred into electronic case report form (eCRF) afterwards. 
Table 1. Schedule of Assessments 
Assessment 
Screening 
visit 
W0 
(Index date/ 
Baseline 
visit) 
Follow-up visits 
(between W0 to 
W104) as per routine 
clinical practice  
W104 
(end of 
study) 
Informed consent 
X 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
Demographics (year of birth, gender) 
 
X 
 
 
Physical examination/ vital signsa 
 
X 
 
 
Body weighta 
 
X 
X 
X 
Concomitant diseasesb 
 
X 
 
 
Concomitant medicationsc 
 
X 
X 
X 
Cancer historyd 
 
X 
 
 
ECOG performance status 
 
X 
 
 
MSKCC risk groupe  
 
X 
 
 
IMDC risk groupf 
 
X 
 
 
HRQoL using the NCCN-FACT FKSI-19 
questionnaireg 
 
X 
X 
X 
Safety assessment 
X 
X 
X 
X 
Avelumab plus Axitinib therapyh 
 
X 
X 
X 
Second-line treatment (if Avelumab plus 
Axitinib discontinued) 
 
 
X 
X 
Third-line treatment (if second-line 
treatment discontinued) 
 
 
X 
X 
Treatment responsei 
 
 
X 
X 
Treatment for AE related to Avelumab plus 
Axitinib therapyj 
 
X 
X 
X 
AE=Adverse event, ECOG=Eastern Cooperative Oncology Group, HRQoL=health-related quality of life, IMDC= 
International Metastatic RCC Database Consortium, MSKCC=Memorial Sloan–Kettering Cancer Center, NCCN-FACT 
FKSI-19=National Comprehensive Cancer Network/Functional Assessment of Cancer Therapy-Kidney Symptom Index 
19, W=Week 
a Results from physical examinations, vital signs, and body weight will be collected upon availability. Physical 
examination includes an examination of major body systems. Vital signs include blood pressure (systolic and diastolic) 
and pulse rate. 
b Information on concomitant diseases such as autoimmune disease, cardiovascular disease, hypertension, renal 
failure, and liver disease.  
c Information on concomitant medications such as the use of corticosteroids, anticoagulants, and antibiotics.  
d Information on cancer history: age at diagnosis, tumor, node, metastasis (TNM) stage, location of metastases, 
received nephrectomy, other prior cancer therapies and procedures, expression of the programmed death ligand 1 
(PD-L1). 
e The MSKCC risk score is based on 5 independent risk factors: low Karnofsky performance status (KPS), low 
hemoglobin level, high serum lactate dehydrogenase, high corrected serum calcium level, and time from diagnosis to 
the initiation of systemic therapy of less than 1 year (Heng 2013). The MSKCC risk score categorizes patients into 3 
risk groups: 0 (low risk), 1 or 2 (intermediate risk), and ≥ 3 (high risk). 
f The IMDC risk score is based on data of patients with metastatic RCC treated with targeted therapies and includes 6 
risk factors: low KPS, low hemoglobin level, high neutrophil count, high platelet count, high corrected serum calcium 
level, and time from diagnosis to the initiation of systemic therapy of less than 1 year (Heng 2013). The IMDC risk score 
categorizes patients into 3 risk groups: 0 (low risk), 1 or 2 (intermediate risk), and ≥ 3 (high risk).  
g All patients will be asked to fill HRQoL data available as ePRO questionnaires at the index date and at every third 
cycle of Avelumab treatment (intervals of about 6 weeks) thereafter, until the end of treatment or end of 24 months of 
study follow-up period, whichever occurs first.  
h Avelumab plus Axitinib therapy: data on dose at regular follow-up visits, therapy modifications (change in dose) due 
to AE, temporary interruption, and treatment discontinuation will be collected upon availability.  
i Treatment response includes data on complete response, partial response, stable disease, or progressive disease 
defined as per RECIST version 1.1. Data on treatment response will be collected upon availability.  

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j Information on treatment used for the management of AE related to Avelumab plus Axitinib therapy such as use of 
corticosteroids, antihypertensive therapy, treatment for thyroid dysfunction, measures to decrease hemoglobin, and 
hematocrit. 
9.2.5 
Withdrawal from the Study 
Patients are free to withdraw from the study at any time without giving their reasons. Patients who 
discontinue treatment will continue to be followed up until end of the study, as per Schedule of 
Assessments (Table 1), regardless of treatment status. 
A patient is considered lost to follow-up after 2 documented failed attempts to reach out to the 
patient. If a patient is lost to follow-up, adequate effort must be made by study center personnel to 
contact the patient and determine the reason for discontinuation. The measures taken to follow-up 
on the patient must be documented. If a patient withdraws before completion of study procedures 
(as described in the Schedule of Assessments in Table 1), the reason for withdrawal shall be 
documented in source documents and in the eCRF. 
9.3 
Variables 
In addition to the outcomes data, data will be collected on: 
• Demographic data at baseline visit: year of birth, gender 
• Physical examination and vital signs at baseline visit 
• Body weight at baseline visit and follow-up visits 
• Concomitant diseases (e.g., autoimmune disease, cardiovascular disease, hypertension, renal 
failure, and liver disease) at baseline visit 
• Concomitant medications including the use of corticosteroids, anticoagulants, and antibiotics at 
baseline visit and follow-up visits 
• Cancer history (age at diagnosis, tumor, node, metastasis (TNM) stage, location of metastases, 
received nephrectomy, other prior cancer therapies and procedures, and expression of the 
PD-L1) at baseline visit 
• ECOG performance status at baseline visit 
• Memorial Sloan–Kettering Cancer Center (MSKCC) risk group at baseline visit (Heng 2013) 
• International Metastatic RCC Database Consortium (IMDC) risk group at baseline visit 
(Heng 2013) 
Derived and transformed data needed for the analysis are described in Section 9.7.2. 
9.4 
Data Source 
The data to be collected in the study will be obtained by means of an eCRF. The data in the eCRF 
should be consistent with the relevant source documents. Further details are provided in 
Section 9.6. 

