Download PDF

Clinical Trial Results:
A Phase 3, Multinational, Randomized, Open-Label, Parallel-Arm study of Avelumab (MSB0010718C) in Combination With Axitinib (Inlyta) Versus Sunitinib (Sutent) Monotherapy in the First-Line Treatment of Patients With Advanced Renal Cell Carcinoma

Summary
EudraCT number	2015-002429-20
Trial protocol	NL FR SE BE GB DE HU AT DK ES IT
Global end of trial date	26 Jun 2024

Results information
Results version number	v1(current)
This version publication date	10 Jul 2025
First version publication date	10 Jul 2025
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

Collapse all Expand all

Trial information

Top of page

Sponsor protocol code

B9991003

ISRCTN number

US NCT number

NCT02684006

WHO universal trial number (UTN)

Sponsor organisation name

Pfizer Inc.

Sponsor organisation address

66 Hudson Boulevard East, New York, United States, NY 10001-2192

Public contact

Pfizer ClinicalTrials.gov Call Center, Pfizer Inc., 001 8007181021, ClinicalTrials.gov_Inquiries@pfizer.com

Scientific contact

Pfizer ClinicalTrials.gov Call Center, Pfizer Inc., 001 8007181021, ClinicalTrials.gov_Inquiries@pfizer.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

26 Jun 2024

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

26 Jun 2024

Was the trial ended prematurely?

Main objective of the trial

To demonstrate that avelumab in combination with axitinib is superior to sunitinib monotherapy in prolonging progression free survival (PFS) or overall survival (OS) in the first-line treatment of programmed death-ligand 1 (PD-L1) positive participants with advanced renal cell carcinoma (aRCC).

Protection of trial subjects

The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Council for Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trials participants were followed.

Background therapy

Evidence for comparator

Actual start date of recruitment

22 Mar 2016

Long term follow-up planned

Yes

Long term follow-up rationale

Efficacy, Safety

Long term follow-up duration

99 Months

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Denmark: 5

Country: Number of subjects enrolled

France: 70

Country: Number of subjects enrolled

Germany: 7

Country: Number of subjects enrolled

Hungary: 2

Country: Number of subjects enrolled

Israel: 41

Country: Number of subjects enrolled

Italy: 15

Country: Number of subjects enrolled

Japan: 67

Country: Number of subjects enrolled

Korea, Republic of: 48

Country: Number of subjects enrolled

Mexico: 12

Country: Number of subjects enrolled

Netherlands: 38

Country: Number of subjects enrolled

New Zealand: 9

Country: Number of subjects enrolled

Romania: 20

Country: Number of subjects enrolled

Russian Federation: 138

Country: Number of subjects enrolled

Spain: 1

Country: Number of subjects enrolled

United Kingdom: 32

Country: Number of subjects enrolled

United States: 261

Country: Number of subjects enrolled

Australia: 32

Country: Number of subjects enrolled

Austria: 5

Country: Number of subjects enrolled

Belgium: 9

Country: Number of subjects enrolled

Canada: 74

Worldwide total number of subjects

886

EEA total number of subjects

172

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

546

From 65 to 84 years

336

85 years and over

Subject disposition

Top of page

Recruitment details

Screening details

A total of 886 participants were enrolled and randomized in the study.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Avelumab + Axitinib

Arm description

Participants with advanced renal cell carcinoma (aRCC) received avelumab 10 milligram per kilogram (mg/kg), intravenously (IV) once every two weeks (Q2W) in a 6-week cycle plus axitinib 5 mg, orally twice daily (BID). Each treatment cycle was of 42 days.

Arm type

Experimental

Investigational medicinal product name

Axitinib 5 mg

Investigational medicinal product code

AG-013736

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Participants received Axitinib 5 mg twice daily administered 12 hours apart orally.

Investigational medicinal product name

Avelumab 10mg

Investigational medicinal product code

MSB0010718C

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Participants received Avelumab 10 mg/kg intravenously once every two weeks of each 42-day cycle

Sunitinib

Arm description

Participants with aRCC received sunitinib 50 mg orally, QD on a schedule of 4 weeks on treatment followed by 2 weeks off treatment (schedule 4/2 in 6-week cycles). Each treatment cycle was of 42 days.

Arm type

Experimental

Investigational medicinal product name

Sunitinib 50 mg

Investigational medicinal product code

SU011248

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Participants received Sunitinib 50 mg once daily orally

Number of subjects in period 1	Avelumab + Axitinib	Sunitinib
Started	442	444
Completed	0	0
Not completed	442	444
Adverse event, serious fatal	25	22
Consent withdrawn by subject	29	43
Physician decision	15	8
Global deterioration of health status	18	20
Adverse event, non-fatal	86	65
No longer met eligibility criteria	6	2
Non-compliance with study drug	1	1
Unspecified	18	6
Progressive disease	236	266
Lost to follow-up	-	1
Protocol deviation	2	1
Participation terminated by sponsor	6	9

Baseline characteristics

Top of page

Reporting group title

Avelumab + Axitinib

Reporting group description

Reporting group title

Sunitinib

Reporting group description

Reporting group values	Avelumab + Axitinib	Sunitinib	Total
Number of subjects	442	444
Age Categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	60.86 ( 9.95 )	60.66 ( 10.28 )	-
Gender categorical
Units: Subjects
Male	316	344	660
Female	126	100	226
Ethnicity
Units: Subjects
Hispanic or Latino	19	18	37
Not Hispanic or Latino	388	377	765
Unknown or Not Reported	35	49	84
Race
Units: Subjects
American Indian or Alaska Native	4	4	8
Asian	70	63	133
Native Hawaiian or Other Pacific Islander	0	1	1
Black or African American	10	10	20
White	332	334	666
Unknown or Not Reported	26	32	58

End points

Top of page

Reporting group title

Avelumab + Axitinib

Reporting group description

Reporting group title

Sunitinib

Reporting group description

Primary: Progression Free Survival (PFS) as Assessed by Blinded Independent Central Review (BICR) in Programmed Death-Ligand 1 (PD-L1) Positive Participants

Top of page

End point title

Progression Free Survival (PFS) as Assessed by Blinded Independent Central Review (BICR) in Programmed Death-Ligand 1 (PD-L1) Positive Participants

End point description

PFS: time from date of randomization to date of first documentation of progressive disease (PD) according to Response Evaluation Criteria in Solid Tumours (RECIST version [v] 1.1) or death due to any cause, whichever occurred first as assessed by BICR. PFS data was censored on date of last adequate tumor assessment for participants who did not have an event (PD/death), who started new anti-cancer therapy prior to an event or for participants with an event after 2/more missing tumor assessments. PD: at least 20%, increase in sum of all longest diameter of target lesions, taking as reference smallest sum on study. In addition to relative increase of 20%, sum must have also demonstrated an absolute more than (>) of at least 5 millimeter (mm). FAS included all participants who were randomized. Analysis was performed on subset of randomized participants, who were PD-L1 positive. 99999 indicates upper limit of 95% CI was not estimable due to insufficient number of participants with event.