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Data on patient demographics, concomitant diseases, concomitant medications, cancer history, 
ECOG performance status, MSKCC risk group, and IMDC risk group will be collected from the 
patient’s medical records at the time of the baseline visit. The data collected from physical 
examinations, vital signs, body weight, treatment response, and AE reporting, upon availability, 
will be transcribed into the eCRF by the site staff. Patient-reported HRQoL data using the NCCN-
FACT FKSI-19 questionnaires will be automatically captured by eCRF from ePRO questionnaires. 
In exceptional cases, when paper questionnaires for patient-reported HRQoL data will be 
completed, those signed and dated paper questionnaires will be considered as source documents. 
9.5 
Study Size 
 
 
 
 
  
In total, approximately 100 patients will be selected from approximately 30 sites in different 
European countries.  
9.6 
Data Management 
The main purpose of the eCRF is to obtain data required by the non-interventional study protocol 
in a complete, accurate, legible, and timely manner. The data in the eCRF should be consistent 
with the relevant source documents. 
The investigator or designee is responsible for ensuring that the data collected in the course of this 
study is accurate and documented appropriately on all applicable forms. Data will then be 
processed, evaluated, and stored in anonymous form in accordance with applicable data protection 
regulations. The investigator must ensure that the eCRFs and any other associated documents 
forwarded to Sponsor or its designated organization contain no mention of any subject names. 
The data will be entered into a validated database. The Sponsor or its designee will be responsible 
for data processing, in accordance with the Sponsor’s data management procedures. Database lock 
will occur once quality control and quality assurance procedures (including serious adverse event 
[SAE]/ serious adverse reaction [SAR] reconciliation) and coding activities have been completed. 
PDF files of the eCRFs will be provided to the investigators at the completion of the study. 
The eCRFs are essential study documents and must be suitable for regulatory inspections and 
submissions. 
9.7 
Data Analysis 
Descriptive analyses will be performed to gain an understanding of the qualitative and quantitative 
nature of the data collected and the characteristics of the sample studied. Continuous variables will 
be described with the following measures of central tendency and dispersion: the number of 
patients, missing observations, mean, standard deviation, median, interquartile range, minimum, 

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and maximum. Frequency, percentage, and number of missing observations will be provided for 
categorical variables. Exact Clopper-Pearson 95% CIs will be included where appropriate. The 
Kaplan-Meier method will be used for the analysis of time to event objectives. 
In general, descriptive statistics of quantitative parameters (results and change from baseline) will 
be provided for observed cases, that is, patients having non-missing assessments at a specific 
timepoint. Missing data count will be presented. 
All AE verbatim terms and medical history terms will be recorded and coded using the MedDRA. 
All previous and concomitant medication being recorded will be coded using World Health 
Organization Drug Dictionary (WHO-DD). 
Baseline data will be defined as the data collected at the index date. 
Computations and generation of tables, listings, and data for figures will be performed using 
statistical analysis system (SAS)® version 9.4 or higher (SAS Institute, Cary, NC, USA).  
The full analysis will be described in a written and approved Integrated Analysis Plan (IAP). 
9.7.1 
Analysis Sets 
All eligible patients, who provided written informed consent and received 1 or 2 cycles of 
Avelumab plus Axitinib treatment as a first-line therapy prior to informed consent, will be included 
in the analysis. All planned analyses will be descriptive, no formal statistical comparisons will be 
performed. 
9.7.2 
Derived and Transformed Data 
Primary and secondary effectiveness outcomes will be derived as per definition reported in 
Section 9.1.2. 
For OS, PFS, PFS2 and DoR, the percentage of patients alive at the time of outcome assessment 
(12 or 24 months) will be calculated as per the Kaplan-Meier approach.  
For PFS, PFS2 and DoR, a patient progressing after stopping current treatment and starting a new 
therapy will be censored at the latest tumor assessment showing no progression before changing 
therapy. 
For safety, time to onset of AE will be calculated as difference in days between start date of AE 
and the index date +1, while duration of AE (applicable for resolved AEs only) will be calculated 
as difference in days between end date of AE and start date of AE +1. 
Time to Avelumab plus Axitinib discontinuation will be derived as difference in days between last 
dose of Avelumab plus Axitinib and the index date +1 and time to second-line therapy after study 
treatment discontinuation will be calculated as difference in days between start date of second-line 
treatment and last dose of Avelumab plus Axitinib +1. 

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As per NCCN-FACT FKSI-19 scoring guidelines (version 2), the total HRQoL score (range 0-76) 
will be calculated as sum of single items scores multiplied by 19 and divided by the number of 
items completed. NCCN-FACT FKSI-19 will also cover 4 subscales: DRS-P (items from 1 to 11, 
range 0-48), DRS-E (item 12, range 0-4), TSE (items from 13 to 15, range 0-12) and FWB (items 
from 16 to 19, range 0-12). The higher the subscores or the total score, the better the HRQoL. The 
subscales will be evaluable, if at least 50% of respective items will be answered and will be 
calculated as sum of items included in the subscale, multiplied by the item included in the subscale, 
and divided by the item answered in the subscale. The FKSI-19 questionnaire as a whole will be 
evaluable, if all subscales will be evaluable and at least 80% of all items will be answered. Score 
of items 11 (C6), 12 (GF5), and from 16 to 19 (GF1, GF3 and GF7) will be reversed before 
calculating total and subscale scores. 
Every effort will be made to capture all available data by:  
• Ensuring that primary variables of interest are those that are routinely collected as part of routine 
clinical practice and are available via medical charts, physician, and/or patient/caregiver 
reporting, as appropriate  
• Collecting only critical data elements (i.e., variables aligned with the study objectives) to 
minimize site/participant burden 
• Training of sites and data abstractors regarding data collection; setting reporting windows 
around a target timepoint  
• Checking for patterns of missingness and addressing any issues with targeted operational 
strategies 
Full details on handling missing data, which are common in observational studies, will be 
described separately in the IAP. In general, missing data will not be imputed and data will be 
analyzed as they are recorded in the study eCRFs. 
9.7.3 
Statistical Methods 
Patient demographics, medical and cancer history, MSKCC and IMDC risk group, and 
concomitant medications will be summarized with appropriate descriptive statistics in the analysis 
set overall. 
Medications will be summarized according to the WHO-DD, considering the first digit of the 
Anatomical Therapeutic Chemical (ATC) classification system (anatomic category) and the first 
3 digits of the ATC class (therapeutic category). Multiple occurrences of the same drug in the same 
patient will be counted only once in the tables. 
Recorded medications will be classified into the following groups:  
• Prior medications are those that the patient took and discontinued prior to the index date 
• Concomitant medications are those that the patient continued or started on or after the index 
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• Medications used for the management of AE related to Avelumab plus Axitinib therapy on or 
after the index date 
• Medications used as second-line or third-line therapy after the index date 
The exposure will be analyzed descriptively by means of summary of treatment duration in weeks 
or months, reasons for dose reduction or temporary interruption, number of patients with 
permanent discontinuation, and reason for permanent discontinuation. 
• The primary analysis will include: 
• OS rate (percentage of patients who are alive) at 12 months after the index date with the 95% 
CI 
• The secondary analysis will include: 
• OS rate (percentage of patients who are alive) at 24 months after the index date with the 95% 
CI  
• OS will be estimated by the Kaplan-Meier method. The percentage of censored patients will 
also be reported. Median event time will be reported, along with 25th and 75th percentiles 
• Summary of absolute and relative frequencies of ORR and DCR up to 24 months after the 
index date together with the 95% CI 
• DoR, PFS, and PFS2 at 24 months after the index date will be estimated by the Kaplan-
Meier method. The percentage of censored patients will also be reported. Median event time 
will be reported, along with 25th and 75th percentiles. Percentage of patients experiencing 
event or being event-free at applicable timepoints will also be reported along with the 
corresponding two-sided 95% CIs 
• There will be subgroup analyses for the primary outcome and selected secondary outcomes 
(OS, PFS, and PFS2 at 24 months and DCR up to 24 months) based on: 
• ECOG performance status at baseline (0-1, > 1) 
• IMDC risk group (low, intermediate, high) 
• MSKCC risk group (low, intermediate, high) 
• RCC histopathology (clear cell, sarcomatoid, others) 
• PD-L1 (±) status 
• Age group (< 65, 65-75, and > 75 years) 
• Concomitant autoimmune disease (yes, no) 
• Prior nephrectomy (yes, no) 
 
Further subgroup analysis will be defined in the IAP. 

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Safety analysis will be performed on AEs incidence tables, presented by MedDRA SOC and PT, 
and the number and percentage of patients experiencing an event. Multiple occurrences of the same 
event in the same patient will be counted only once in the tables. 
Summaries of AEs will include: 
• The overview of AEs, summarizing number (%) of patients with any:  
• AEs 
• SAEs 
• National Cancer Institute - Common Terminology Criteria for Adverse Events 
(NCI-CTCAE) (version 5.0) AEs ≥ Grade 3 
• Related AEs 
• AEs leading to permanent treatment discontinuation 
• AEs leading to death 
• Summary of AEs by SOC and PT 
• Summary of SAEs by SOC and PT 
• Summary of NCI-CTCAE (version 5.0) AEs ≥ Grade 3 by SOC and PT 
• Summary of related AEs by SOC and PT 
• Summary of related AEs (NCI-CTCAE [version 5.0]) ≥ Grade 3 by SOC and PT 
• Summary of AEs leading to permanent treatment discontinuation by SOC and PT 
• Summary of AEs (NCI-CTCAE [version 5.0]) ≥ Grade 3 leading to permanent treatment 
discontinuation by SOC and PT 
• Summary of potential signs and symptoms of immune-related AEs 
• Summary of AEs leading to death by SOC and PT 
 
Exposure among the patients who discontinued the study drug due to all-cause AEs ≥ Grade 3 will 
be summarized as per appropriate statistics. 
Percentage of patients with therapy modifications due to related AEs (e.g., therapy interruptions 
and reductions of infusion rate for Avelumab, therapy interruptions and dose reductions for 
Axitinib) and frequency and type of medical intervention or medications used for the management 
of related AEs (e.g., use of corticosteroids, antihypertensive therapy, treatment for thyroid 
dysfunction, and measures to decrease hemoglobin and hematocrit) will be presented. 
Percentage of patients receiving later-line therapy (e.g., second-line therapy, third-line therapy) 
and frequency distribution of later-line therapy regimes among patients progressing on Avelumab 
plus Axitinib therapy will be presented. 
 

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Time to onset and duration of AEs, time to Avelumab plus Axitinib therapy discontinuation, and 
time to second-line therapy after study treatment discontinuation will be summarized by 
descriptive statistics for continuous variables. 
Type of therapy for management of related AEs and type of second-line therapy and third-line 
therapy will be presented according to the WHO-DD, considering the first digit of the ATC 
classification system (anatomic category) and the first 3 digits of the ATC class (therapeutic 
category). 
Descriptive statistics will also be provided on body weight over the course of the study.  
 