End point type

Primary

End point timeframe

From date of randomization to the first documentation of PD or death due to any cause or censoring date, whichever occurred first (maximum up to approximately 26 months)

End point values	Avelumab + Axitinib	Sunitinib
Number of subjects analysed	270	290
Units: Months
median (confidence interval 95%)	13.8 (11.1 to 99999)	7.2 (5.7 to 9.7)

Avelumab + Axitinib versus Sunitinib

Comparison groups

Avelumab + Axitinib v Sunitinib

Number of subjects included in analysis

560

Analysis specification

Pre-specified

Analysis type

superiority ^[1]

P-value

= 0.0001 ^[2]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.61

Confidence interval

level

95%

sides

2-sided

lower limit

0.475

upper limit

0.79

Notes
[1] - 2-sided p-value
[2] - 2-sided p-value

Primary: Overall Survival (OS) in PD-L1 Positive Participants

Top of page

End point title

Overall Survival (OS) in PD-L1 Positive Participants

End point description

OS was defined as the time from the date of randomization to the date of death due to any cause. Participants last known to be alive were censored at date of last contact. Analysis was performed using Kaplan-Meier method. FAS included all participants who are randomized. Analysis was performed on subset of randomized participants, who were PD-L1 positive.

End point type

Primary

End point timeframe

From the date of randomization to the date of death due to any cause or censoring date, whichever occurred first (maximum up to approximately 89 months)

End point values	Avelumab + Axitinib	Sunitinib
Number of subjects analysed	270	290
Units: Months
median (confidence interval 95%)	43.2 (36.5 to 51.7)	36.2 (29.8 to 44.2)

Avelumab + Axitinib versus Sunitinib

Comparison groups

Avelumab + Axitinib v Sunitinib

Number of subjects included in analysis

560

Analysis specification

Pre-specified

Analysis type

superiority ^[3]

P-value

= 0.1509 ^[4]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.86

Confidence interval

level

95%

sides

2-sided

lower limit

0.701

upper limit

1.057

Notes
[3] - 2-sided p-value
[4] - 2-sided p-value

Secondary: PFS as Assessed by BICR in Participants Irrespective of PD-L1 Expression

Top of page

End point title

PFS as Assessed by BICR in Participants Irrespective of PD-L1 Expression

End point description

PFS: time from the date of randomization to the date of the first documentation of PD or death due to any cause, whichever occurred first as assessed by BICR. PFS data was censored on date of last adequate tumor assessment for participants who did not have an event (PD or death), who started new anti-cancer therapy prior to an event or for participants with an event after 2 or more missing tumor assessments. PD was defined as at least a 20% increase in the sum of all the longest diameter of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to relative increase of 20%, sum must have also demonstrated an absolute > of at least 5 mm. The appearance of one or more new lesions was also considered progression. FAS included all randomized participants. 99999 indicates upper limit of 95% CI was not estimable due to insufficient number of participants with event.

End point type

Secondary

End point timeframe

From date of randomization to the first documentation of PD or death due to any cause or censoring date, whichever occurred first (maximum up to approximately 26 months)

End point values	Avelumab + Axitinib	Sunitinib
Number of subjects analysed	442	444
Units: Months
median (confidence interval 95%)	13.8 (11.1 to 99999)	8.4 (6.9 to 11.1)

Avelumab + Axitinib versus Sunitinib

Comparison groups

Avelumab + Axitinib v Sunitinib

Number of subjects included in analysis

886

Analysis specification

Pre-specified

Analysis type

superiority ^[5]

P-value

= 0.0002 ^[6]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.69

Confidence interval

level

95%

sides

2-sided

lower limit

0.563

upper limit

0.84

Notes
[5] - 2-sided p-value
[6] - 2-sided p-value

Secondary: OS in Participants Irrespective of PD-L1 Expression

Top of page

End point title

OS in Participants Irrespective of PD-L1 Expression

End point description

OS was defined as the time (in months) from the date of randomization to the date of death due to any cause. Participants last known to be alive were censored at date of last contact. Analysis was performed using Kaplan-Meier method. FAS included all randomized participants.

End point type

Secondary

End point timeframe

From the date of randomization to the date of death due to any cause or censoring date, whichever occurred first (maximum up to approximately 89 months)

End point values	Avelumab + Axitinib	Sunitinib
Number of subjects analysed	442	444
Units: Months
median (confidence interval 95%)	44.8 (39.7 to 51.1)	38.9 (31.4 to 45.2)

Avelumab + Axitinib versus Sunitinib

Comparison groups

Sunitinib v Avelumab + Axitinib

Number of subjects included in analysis

886

Analysis specification

Pre-specified

Analysis type

superiority ^[7]

P-value

= 0.1338 ^[8]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.88

Confidence interval

level

95%

sides

2-sided

lower limit

0.749

upper limit

1.039

Notes
[7] - 2-sided p-value
[8] - 2-sided p-value

Secondary: Percentage of Participants With OR as Assessed by Investigator Irrespective of PD-L1 Expression

Top of page

End point title

Percentage of Participants With OR as Assessed by Investigator Irrespective of PD-L1 Expression

End point description

OR was defined as best overall response of CR or PR according to RECIST v1.1 as assessed by investigator recorded from date of randomization until disease progression. CR was defined as complete disappearance of all target and non-target lesions with the exception of nodal disease. All lymph nodes must decrease to normal size (short axis<10 mm). All target lesions must be assessed. PR was defined as greater than or equal to 30% decrease under baseline of the sum of diameters of all target measurable lesions. All target lesions must be assessed. 95% CI was based on Clopper-Pearson method. FAS included all randomized participants.

End point type

Secondary

End point timeframe

From date of randomization until PD (maximum up to approximately 89 months)

End point values	Avelumab + Axitinib	Sunitinib
Number of subjects analysed	442	444
Units: Percentage of participants
number (confidence interval 95%)	59.7 (55.0 to 64.3)	32.0 (27.7 to 36.5)

No statistical analyses for this end point

Secondary: Percentage of Participants With Objective Response (OR) as Assessed by BICR Irrespective of PD-L1 Expression

Top of page

End point title

Percentage of Participants With Objective Response (OR) as Assessed by BICR Irrespective of PD-L1 Expression

End point description

OR was defined as best overall response of complete response (CR) or partial response (PR) according to RECIST v1.1 as assessed by BICR recorded from date of randomization until disease progression. CR was defined as complete disappearance of all target and non-target lesions with the exception of nodal disease. All lymph nodes must decrease to normal size (short axis<10 mm). All target lesions must be assessed. PR was defined as greater than or equal to 30% decrease under baseline of the sum of diameters of all target measurable lesions. All target lesions must be assessed. 95% CI was based on Clopper-Pearson method. FAS included all randomized participants.