The scores (total and subscales) of the HRQoL at the index date and at every third cycle of 
Avelumab treatment (intervals of about 6 weeks) will be summarized using descriptive statistics 
for continuous variables. Possible trend in HRQoL will be also analyzed by repeated measure 
analysis. 
9.7.4 
Sequence of Analyses 
No interim analyses are planned, but the primary outcome will be analyzed as soon as all evaluable 
patients complete 12 months of follow-up from the index date. All other study outcomes will be 
analyzed after completing 24 months study follow-up for all enrolled patients. 
9.8 
Quality Control 
Quality control activities will include verification of data and ensure the data collected in eCRF is 
accurate, valid, and in accordance with the study protocol. Only authorized staff will have access 
to the Electronic Data Capture (EDC) system via a secure website and will receive training 
regarding data entering in the eCRF. 
9.9 
Limitations of the Research Methods 
 
 
 
 
 
 
 
 
 
Treatment response evaluated by RECIST (version 1.1) in real-world observational study may not 
be as accurate and timely as in a randomized controlled trial. However, the treating physicians will 
be requested to provide their best judgment on treatment response by evaluating results of patients’ 
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Despite these limitations, real-world observational data reflects routine clinical practice more 
closely compared to randomized controlled trials in terms of selection of heterogeneous patient 
populations and medical treatment they receive. Real-world observational data is essential to 
assess and improve clinical practice worldwide and complement results of randomized controlled 
trials. The HRQoL data collected in this study will provide a unique insight into the patient 
experience and self-assessed impact of the treatment in daily life. 
9.10 
Other Aspects 
9.10.1 
Independent Ethics Committee or Institutional Review Board 
Prior to commencement of the study at a given site, the protocol will be submitted together with 
its associated documents (e.g., ICF, subject information) to the responsible Independent Ethics 
Committee (IEC)/Institutional Review Board (IRB) for its favorable opinion/approval. The written 
favorable opinion/approval of the IEC/IRB will be filed by the investigator and a copy will be sent 
to the Sponsor. 
The study must not start at a site before the Sponsor has obtained written confirmation of favorable 
opinion/approval from the concerned IEC/IRB. The IEC/IRB will be asked to provide 
documentation of the date of the meeting at which the favorable opinion/approval was given, and 
of the members and voting members present at the meeting. Written evidence of favorable 
opinion/approval that clearly identifies the study, the protocol version, and the Subject Information 
and Consent Form version reviewed should be provided. Where possible, copies of the meeting 
minutes should be obtained. 
Amendments to the protocol will also be submitted to the concerned IEC/IRB, before 
implementation in case of substantial changes. 
9.10.2 
Monitoring 
A study Monitor will perform visits to the site at regular intervals. Monitoring visits will involve 
checking of eCRFs against original patient records and identification of any questions or problems 
related to study conduct or data collection. Investigators must therefore ensure that the study 
Monitor has access to relevant documents during monitoring visits, and that they and/or relevant 
site staff members are available to discuss any issues that may arise. 
The study Monitor will send monitoring reports to the Sponsor. 

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9.10.3 
Health Authorities 
The protocol and any applicable documentation (Subject Information and Consent Form) will be 
submitted or notified to the National Health Authorities (HA) in accordance with the regulations 
of the country or countries involved in the study. 
9.10.4 
Quality Assurance 
In compliance with regulatory requirements, the Sponsor, a third party on behalf of the Sponsor, 
regulatory agencies, or IRB/IECs may conduct quality assurance audits/inspections at any time 
during or following a study. The investigator must agree to allow auditors/inspectors direct access 
to all study-related documents, including source documents, and must agree to allocate his or her 
time and the time of his or her study staff to the auditors/inspectors in order to discuss findings 
and issues. 
The protocol, each step of the data capture procedure, and the handling of the data, as well as the 
study report, may be subject to independent Clinical Quality Assurance. Audits may be conducted 
at any time during or after the study to ensure the validity and integrity of the study data. 
9.10.5 
Archiving 
The archive should be maintained for the period specified by local regulations, where applicable. 
All original patient files (medical records) must be stored at the site (hospital, research institute, 
or practice) for the longest possible time permitted by the applicable regulations. In the absence of 
applicable regulations, the archive should be maintained for at least 5 years after the final study 
report or the first publication of study results, whichever comes later. In any case, the investigator 
should ensure that no destruction of medical records is performed without the written approval of 
the Sponsor. 
10 
Protection of Human Subjects 
10.1 
Subject Information and Informed Consent 
An unconditional prerequisite for a subject’s participation in the study is his/her written informed 
consent. The subject’s written informed consent to participate in the study must be given before 
any study-related activities are carried out. 
Adequate information must therefore be given to the subject by the investigator before informed 
consent is obtained (a person designated by the investigator may give the information, if permitted 
by local regulations). A subject information sheet in the local language will be provided by the 
Sponsor for the purpose of obtaining informed consent. In addition to providing this written 
information to a potential subject, the investigator or his/her designee will inform the subject 
verbally of all pertinent aspects of the study (the language used in doing so must be chosen so that 
the information can be fully and readily understood by laypersons). Depending on national 
regulations, a person other than the investigator may inform the subject and sign the ICF. 

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The ICF must be signed and personally dated by the subject and the investigator. The signed and 
dated declaration of informed consent will remain at the investigator’s site and must be safely 
archived by the investigator. A copy of the signed and dated information and consent form should 
be provided to the subject prior to participation. 
Whenever important new information becomes available that may be relevant to the subject’s 
consent, the written subject information sheet and any other written information provided to 
subjects will be revised by the Sponsor and be submitted again to the IEC/IRB for review and 
favorable opinion. The agreed, revised information will be forwarded to each subject in the study. 
The investigator will explain the changes to the previous version. 
10.2 
Subject Identification and Privacy 
A unique subject number will be assigned to each subject at screening. This number will serve as 
the subject’s identifier in the study as well in the study database. 
The investigator must ensure that the subject’s anonymity is maintained. On the eCRFs or other 
documents submitted to the Sponsor, subjects should not be identified by their names, but by their 
assigned identification numbers. If subject names are included on copies of documents submitted 
to the Sponsor, the names (except for initials) must be obliterated and the assigned subject numbers 
be added to the documents. 
The investigator should keep a separate log of subjects’ identification numbers, names, addresses, 
telephone numbers, and hospital numbers (if applicable). Documents not for submission to the 
Sponsor, such as signed ICFs, should be maintained in strict confidence by the investigator. 
Only authorized persons will have access to identifiable personal details, if required for data 
verification. The subject’s original medical data that are reviewed at the site during source data 
verification by the Monitor, audits, and Health Authority inspections will be kept strictly 
confidential. The investigator agrees to provide direct access to these documents to the Sponsor 
and to Health Authority representatives. The investigator is responsible for retrieving information 
from personal medical records. 
Data protection and privacy regulations will be observed in capturing, forwarding, processing, and 
storing subject data. Subjects will be informed accordingly and will be requested to give their 
consent on data handling procedures in accordance with national regulations. 
11 
Management and Reporting of Adverse Events 
11.1 
Adverse Events 
Adverse Event (AE) 
An AE is any untoward medical occurrence in a patient or clinical study subject administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 

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laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product. 
Adverse Reaction (AR) 
An AR is a response to a medicinal product which is noxious and unintended. 
Response in this context means that a causal relationship between a medicinal product and an AE 
is at least a reasonable possibility.  
ARs may arise from use of the product within or outside the terms of the marketing authorization 
or from occupational exposure. Conditions of use outside the marketing authorization include off-
label use, overdose, misuse, abuse, and medication errors. 
Reports of Special Situations: Pregnancy, Overdose, Off-label use, Misuse, Medication Error 
or Occupational Exposure, Lack of Therapeutic Efficacy, and Others 
• Use of a medicinal product during pregnancy or breastfeeding: reports where embryo, fetus, or 
child may have been exposed to medicinal products (either through maternal exposure or 
transmission of a medicinal product via semen following paternal exposure) 
• Reports of overdose, abuse, off-label use, misuse, medication error, or occupational exposure 
• Lack of therapeutic efficacy 
• Prescription error/dispensing error, (e.g., due to confusion of invented names of the medicinal 
products) 
• Drug interaction 
• Suspected transmission of an infectious agent via a medicinal product 
• Product complaints, including falsified product or counterfeit 
Reports of special situation with no associated AR will not be submitted to the authorities as 
individual case safety reports. They will be collected and considered in the study report or any 
interim reports, as applicable. 
Serious Adverse Event (SAE)/Serious Adverse Reaction (SAR) 
An SAE/SAR is any AE/AR as defined above, which also fulfills at least one of the seriousness 
criteria below: 
• Results in death  
• Is life-threatening1)  
• Requires in-patient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity 
• Is a congenital anomaly/birth defect 
• Is otherwise considered as medically important2) 

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1) Life-threatening in this context refers to a reaction in which the patient was at risk of death at the time of the reaction; it does 
not refer to a reaction that hypothetically might have caused death if more severe.  
2) Medical and scientific judgment should be exercised in deciding whether other situations should be considered as serious 
reactions, such as important medical events (IMEs) that might not be immediately life-threatening or result in death or 
hospitalization but might jeopardize the patient or might require an intervention to prevent one of the other outcomes listed 
above. Such IMEs should be considered 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 dependency or abuse. As a guidance, the IME terms list is intended to be used for 
assessment of suspected ARs (see EMA/207865/2017). 
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
SAR. 
Events Not to be Considered as AEs 
Medical conditions present and documented at study start, which do not worsen in severity or 
frequency during the study are defined as Baseline Medical Conditions and elective procedures 
and are NOT to be considered AEs. 
11.2 
Severity of Adverse Events 
Investigators should assess the severity/intensity of any AE as follows: 
Mild: 
The subject is aware of the event or symptom, but the event or symptom is easily 
tolerated. 
Moderate: 
The subject experiences sufficient discomfort to interfere with or reduce his or 
her usual level of activity. 
Severe: 
Significant impairment of functioning: the subject is unable to carry out usual 
activities. 
Investigators are required to grade the severity/intensity of each AE (including serious) recorded. 
In oncology indications, investigators will reference the NCI-CTCAE, current version 5.0 
(publication date: 27 November 2017). This is a descriptive terminology with 5 Grades: Grade 1 
(Mild), Grade 2 (Moderate), Grade 3 (Severe), Grade 4 (Life-threatening) and Grade 5 (Death due 
to AE). 
Note: NCI-CTCAE Grade 4 or 5  
If events are graded in accordance to the NCI-CTCAE criteria, then all AEs with severity Grade 4 
or 5 should be classified as serious. Exception: Asymptomatic Grade 4 laboratory abnormalities 
(e.g., Grade 4 anemia, Grade 4 neutropenia) may be considered non-serious, if not meeting any of 
the above seriousness criteria. 
If the severity/intensity of a particular AE cannot be specifically graded by NCI-CTCAE, the 
investigator is to revert to the general definitions of Grade 1 through Grade 5 and use his or her 
best medical judgment grading the AE according to the Qualitative Toxicity Scale below: 