End point type

Secondary

End point timeframe

From date of randomization until PD (maximum up to approximately 26 months)

End point values	Avelumab + Axitinib	Sunitinib
Number of subjects analysed	442	444
Units: Percentage of participants
number (confidence interval 95%)	51.4 (46.6 to 56.1)	25.7 (21.7 to 30.0)

No statistical analyses for this end point

Secondary: Percentage of Participants With DC as Assessed by Investigator Irrespective of PD-L1 Expression

Top of page

End point title

Percentage of Participants With DC as Assessed by Investigator Irrespective of PD-L1 Expression

End point description

DC was defined as a best overall response of CR, PR, non-CR/non-PD or SD according to RECIST v1.1 as assessed by investigator. CR was defined as complete disappearance of all target and non-target lesions, with the exception of nodal disease and sustained for at least 4 weeks. All lymph nodes must decrease to normal size (short axis<10mm). PR was defined as at least 30% decrease in the sum of the longest dimensions of target lesions taking as reference the baseline sum longest dimensions. Non-CR/Non-PD was defined as persistence of any non-target lesions and/or tumor marker level above the normal limits. SD was defined as not to qualify for CR, PR or PD for target lesions and followed PR only if the sum increased by less than 20% from the nadir (smallest sum of diameters consider baseline and all assessments prior to the time point under evaluation), but enough that a previously documented 30% decrease no longer holds. FAS included all randomized participants.

End point type

Secondary

End point timeframe

From date of randomization until PD (maximum up to approximately 89 months)

End point values	Avelumab + Axitinib	Sunitinib
Number of subjects analysed	442	444
Units: Percentage of participants
number (confidence interval 95%)	85.1 (81.4 to 88.3)	76.4 (72.1 to 80.2)

No statistical analyses for this end point

Secondary: Percentage of Participants With Disease Control (DC) as Assessed by BICR Irrespective of PD-L1 Expression

Top of page

End point title

Percentage of Participants With Disease Control (DC) as Assessed by BICR Irrespective of PD-L1 Expression

End point description

DC was defined as a best overall response of CR, PR, non-CR/non-PD or stable disease (SD) according to RECIST v1.1 as assessed by BICR. CR was defined as complete disappearance of all target and non-target lesions, with the exception of nodal disease and sustained for at least 4 weeks. All lymph nodes must decrease to normal size (short axis<10mm). PR was defined as at least 30% decrease in the sum of the longest dimensions of target lesions taking as reference the baseline sum longest dimensions. Non-CR/Non-PD was defined as persistence of any non-target lesions and/or tumor marker level above the normal limits. SD was defined as not to qualify for CR, PR or PD for target lesions and followed PR only if the sum increased by less than 20% from the nadir (smallest sum of diameters consider baseline and all assessments prior to the time point under evaluation), but enough that a previously documented 30% decrease no longer holds. FAS included all randomized participants.

End point type

Secondary

End point timeframe

From date of randomization until PD (maximum up to approximately 26 months)

End point values	Avelumab + Axitinib	Sunitinib
Number of subjects analysed	442	444
Units: Percentage of participants
number (confidence interval 95%)	82.8 (79.0 to 86.2)	73.4 (69.1 to 77.5)

No statistical analyses for this end point

Secondary: TTR as Assessed by Investigator in Participants Irrespective of PD-L1 Expression

Top of page

End point title

TTR as Assessed by Investigator in Participants Irrespective of PD-L1 Expression

End point description

TTR was defined as the time from randomization to the first documentation of objective tumor response according to RECIST v1.1 as assessed by investigator (CR or PR) which is subsequently confirmed. CR was defined as complete disappearance of all target and non-target lesions with the exception of nodal disease. All lymph nodes must decrease to normal size (short axis<10 mm). All target lesions must be assessed. PR was defined as greater than or equal to 30% decrease under baseline of the sum of diameters of all target measurable lesions. All target lesions must be assessed. FAS included all randomized participants. Here "Participants Analyzed" signifies number of participants evaluable for this endpoint.

End point type

Secondary

End point timeframe

From the date of randomization to the first documentation of objective response (CR or PR) (maximum up to approximately 89 months)

End point values	Avelumab + Axitinib	Sunitinib
Number of subjects analysed	264	142
Units: Months
median (full range (min-max))	2.8 (1.1 to 34.5)	2.8 (1.2 to 65.2)

No statistical analyses for this end point

Secondary: Time to Tumor Response (TTR) as Assessed by BICR in Participants Irrespective of PD-L1 Expression

Top of page

End point title

Time to Tumor Response (TTR) as Assessed by BICR in Participants Irrespective of PD-L1 Expression

End point description

TTR was defined as the time from randomization to the first documentation of objective tumor response according to RECIST v1.1 as assessed by BICR (CR or PR) which is subsequently confirmed. CR was defined as complete disappearance of all target and non-target lesions with the exception of nodal disease. All lymph nodes must decrease to normal size (short axis<10 mm). All target lesions must be assessed. PR was defined as greater than or equal to 30% decrease under baseline of the sum of diameters of all target measurable lesions. All target lesions must be assessed. FAS included all randomized participants. Here "Participants Analyzed" signifies number of participants evaluable for this endpoint.

End point type

Secondary

End point timeframe

From the date of randomization to the first documentation of objective response (CR or PR) (maximum up to approximately 26 months)

End point values	Avelumab + Axitinib	Sunitinib
Number of subjects analysed	227	114
Units: Months
median (full range (min-max))	2.6 (1.2 to 13.8)	3.2 (1.2 to 11.6)

No statistical analyses for this end point

Secondary: PFS as Assessed by Investigator in Participants Irrespective of PD-L1 Expression

Top of page

End point title

PFS as Assessed by Investigator in Participants Irrespective of PD-L1 Expression

End point description

Investigator assessed PFS: time from the date of randomization to the date of the first documentation of PD according to RECIST v1.1 or death due to any cause, whichever occurred first. PFS data was censored on date of last adequate tumor assessment for participants who did not have an event (PD or death), who started new anti-cancer therapy prior to an event or for participants with an event after 2 or more missing tumor assessments. PD was defined as at least a 20% increase in the sum of all the longest diameter of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to relative increase of 20 %, sum must have also demonstrated an absolute > of at least 5 mm. The appearance of one or more new lesions was also considered progression. FAS included all randomized participants.