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Grade 1 (mild): 
asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated. 
Grade 2 (moderate): 
Moderate; minimal, local or noninvasive intervention indicated; 
limiting age-appropriate instrumental activities of daily living (ADL). 
Grade 3 (severe): 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting selfcare ADL. Significant impairment of functioning: the 
subject is unable to carry out usual activities. 
Grade 4 (life-threatening): Life-threatening consequences; urgent intervention indicated. 
Grade 5 (fatal): 
AE with fatal outcome 
11.3 
Causality Assessment 
Investigators must assess the causal relationship between AEs and study drug (including any other 
non-medicinal product, radiation therapy, etc.) considering temporal relationship between the AE 
onset and study drug administration, safety profile of study drug (known ARs), the patient’s 
condition (medical history, underlying disease), concomitant medication, and study procedures. 
Related: 
Suspected to be reasonably related to any study medication.  
Not related: Not suspected to be reasonably related to any study medication. A reasonable 
alternative explanation must be provided. 
11.4 
Collection and Recording of Adverse Events 
The recording period for AEs begins when the subject is initially included in the study (date of 
signature of first informed consent) and continues to at least end of the mandatory safety-follow-
up period (90 days post discontinuation of Avelumab plus Axitinib therapy or completion of the 
24 months (i.e., end of the study) follow-up from the index date, whichever occurs first).  
All safety data, as specified above, occurring during the study, must be documented by the 
investigator within 24 hours of awareness and recorded in the eCRF, including its description, 
seriousness, severity (grading), duration (onset and resolution dates), causal relationship, any other 
potential causal factors, actions taken with the study drug (e.g., dose reduction, withdrawal), 
required treatment, and outcome of the AE. 
Note: Event term‘Death’, ‘Disability’ and ‘Hospitalization’ 
Death, disability, and hospitalization are considered outcomes in the context of safety reporting 
and not usually considered ARs/AEs. Therefore, the primary cause of death, disability, or 
hospitalization should be recorded and reported as an SAE/AR, and the outcome should be 
recorded in a separate data field. However, a term for the outcome will be selected if it is the only 
information reported or provides significant clinical information. 

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If death occurs, the primary cause of death or event leading to death should be recorded and 
reported as an SAE. “Fatal” will be recorded as the outcome of this respective event and not as a 
separate event. Only if no cause of death can be reported (for example, sudden death, unexplained 
death), the death per se might then be reported as an SAE. 
All SAEs/AEs due to Avelumab as well as Axitinib will be collected in the study database.  
Reports of Special Situations (see definition) are also to be recorded in the eCRF following the 
AE procedure, even if occurring without AE.  
Pregnancy and Breastfeeding. Pregnancy or breastfeeding must be recorded in the eCRF and 
additionally be reported to the Sponsor immediately (within 24 hours of awareness) by using 
separate paper data collection forms for pregnancy, independent if an AE was reported or not. The 
outcome of the pregnancy should be followed up and reported to the Sponsor until delivery.  
11.5 
Safety Data Reporting  
Safety Data Collection Forms: 
The following safety data collection forms are used in this study: 
• (Serious) Adverse Event Report Form  
• Pregnancy Report Form 
• Parent-Child/Fetus AE Report Form  
Events Reported via the Safety Check Desk 
The following events are reportable to the Safety Check Desk within 24 hours of awareness:  
• All SARs related to Avelumab are to be reported to the Safety Check Desk. Also, the only SARs 
related to Axitinib that should be reported to Safety Check Desk are those which are also related 
to Avelumab.  
• Pregnancy or lactation is to be reported by using the Pregnancy Report Form. 
• All events that occur in a child/fetus of a pregnant woman who was exposed to the study drug 
are to be reported by using the Parent-Child/Fetus Report Form. 
• Special situations (see definition) should be reported on the (Serious) Adverse Event Report 
Form by indicating whether serious or not. 
Events Reported Directly to Global Patient Safety (GPS): 
• All Non-Serious ARs related to Avelumab are to be reported to Global Patient Safety (GPS). 
Also, the only Non-Serious ARs related to Axitinib that should be reported to GPS are those 
which are also related to Avelumab. Non-Serious ARs are to be reported within 4 calendar days 
via the eCRF system or via paper (Serious) Adverse Event Report form (only if eCRF 
system/eCRF email notifications are not available). 

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Procedure for Safety Data Reporting (Completion and Forwarding): 
For any new events that are serious, fatal, or related to a special situation, the 
investigator/healthcare professional must immediately (within 24 hours after becoming aware of 
the event) send a report using eCRF or respective paper Safety Data Collection Form to the 
Sponsor in English via the Safety Check Desk. For Non-Serious ARs, an electronic data transfer 
or a paper form (only in case electronic data transfer is not available) must be transmitted within 
4 calendar days to the Sponsor, including the GPS.  
The investigator must respond to any request by the Safety Check Desk for follow-up information, 
as noted above for initial report. The Safety Check Desk should forward the follow-up information 
within 24 hours to GPS, as noted above for initial reports. The Sponsor has to meet strict regulatory 
timelines associated with expedited safety reporting obligations. 
Safety Check Desk: 
• Email: OSM_Safety@merckgroup.com 
Global Patient Safety: 
• Email: GlobalDrugSafety@merckgroup.com 
• Fax: +49 (0) 6151 72 6914 
The data entered on the safety data collection forms must be consistent with the information 
recorded in the eCRF. If some data are missing, the form should be completed with the available 
data and a follow-up report will be sent as soon as possible. The minimum information to be 
included in the initial report is the following: 
• Investigator name and contact details 
• Subject identification (e.g., ID number, site number, gender, age/year of birth)Product 
(including lot/batch number) 
• Description of SAE/AR/fatal case/special situation 
o Diagnosis of the event with its clinical course or, if a diagnosis is not available, a 
short description of signs/symptoms/clinical course 
o Date of onset 
o Seriousness criteria 
o Causality assessment  
o Date of report and reporter’s signature  
The report should contain causality and seriousness information (for AEs) and must be signed off 
by the investigator. 
When AE information is communicated via telephone, a written/EDC report must be sent 
immediately within 24 hours thereafter by fax or email. In such cases, the “clock start” for case 
reporting to Health Authorities is the date and time of the telephone communication.  

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AE/SAE Observed in Association with Disease Progression 
Progression of the disease / disorder being studied assessed by measurement of lesions on 
radiographs or other methods as well as associated clinical signs or symptoms (including 
laboratory abnormalities) does not need to be reported as an (S)AE, unless the subject´s general 
condition is more severe than expected for the subject´s condition and / or unless the outcome is 
fatal within the AE reporting period, as defined in Section 11.4. 
Exposure During Pregnancy 
All pregnancies with an estimated conception date in the period from the date of informed consent 
signature (where applicable) until the last post-treatment safety visit, or as defined in the protocol, 
must be recorded by convention in the AE page/section of the eCRF. The same rule applies to 
pregnancies in female subjects and to pregnancies in female partners of male subjects. The 
investigator must notify the Sponsor in an expedited manner of any pregnancy using the Pregnancy 
Report Form, which must be transmitted according to the same process as described for SAE 
reporting. The Sponsor must be notified about any pregnancy independent whether the pregnancy 
is associated with an AE or not. 
Investigators must actively follow-up, document, and report to the Sponsor on the outcome of all 
these pregnancies and deliveries even if the subject is withdrawn from the study. If an abnormal 
outcome occurs, the respective safety data collection form (Pregnancy Report Form, Parent-
Child/Fetus AE Report Form) is to be completed and sent to the Sponsor. 
Procedure for Follow-up Information 
The investigator must promptly respond to any request for follow-up information or questions 
from the Sponsor or delegate, as noted above for initial report. Such requests will be sent to the 
investigator via the Safety Check Desk. SAEs/ARs and special situations occurring during the 
study must be monitored and followed up by the investigator until stabilization or until the outcome 
is known, unless the subject has a fatal outcome or is lost to follow-up.  
The investigator will ensure any necessary additional therapeutic measures and follow-up 
procedures are recorded and reported via a follow-up report form. For all serious cases/ARs/fatal 
cases, and special situations, missing information such as outcome, confounders, and causality 
are to be provided. In addition, follow-up information of non-serious adverse drug reactions may 
be required by the Sponsor for medical assessment. Reasonable attempts to obtain follow-up 
information must be made and documented. 
Reporting of any new information on a previously reported event (follow-up) will follow the 
procedures and timelines of the original report. 
The Safety Check Desk should forward the follow-up information within 24 hours to GPS, as 
noted above for initial reports. The Sponsor has to meet strict regulatory timelines associated with 
expedited safety reporting obligations. 

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11.6 
Regulatory Submission to the Health Authorities 
Expedited submissions of serious ARs and non-serious adverse drug reactions to HA is performed 
- for Merck’s authorized medicinal products - by GPSaccording to applicable global and local 
requirements. Merck, as the marketing authorization holder of Avelumab, is only required to 
submit SARs/ARs due to Avelumab to the HAs of the participating countries, or in case of 
EU/EEA countries to the EMA only. SAR/AR due to Axitinib only will not be submitted to the 
authorities by Merck, unless they are also related to Avelumab. 
In addition, the investigator will comply with any applicable local pharmacovigilance 
requirements to report appropriate safety data, to national pharmacovigilance systems (e.g., 
Yellow Card Scheme in UK), as required by country-specific reporting requirements. For 
non-Merck products the investigator is responsible to report safety information to regulatory 
authorities directly, where required per local regulations. 
 
12 
Plans for Disseminating and Communicating Study Results 
12.1 
Study Report 
The completed study will be summarized in a final report that accurately and completely presents 
the study objectives, methods, results, limitations of the study, and interpretation of the findings. 
12.2 
Publication 
The first publication will be a publication of study design followed by a publication of the results 
of the analysis of the primary outcome(s), which will include data from all study sites. The third 
publication will be a publication of the results of all final analyses.  
The investigator will inform the Sponsor in advance about any plans to publish or present data 
from the study. Any publications and presentations of the results (abstracts in journals or 
newspapers, oral presentations, etc.), either in whole or in part, by investigators or their 
representatives will require pre-submission review and approval by the Sponsor. 
The Sponsor will not suppress or veto publications but maintains the right to delay publication in 
order to protect intellectual property rights. 
 