End point type

Secondary

End point timeframe

From date of randomization until PD or death due to any cause or censoring date, whichever occurred first (maximum up to approximately 89 months)

End point values	Avelumab + Axitinib	Sunitinib
Number of subjects analysed	442	444
Units: Months
median (confidence interval 95%)	13.9 (11.1 to 16.6)	8.5 (8.2 to 9.7)

Avelumab + Axitinib Versus Sunitinib

Comparison groups

Avelumab + Axitinib v Sunitinib

Number of subjects included in analysis

886

Analysis specification

Pre-specified

Analysis type

superiority ^[9]

P-value

< 0.0001 ^[10]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.66

Confidence interval

level

95%

sides

2-sided

lower limit

0.565

upper limit

0.768

Notes
[9] - 2-sided p-value
[10] - 2-sided p-value

Secondary: DR as Assessed by Investigator in Participants Irrespective of PD-L1 Expression

Top of page

End point title

DR as Assessed by Investigator in Participants Irrespective of PD-L1 Expression

End point description

Investigator assessed DR: time from first documentation of OR (confirmed CR or PR) to date of first documentation of objective tumor progression (PD) assessed by investigator or death due to any cause whichever occurred first. As per RECIST v1.1. CR: complete disappearance of all target and non-target lesions with the exception of nodal disease. All lymph nodes must decrease to normal size (short axis<10 mm). All target lesions must be assessed. PR: >=30% decrease under baseline of the sum of diameters of all target measurable lesions. All target lesions must be assessed. PD: at least a 20% increase in the sum of all the longest diameter of target lesions, taking as reference the smallest sum on study. In addition to relative increase of 20%, sum must have also demonstrated an absolute > of at least 5 mm. Appearance of one or more new lesions was also considered progression. FAS was used. N= participants evaluable for this endpoint.

End point type

Secondary

End point timeframe

From documentation of OR until date of first documentation of PD or death due to any cause, whichever occurred first (maximum up to approximately 89 months)

End point values	Avelumab + Axitinib	Sunitinib
Number of subjects analysed	264	142
Units: Months
median (confidence interval 95%)	19.4 (16.4 to 22.3)	14.5 (8.7 to 16.6)

No statistical analyses for this end point

Secondary: Duration of Response (DR) as Assessed by BICR in Participants Irrespective of PD-L1 Expression

Top of page

End point title

Duration of Response (DR) as Assessed by BICR in Participants Irrespective of PD-L1 Expression

End point description

BICR assessed DR: time from first documentation of OR(confirmed CR or PR) to date of first documentation of objective tumor progression assessed by BICR or death due to any cause whichever occurred first. As per RECIST v1.1. CR: complete disappearance of all target and non-target lesions with the exception of nodal disease. All lymph nodes must decrease to normal size (short axis<10 mm). All target lesions must be assessed. PR: >=30% decrease under baseline of sum of diameters of all target measurable lesions. All target lesions must be assessed. PD: at least 20% increase in sum of all longest diameter of target lesions, taking as reference smallest sum on study. In addition to relative increase of 20%, sum must have also demonstrated an absolute > of at least 5 mm. Appearance of one or more new lesions was also considered progression. FAS was used. N= participants evaluable for this endpoint. “99999” = values could not estimated due to insufficient number of participants with event.

End point type

Secondary

End point timeframe

From documentation of OR until date of first documentation of PD or death due to any cause, whichever occurred first (maximum up to approximately 26 months)

End point values	Avelumab + Axitinib	Sunitinib
Number of subjects analysed	227	114
Units: Months
median (confidence interval 95%)	99999 (99999 to 99999)	99999 (11.2 to 99999)

No statistical analyses for this end point

Secondary: Number of Participants With Treatment-Emergent Adverse Events (AEs) Graded Based on National Cancer Institute -Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version (V) 4.03

Top of page

End point title

Number of Participants With Treatment-Emergent Adverse Events (AEs) Graded Based on National Cancer Institute -Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version (V) 4.03

End point description

An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. TEAEs were those events with onset dates occurring during the on-treatment period for the first time, or if the worsening of an event was during the on-treatment period (time from the first dose of study treatment through 90 days after last dose of study treatment or start day of new anti-cancer drug therapy–1 day). As per NCI-CTCAE v4.03, grade 1=mild, grade 2=moderate, grade 3=severe, grade 4=life-threatening consequences and grade 5=death. Safety analysis set included all participants who received at least one dose of study drug.

End point type

Secondary

End point timeframe

From start of study treatment until 90 days after last dose of study treatment (maximum up to approximately 92 months)

End point values	Avelumab + Axitinib	Sunitinib
Number of subjects analysed	434	439
Units: Participants
Grade 1	5	17
Grade 2	64	73
Grade 3	271	268
Grade 4	64	54
Grade 5	30	24

No statistical analyses for this end point

Secondary: Progression-Free Survival on Next-line Therapy (PFS2) in Participants Irrespective of PD-L1 Expression

Top of page

End point title

Progression-Free Survival on Next-line Therapy (PFS2) in Participants Irrespective of PD-L1 Expression

End point description

PFS2 is defined as the time (in months) from randomization to discontinuation of next-line treatment after first objective disease progression by investigator assessment, second objective disease progression by investigator assessment after initiation of next-line treatment, or death from any cause, whichever occurred first. PD was defined as at least a 20% increase in the sum of all the longest diameter of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to relative increase of 20 %, sum must have also demonstrated an absolute > of at least 5 mm. The appearance of one or more new lesions was also considered progression. FAS included all randomized participants.

End point type

Secondary

End point timeframe

From date of randomization until PD or death due to any cause or censoring date, whichever occurred first (maximum up to approximately 89 months)

End point values	Avelumab + Axitinib	Sunitinib
Number of subjects analysed	442	444
Units: Months
median (confidence interval 95%)	30.4 (25.8 to 34.6)	19.4 (17.0 to 22.4)

Avelumab + Axitinib Versus Sunitinib

Comparison groups

Avelumab + Axitinib v Sunitinib

Number of subjects included in analysis

886

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Hazard ratio (HR)

Point estimate

0.64

Confidence interval

level

95%

sides

2-sided

lower limit

0.551

upper limit

0.754

Secondary: Number of Participants According to Grade Shift in Hematology Parameters

Top of page

End point title

Number of Participants According to Grade Shift in Hematology Parameters

End point description

Following hematology parameters were assessed: hemoglobin decreased (anemia), hemoglobin increased, lymphocyte count decreased, lymphocyte count increased, neutrophil count decreased, platelet count decreased and white blood cell (WBC) decreased. Laboratory abnormalities were graded as per NCI- CTCAE v 4.03 where, grade(G) 0= non-missing lab value that does not meet either of G1 through 4 criteria, G1=mild, G2=moderate, G3=severe, G4=life-threatening consequences and G5=death. Baseline was defined as last assessment prior to first dose of study treatment. Number of participants with a baseline grade of either 0,1,2,3 or 4 which shifted to G3-4 post-baseline are reported in this endpoint. Only non-zero categories for any reporting arm are reported. Safety analysis set included all participants who received at least one dose of study drug. N= number of participants evaluable for this endpoint.

End point type

Secondary

End point timeframe

From start of study treatment until 90 days after last dose of study treatment (maximum up to approximately 92 months)

End point values	Avelumab + Axitinib	Sunitinib
Number of subjects analysed	428	434
Units: Participants
Anemia (B G0 to PB G3-4)	3	9
Anemia (B G1 to PB G3-4)	6	21
Anemia (B G2 to PB G3-4)	4	14
Anemia (B G3 to PB G3-4)	0	2
Lymphocytes count decreased (B G0 to PB G3-4)	21	53
Lymphocytes count decreased (B G1 to PB G3-4)	11	18
Lymphocytes count decreased (B G2 to PB G3-4)	7	15
Lymphocytes count decreased (B G3 to PB G3-4)	2	6
Neutrophils count decreased (B G0 to PB G3-4)	7	108
Neutrophils count decreased (B G1 to PB G3-4)	0	2
Neutrophils count decreased (B G2 to PB G3-4)	0	1
Platelets count decreased (B G0 to PB G3-4)	3	61
Platelets count decreased (B G1 to PB G3-4)	1	6
WBC decreased (B G0 to PB G3-4)	1	35
WBC decreased (B G1 to PB G3-4)	0	7
WBC decreased (B G2 to PB G3-4)	0	2

No statistical analyses for this end point

Secondary: Number of Participants According to Grade Shift in Chemistry Parameters

Top of page

End point title

Number of Participants According to Grade Shift in Chemistry Parameters

End point description

Following chemistry parameters were assessed: alanine aminotransferase(ALT) increased,alkaline phosphatase(ALP) increased, aspartate aminotransferase(AST) increased (inc.), blood bilirubin increased, cholesterol high, creatinine phosphokinase(CPK) increased, creatinine increased,gamma glutamyl transferase(GGT) increased, hypercalcemia, hyperglycemia, hyperkalemia, hypermagnesmia, hypernatremia, hypertriglyceridemia, hypoalbuminemia, hypokalemia, hypomagnesemia, hyponatremia, lipase increased and serum amylase increased. Laboratory abnormality graded- NCI CTCAE v4.03; G0=non-missing lab value that does not meet either of G1 through 4 criteria, G1=mild,G2=moderate,G3=severe,G4=life-threatening consequences,G5=death. No. of participants with B grade of either 0,1,2,3/4 which shifted to G3-4 PB are reported. Only non-zero categories for any reporting arm reported. Safety analysis set. N= no. of participants evaluable for this endpoint. n= no. of participants evaluable for specified rows.

End point type

Secondary

End point timeframe

From start of study treatment until 90 days after last dose of study treatment (maximum up to approximately 92 months)

End point values	Avelumab + Axitinib	Sunitinib
Number of subjects analysed	428	433
Units: Participants
ALT increased (B G0 to PB G3-4) (n=428,433)	42	19
ALT increased (B G1 to PB G3-4) (n=428,433)	3	0
ALP increased (B G0 to PB G3-4) (n=428,433)	9	0
ALP increased (B G1 to PB G3-4) (n=428,433)	5	6
ALP increased (B G2 to PB G3-4) (n=428,433)	1	3
ALP increased (B G3 to PB G3-4) (n=428,433)	4	1
AST increased (B G0 to PB G3-4) (n=428,433)	26	16
AST increased (B G1 to PB G3-4) (n=428,433)	6	4
AST increased (B G3 to PB G3-4) (n=428,433)	1	0
Blood bilirubin inc(B G0 to PB G3-4) (n=428,433)	3	6
Blood bilirubin inc(B G1 to PB G3-4) (n=428,433)	2	0
Cholesterol high (B G0 to PB G3-4) (n=419,413)	8	3
Cholesterol high (B G1 to PB G3-4) (n=419,413)	4	3
Cholesterol high (B G2 to PB G3-4) (n=419,413)	0	1
CPK increased (B G0 to PB G3-4) (n=417,415)	7	7
CPK increased (B G1 to PB G3-4) (n=417,415)	0	2
CPK increased (B G2 to PB G3-4) (n=417,415)	0	1
CPK increased (B G3 to PB G3-4) (n=417,415)	1	0
Creatinine increased(B G0 to PB G3-4) (n=428,433)	7	2
Creatinine increased(B G1 to PB G3-4) (n=428,433)	4	5
Creatinine increased(B G2 to PB G3-4) (n=428,433)	0	1
Creatinine increased(B G3 to PB G3-4) (n=428,433)	0	1
GGT increased (B G0 to PB G3-4) (n=419,415)	15	16
GGT increased (B G1 to PB G3-4) (n=419,415)	20	7
GGT increased (B G2 to PB G3-4) (n=419,415)	12	4
GGT increased (B G3 to PB G3-4) (n=419,415)	7	2
GGT increased (B G4 to PB G3-4) (n=419,415)	0	1
Hypercalcemia (B G0 to PB G3-4) (n=418,419)	4	4
Hypercalcemia (B G1 to PB G3-4) (n=418,419)	1	2
Hypercalcemia (B G2 to PB G3-4) (n=418,419)	1	1
Hypercalcemia (B G3 to PB G3-4) (n=418,419)	0	2
Hypercalcemia (B G4 to PB G3-4) (n=418,419)	0	1
Hyperglycemia (B G0 to PB G3-4) (n=428,433)	37	20
Hyperglycemia (B G1 to PB G3-4) (n=428,433)	4	3
Hyperglycemia (B G2 to PB G3-4) (n=428,433)	5	3
Hyperglycemia (B G3 to PB G3-4) (n=428,433)	6	4
Hyperkalemia (B G0 to PB G3-4) (n=428,433)	19	16
Hyperkalemia (B G1 to PB G3-4) (n=428,433)	1	5
Hyperkalemia (B G2 to PB G3-4) (n=428,433)	3	3
Hyperkalemia (B G3 to PB G3-4) (n=428,433)	1	0
Hyperkalemia (B G4 to PB G3-4) (n=428,433)	0	1
Hypermagnesemia (B G0 to PB G3-4) (n=428,433)	13	20
Hypermagnesemia (B G1 to PB G3-4) (n=428,433)	1	2
Hypernatremia (B G0 to PB G3-4) (n=428,433)	7	2
Hypertriglyceridemia(B G0 to PB G3-4) (n=419,411)	18	3
Hypertriglyceridemia(B G1 to PB G3-4) (n=419,411)	31	23
Hypertriglyceridemia(B G2 to PB G3-4) (n=419,411)	15	6
Hypertriglyceridemia(B G3 to PB G3-4) (n=419,411)	4	5
Hypertriglyceridemia(B G4 to PB G3-4) (n=419,411)	0	1
Hypoalbunemia (B G0 to PB G3-4) (n=418,419)	3	6
Hypoalbunemia (B G1 to PB G3-4) (n=418,419)	1	1
Hypoalbunemia (B G2 to PB G3-4) (n=418,419)	2	2
Hypoalbunemia (B G3 to PB G3-4) (n=418,419)	1	2
Hypocalcemia (B G0 to PB G3-4) (n=418,419)	4	4
Hypocalcemia (B G1 to PB G3-4) (n=418,419)	0	1
Hypocalcemia (B G2 to PB G3-4) (n=418,419)	1	0
Hypoglycemia (B G0 to PB G3-4) (n=428,433)	2	1
Hypokalemia (B G0 to PB G3-4) (n=428,433)	17	15
Hypomagnesemia (B G0 to PB G3-4) (n=428,433)	3	1
Hypokalemia (B G2 to PB G3-4) (n=428,433)	2	1
Hypomagnesemia (B G1 to PB G3-4) (n=428,433)	2	1
Hypomagnesemia (B G2 to PB G3-4) (n=428,433)	1	0
Hyponatremia (B G0 to PB G3-4) (n=428,433)	42	35
Hyponatremia (B G1 to PB G3-4) (n=428,433)	19	14
Hyponatremia (B G3 to PB G3-4) (n=428,433)	1	2
Lipase increased (B G0 to PB G3-4) (n=419,414)	63	27
Lipase increased (B G1 to PB G3-4) (n=419,414)	19	8
Lipase increased (B G2 to PB G3-4) (n=419,414)	7	3
Lipase increased (B G3 to PB G3-4) (n=419,414)	2	7
Lipase increased (B G4 to PB G3-4) (n=419,414)	1	0
Serum amylase inc(B G0 to PB G3-4) (n=412,407)	21	4
Serum amylase inc(B G1 to PB G3-4) (n=412,407)	12	4
Serum amylase inc(B G2 to PB G3-4) (n=412,407)	4	4
Serum amylase inc(B G3 to PB G3-4) (n=412,407)	1	3

No statistical analyses for this end point

Secondary: Change From Baseline in Vital Signs - Blood Pressure at Day 1 of Cycle 2, 3, 4, 5, 6, 7 and End of Treatment (EOT) Visit

Top of page

End point title

Change From Baseline in Vital Signs - Blood Pressure at Day 1 of Cycle 2, 3, 4, 5, 6, 7 and End of Treatment (EOT) Visit

End point description

Systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured with the participant in the seated position after the participant had been sitting quietly for at least 5 minutes. Safety analysis set included all participants who received at least one dose of study drug. "n" signifies number of participants evaluable for the specified time points.

End point type

Secondary

End point timeframe

Baseline (pre-dose on Day 1 of Cycle 1), Day 1 of Cycle 2, 3, 4, 5, 6, 7, EOT visit (maximum up to approximately 89 months) (each cycle=42 days)

End point values	Avelumab + Axitinib	Sunitinib
Number of subjects analysed	434	439
Units: Millimeters of mercury
arithmetic mean (standard deviation)
Baseline: Sitting SBP (n=434,439)	126.5 ( 13.52 )	126.3 ( 12.00 )
Change at Cycle 2, Day 1: Sitting SBP(n=380,344)	4.7 ( 16.08 )	0.8 ( 12.49 )
Change at Cycle 3, Day 1: Sitting SBP(n=363,310)	3.8 ( 16.43 )	1.2 ( 12.81 )
Change at Cycle 4, Day 1: Sitting SBP(n=342,271)	3.0 ( 15.95 )	0.1 ( 13.01 )
Change at Cycle 5, Day 1: Sitting SBP(n=332,244)	2.5 ( 15.42 )	-0.1 ( 12.26 )
Change at Cycle 6, Day 1: Sitting SBP(n=310,215)	1.6 ( 15.39 )	-0.1 ( 12.97 )
Change at Cycle 7, Day 1: Sitting SBP(n=282,191)	1.9 ( 15.39 )	0.4 ( 13.56 )
Change at End of Treatment:SittingSBP (n=205,273)	0.9 ( 17.40 )	1.7 ( 15.67 )
Baseline: Sitting DBP (n=434,439)	75.7 ( 9.32 )	75.9 ( 9.41 )
Change at Cycle 2, Day 1: Sitting DBP(n=380,344)	5.8 ( 10.92 )	-0.1 ( 8.60 )
Change at Cycle 3, Day 1: Sitting DBP(n=363,310)	4.9 ( 10.98 )	0.0 ( 9.64 )
Change at Cycle 4, Day 1: Sitting DBP(n=342,271)	4.8 ( 11.61 )	-1.9 ( 9.30 )
Change at Cycle 5, Day 1: Sitting DBP(n=332,244)	4.5 ( 11.17 )	-1.9 ( 9.71 )
Change at Cycle 6, Day 1: Sitting DBP(n=310,215)	3.8 ( 10.18 )	-1.3 ( 9.89 )
Change at Cycle 7, Day 1: Sitting DBP(n=282,191)	3.8 ( 11.04 )	-1.1 ( 9.90 )
Change at End of Treatment:SittingDBP (n=205,273)	1.5 ( 12.70 )	-0.9 ( 10.92 )

No statistical analyses for this end point

Secondary: Change From Baseline in Vital Signs - Pulse Rate at Day 1 of Cycle 2, 3, 4, 5, 6, 7 and EOT Visit

Top of page

End point title

Change From Baseline in Vital Signs - Pulse Rate at Day 1 of Cycle 2, 3, 4, 5, 6, 7 and EOT Visit

End point description

Pulse rate (PR) was measured with the participant in the seated position after the participant had been sitting quietly for at least 5 minutes. Safety analysis set included all participants who received at least one dose of study drug. Here "Participants Analyzed" signifies number of participants evaluable for this outcome measure. "n" signifies number of participants evaluable for the specified time points.

End point type

Secondary

End point timeframe

Baseline (pre-dose on Day 1 of Cycle 1), Day 1 of Cycle 2, 3, 4, 5, 6, 7, EOT visit (maximum up to approximately 89 months) (each cycle=42 days)

End point values	Avelumab + Axitinib	Sunitinib
Number of subjects analysed	433	439
Units: Beats per minute
arithmetic mean (standard deviation)
Baseline: Sitting PR (n=433,439)	75.4 ( 12.49 )	75.6 ( 12.63 )
Change at Cycle 2, Day 1: Sitting PR (n=347,319)	0.4 ( 12.77 )	3.1 ( 10.69 )
Change at Cycle 3, Day 1: Sitting PR(n=338,289)	0.8 ( 12.58 )	3.1 ( 11.34 )
Change at Cycle 4, Day 1: Sitting PR(n=327,244)	-0.6 ( 12.79 )	2.8 ( 10.34 )
Change at Cycle 5, Day 1: Sitting PR(n=319,227)	-0.5 ( 12.00 )	2.5 ( 10.82 )
Change at Cycle 6, Day 1: Sitting PR(n=299,203)	-1.9 ( 12.37 )	1.6 ( 10.75 )
Change at Cycle 7, Day 1: Sitting PR(n=269,182)	-1.9 ( 11.69 )	2.1 ( 10.13 )
Change at End of Treatment:Sitting PR (n=196,250)	2.9 ( 15.29 )	3.5 ( 12.27 )

No statistical analyses for this end point

Secondary: Number of Participants who Discontinued Treatment due to Toxicity

Top of page

End point title

Number of Participants who Discontinued Treatment due to Toxicity

End point description

Number of participants who discontinued treatment due to toxicity are reported in this endpoint. Safety analysis set included all participants who received at least one dose of study drug.

End point type

Secondary

End point timeframe

From first dose of study treatment until discontinuation of study treatment (maximum up to approximately 92 months)

End point values	Avelumab + Axitinib	Sunitinib
Number of subjects analysed	434	439
Units: Participants	136	65

No statistical analyses for this end point

Secondary: Trough Plasma Concentration (Ctrough) of Avelumab

Top of page

End point title

Trough Plasma Concentration (Ctrough) of Avelumab ^[11]

End point description

Predose concentration during multiple dosing. Avelumab PK concentration analysis set: all participants who had at least one post-dose concentration above lower limit of quantitation (LLQ) for avelumab. Here "Participants Analyzed" signifies participants evaluable for this endpoint. "n" signifies number of participants evaluable for the specified rows. This endpoint was not planned to be analyzed in ‘’Sunitinib’’ reporting group.

End point type

Secondary

End point timeframe

Pre dose (0 hour) on Day 1, 15 and 29 of Cycle 1, Day 1 and 29 of Cycles 2, 3, 4 and Day 1 of Cycle 6

Notes
[11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint is specific to Avelumab; hence, only arm for Avelumab was included.

End point values	Avelumab + Axitinib
Number of subjects analysed	389
Units: Micrograms per milliliter
geometric mean (geometric coefficient of variation)
Cycle 1 (day 1) (n=389)	4.218 ( 1232 )
Cycle 1 (day 15) (n=267)	18.69 ( 102 )
Cycle 1 (day 29) (n=270)	21.99 ( 96 )
Cycle 2 (day 1) (n=314)	24.87 ( 92 )
Cycle 2 (day 29) (n=215)	22.62 ( 113 )
Cycle 3 (day 1) (n=202)	26.04 ( 98 )
Cycle 3 (day 29) (n=181)	30.13 ( 82 )
Cycle 4 (day 1) (n=186)	29.15 ( 98 )
Cycle 4 (day 29) (n=160)	31.38 ( 86 )
Cycle 6 (day 1) (n=130)	39.11 ( 58 )

No statistical analyses for this end point

Secondary: Time to Treatment Discontinuation/Failure Due to Toxicity

Top of page

End point title

Time to Treatment Discontinuation/Failure Due to Toxicity

End point description

Time to treatment discontinuation/ failure due to toxicity was defined as the time from first dose of study treatment to discontinuation of study treatment due to an adverse event or death due to study treatment toxicity. Safety analysis set included all participants who received at least one dose of study drug. Here "Participants Analyzed" signifies number of participants evaluable for this endpoint.

End point type

Secondary

End point timeframe

From first dose of study treatment until discontinuation of study treatment (maximum up to approximately 92 months)

End point values	Avelumab + Axitinib	Sunitinib
Number of subjects analysed	136	65
Units: Months
arithmetic mean (standard deviation)	13.5 ( 17.41 )	10.5 ( 12.82 )

No statistical analyses for this end point

Secondary: Maximum Plasma Concentration (Cmax) of Axitinib

Top of page

End point title

Maximum Plasma Concentration (Cmax) of Axitinib ^[12]

End point description

Axitinib PK concentration analysis set: all participants who received at least one dose of study drug and had at least one post-dose concentration above LLQ for axitinib. Here "Participants Analyzed" signifies participants evaluable for this endpoint. "n" signifies number of participants evaluable for the specified rows. This endpoint was not planned to be analyzed in ‘’Sunitinib’’ reporting group.

End point type

Secondary

End point timeframe

2 hours post-dose on Day 1, pre-dose and 2 hours post dose on Days 15 and 29 of Cycle 1

Notes
[12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint is specific to Axitinib; hence, only arm for Axitinib was included.

End point values	Avelumab + Axitinib
Number of subjects analysed	316
Units: Nanograms per milliliter
geometric mean (geometric coefficient of variation)
Cycle1 (day 1); Post Dose (n=316)	17.93 ( 182 )
Cycle1 (day 15); Pre-Dose (n=312)	4.904 ( 172 )
Cycle1 (day 15); Post Dose (n=286)	18.45 ( 157 )
Cycle1 (day 29); Pre-Dose (n=302)	6.272 ( 174 )
Cycle1 (day 29); Post Dose (n=272)	17.19 ( 174 )

No statistical analyses for this end point

Secondary: Ctrough of Axitinib

Top of page

End point title

Ctrough of Axitinib ^[13]

End point description

Predose concentration during multiple dosing. Axitinib PK concentration analysis set: all participants who received at least one dose of study drug and had at least one post-dose concentration above lower limit of quantitation (LLQ) for axitinib. Here "Number of Participants Analyzed" signifies participants evaluable for this endpoint. "Number Analyzed" signifies number of participants evaluable for the specified rows. This endpoint was not planned to be analyzed in ‘’Sunitinib’’ reporting group.

End point type

Secondary

End point timeframe

Pre dose (0 hour) on day 15 and 29 of cycle 1

Notes
[13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint is specific to Axitinib; hence, only arm for Axitinib was included.

End point values	Avelumab + Axitinib
Number of subjects analysed	312
Units: Nanograms per milliliter
geometric mean (geometric coefficient of variation)
Cycle1 (day 15) (n=312)	4.904 ( 172 )
Cycle1 (day 29) (n=302)	6.272 ( 174 )

No statistical analyses for this end point

Secondary: PFS in PD-L1 Biomarker-Positive and PD-L1 Biomarker-Negative Subgroups

Top of page

End point title

PFS in PD-L1 Biomarker-Positive and PD-L1 Biomarker-Negative Subgroups

End point description

PFS: time from date of randomization to date of first documentation of PD according to RECIST v1.1 or death due to any cause, whichever occurred first. PFS data was censored on date of last adequate tumor assessment for participants who did not have an event (PD or death), who started new anti-cancer therapy prior to an event or for participants with an event after 2 or more missing tumor assessments. PD was defined as at least 20% increase in sum of all longest diameter of target lesions, taking as reference smallest sum on study. In addition to relative increase of 20 %, sum must have also demonstrated an absolute > of at least 5 mm. Biomarker positive/negative subset in FAS included participants who had at least one biomarker baseline assessment. “N”= participants evaluable for this endpoint. "n" number of participants evaluable for specified rows. “99999” = upper limit of 95% CI was not estimable due to insufficient number of participants with event.

End point type

Secondary

End point timeframe

From date of randomization to the first documentation of PD or death due to any cause or censoring date, whichever occurred first (maximum up to approximately 26 months)

End point values	Avelumab + Axitinib	Sunitinib
Number of subjects analysed	402	410
Units: Months
median (confidence interval 95%)
PD-L1 Positive Tumors (n=270,290)	13.8 (11.1 to 99999)	7.2 (5.7 to 9.7)
PD-L1 Negative Tumors (n=132,120)	16.1 (9.7 to 99999)	11.1 (6.9 to 17.3)

No statistical analyses for this end point

Secondary: Percentage of Participants With OR in PD-L1 Biomarker-Positive and PD-L1 Biomarker-Negative Subgroups

Top of page

End point title

Percentage of Participants With OR in PD-L1 Biomarker-Positive and PD-L1 Biomarker-Negative Subgroups

End point description

OR was defined as best overall response of CR or PR according to RECIST v1.1 as assessed by BICR recorded from date of randomization until disease progression. CR was defined as complete disappearance of all target and non-target lesions with the exception of nodal disease. All lymph nodes must decrease to normal size (short axis<10 mm). All target lesions must be assessed. PR was defined as greater than or equal to 30% decrease under baseline of the sum of diameters of all target measurable lesions. All target lesions must be assessed. Biomarker positive/negative subset in FAS included participants who had at least one biomarker baseline assessment. Here "Participants Analyzed" signifies participants evaluable for this endpoint. "n" signifies number of participants evaluable for the specified rows.

End point type

Secondary

End point timeframe

From date of randomization until PD (maximum up to approximately 26 months)

End point values	Avelumab + Axitinib	Sunitinib
Number of subjects analysed	402	410
Units: Percentage of participants
number (confidence interval 95%)
PD-L1 Positive Tumors (n=270,290)	55.2 (49.0 to 61.2)	25.5 (20.6 to 30.9)
PD-L1 Negative Tumors (n=132,120)	47.0 (38.2 to 55.8)	28.3 (20.5 to 37.3)

No statistical analyses for this end point

Secondary: Number of Participants With Positive PD-L1 Biomarker Expression in Pre-treatment Tumor Tissue

Top of page

End point title

Number of Participants With Positive PD-L1 Biomarker Expression in Pre-treatment Tumor Tissue

End point description

Tumor biospecimens from pre-treatment tissue samples were analyzed by immunohistochemistry for PD-L1 biomarker expression. Number of participants with positive PD-L1 biomarker expression are reported in this endpoint. Biomarker analysis set for biomarkers that are measured only at screening, included all participants who received at least one dose of study drug and who had at least one screening biomarker assessment. Here "n" signifies participants evaluable for this endpoint.

End point type

Secondary

End point timeframe

At screening

End point values	Avelumab + Axitinib	Sunitinib
Number of subjects analysed	397	407
Units: Participants	266	288

No statistical analyses for this end point

Secondary: Percentage of Participants With DC in Biomarker-Positive Subgroup

Top of page

End point title

Percentage of Participants With DC in Biomarker-Positive Subgroup

End point description

DC was defined as a best overall response of CR, PR, or SD according to the RECIST v.1.1 recorded from randomization until disease progression or death due to any cause, whichever occurred first. CR was defined as complete disappearance of all target and non-target lesions with the exception of nodal disease. All lymph nodes must decrease to normal size (short axis<10 mm). All target lesions must be assessed. PR was defined as greater than or equal to 30% decrease under baseline of the sum of diameters of all target measurable lesions. All target lesions must be assessed. SD was defined as PR that the sum increases by less than 20% from the nadir, (smallest sum of diameters consider baseline and all assessments prior to the time point under evaluation), but enough that a previously documented 30% decrease no longer holds. Biomarker positive subset in FAS included participants who had at least one biomarker baseline assessment.

End point type

Secondary

End point timeframe

From date of randomization until PD or death, whichever occurred first (maximum up to approximately 26 months)

End point values	Avelumab + Axitinib	Sunitinib
Number of subjects analysed	270	290
Units: Percentage of participants
number (confidence interval 95%)	84.4 (79.6 to 88.6)	71.0 (65.4 to 76.2)

No statistical analyses for this end point

Secondary: TTR in Biomarker-Positive Subgroup

Top of page

End point title

TTR in Biomarker-Positive Subgroup

End point description

TTR was defined as the time from randomization to the first documentation of objective tumor response (CR or PR) according to RECIST v1.1 which is subsequently confirmed. CR was defined as complete disappearance of all target and non-target lesions with the exception of nodal disease. All lymph nodes must decrease to normal size (short axis<10 mm). All target lesions must be assessed. PR was defined as greater than or equal to 30% decrease under baseline of the sum of diameters of all target measurable lesions. All target lesions must be assessed. Biomarker positive subset in FAS included participants who had at least one biomarker baseline assessment. Here "Participants Analyzed" signifies participants evaluable for this endpoint.

End point type

Secondary

End point timeframe

From the date of randomization to the first documentation of objective response (CR or PR) (maximum up to approximately 26 months)

End point values	Avelumab + Axitinib	Sunitinib
Number of subjects analysed	149	74
Units: Months
median (full range (min-max))	1.6 (1.2 to 10.1)	3.0 (1.2 to 11.6)

No statistical analyses for this end point

Secondary: DR in PD-L1 Biomarker-Positive and PD-L1 Biomarker-Negative Subgroups

Top of page

End point title

DR in PD-L1 Biomarker-Positive and PD-L1 Biomarker-Negative Subgroups

End point description

DR: time from first documentation of OR (confirmed CR or PR) to date of first documentation of PD or death due to any cause, whichever occurred first. As per RECIST version 1.1, CR: disappearance of all target and non-target lesions, and sustained for at least 4 weeks. Any pathological lymph nodes (target or non-target) must have reduction in short axis to <10 mm. PR: at least 30%< in sum of longest dimensions of target lesions taking as reference baseline sum longest dimensions. PD: defined as at least a 20% > in sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to relative increase of 20%, sum must have also demonstrated an absolute increase of at least 5 mm. Biomarker positive/