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13 
References 
BAVENCIO®, 
Summary 
of 
Product 
Characteristics 
[Available 
from: 
https://www.ema.europa.eu/en/documents/product-information/bavencio-epar-product-
information_en.pdf].  
Choueiri TK, Larkin J, Oya M, et al. Preliminary results for avelumab plus axitinib as first-line 
therapy in patients with advanced clear-cell renal cell carcinoma (JAVELIN Renal 100): an open-
label, dose-finding and dose-expansion, phase 1b trial. Lancet Oncol. 2018;19(4):451-60. 
Choueiri TK, Motzer RJ, Rini BI, et al. Updated efficacy results from the JAVELIN Renal 101 
trial: first-line avelumab plus axitinib versus sunitinib in patients with advanced renal cell 
carcinoma. Ann Oncol. 2020;31(8):1030-1039.  
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: 
revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228-47. 
Ferlay J, Colombet M, Soerjomataram I, et al. Cancer incidence and mortality patterns in Europe: 
Estimates for 40 countries and 25 major cancers in 2018. Eur J Cancer. 2018;103:356-87. 
Heng DY, Xie W, Regan MM, et al. External validation and comparison with other models of the 
International Metastatic Renal-Cell Carcinoma Database Consortium prognostic model: a 
population-based study. Lancet Oncol. 2013;14(2):141-8. 
Hutson TE, Lesovoy V, Al-Shukri S, et al. Axitinib versus sorafenib as first-line therapy in patients 
with metastatic renal-cell carcinoma: a randomised open-label phase 3 trial. Lancet Oncol. 
2013;14(13):1287-94. 
KEYTRUDA®, 
Summary 
of 
Product 
Characteristics 
[Available 
from: 
https://www.ema.europa.eu/en/documents/product-information/keytruda-epar-product-
information_en.pdf].  
Ljungberg B, Albiges L, Abu-Ghanem Y, et al. European Association of Urology Guidelines on 
Renal Cell Carcinoma: The 2019 Update. Eur Urol. 2019;75(5):799-810. 
Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus Ipilimumab versus Sunitinib in 
Advanced Renal-Cell Carcinoma. N Engl J Med. 2018;378(14):1277-90. 
Motzer RJ, Penkov K, Haanen J, et al. Avelumab plus Axitinib versus Sunitinib for Advanced 
Renal-Cell Carcinoma. N Engl J Med. 2019;380(12):1103-15. 
Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern 
Cooperative Oncology Group. Am J Clin Oncol. 1982;5(6):649-55. 
OPDIVO®, 
Summary 
of 
Product 
Characteristics 
[Available 
from: 
https://www.ema.europa.eu/en/documents/product-information/opdivo-epar-product-
information_en.pdf]. 
Rao D, Butt Z, Rosenbloom S, et al. A Comparison of the Renal Cell Carcinoma-Symptom Index 
(RCC-SI) and the Functional Assessment of Cancer Therapy-Kidney Symptom Index (FKSI). J 
Pain Symptom Manage. 2009;38(2):291-8. 
Rini BI, Plimack ER, Stus V, et al. Pembrolizumab plus Axitinib versus Sunitinib for Advanced 
Renal-Cell Carcinoma. N Engl J Med. 2019;380(12):1116-27. 

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Rini BI, Battle D, Figlin RA, et al. The society for immunotherapy of cancer consensus statement 
on immunotherapy for the treatment of advanced renal cell carcinoma (RCC). J Immunother 
Cancer. 2019;7(1):354. 
Rothrock NE, Jensen SE, Beaumont JL, et al. Development and initial validation of the 
NCCN/FACT symptom index for advanced kidney cancer. Value Health. 2013;16(5):789-96. 
Vaishampayan U, Schoffski P, Ravaud A, et al. Avelumab monotherapy as first-line or second-
line treatment in patients with metastatic renal cell carcinoma: phase Ib results from the JAVELIN 
Solid Tumor trial. J Immunother Cancer. 2019;7(1):275. 

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14 
Appendices 
 
 
 
 

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14.1 
Signature Pages and Responsible Persons for the Study 
 

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Signature Page – Protocol Lead 
 
Study Title: 
Real-world evaluation of efficacy and safety with 
AVelumab (BAVENCIO®) + Axitinib (INLYTA®) in 
patients with Advanced Renal-Cell CarcinOma 
(RCC) in multiple EU couNtries 
 
Study Protocol Date / Version: 
24 April 2023 / Version 4.0 
 
Protocol Lead Responsible for Designing the Non-Interventional Study: 
I approve the design of the non-interventional study: 
____________________________ 
Signature 
Date of Signature 
Name, academic degree:
Function/title: 
 
 
 
 
 
Telephone number: 
 
Fax number: 
Not Available 
Email address: 
 
 
 
 
 
 

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Signature Page – Coordinating Investigator 
 
Study Title 
Real-world evaluation of efficacy and safety with 
AVelumab (BAVENCIO®) + Axitinib (INLYTA®) in 
patients with Advanced Renal-Cell CarcinOma (RCC) 
in multiple EU couNtries 
 
Study Protocol Date / Version 
24 April 2023 / Version 4.0 
 
I approve the design of the non-interventional study and I understand and will conduct the study 
according to the study protocol, any approved protocol amendments, Good Pharmaco-
epidemiology Practices (GPP) and all applicable Health Authority requirements and national laws. 
____________________________ 
Signature 
Date of Signature 
Name, academic degree: 
 
Function/title: 
) 
Institution: 
 
Address: 
 
Telephone number: 
 
Email address: 
 
 
 
 
 
 
 
 

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Signature Page – Principal Investigator 
 
Study Title 
Real-world evaluation of efficacy and safety with 
AVelumab (BAVENCIO®) + Axitinib (INLYTA®) in 
patients with Advanced Renal-Cell CarcinOma 
(RCC) in multiple EU couNtries 
 
Study Protocol Date / Version 
24 April 2023 / Version 4.0 
 
Center Number 
 
 
Principal Investigator 
 
 
I, the undersigned, am responsible for the conduct of the study at this site and affirm that I 
understand and will conduct the study according to the study protocol, any approved protocol 
amendments, GPP and all applicable Health Authority requirements and national laws. 
I also affirm that I understand that Health Authorities may require the Sponsors of the study to 
obtain and supply details about ownership interests in the Sponsor or Investigational Medicinal 
Product and any other financial ties with the Sponsor. The Sponsor will use any such information 
solely for the purpose of complying with the regulatory requirements. I therefore agree to supply 
the Sponsor with any necessary information regarding ownership interest and financial ties 
including those of my spouse and dependent children, and to provide updates as necessary to meet 
Health Authority requirements. 
 
_____________________________________ 
____________________________ 
Signature 
Date of Signature 
Name, academic degree: 
 
Function/title: 
 
Institution: 
 
Address: 
 
Telephone number: 
 
Fax number: 
 
Email address: 
 

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Sponsor Responsible Persons Not Named on the Cover Page 
Name, academic 
degree: 
 
Function/title: 
 
 
 
 
 
Telephone 
number: 
 
Fax number: 
 
Email address: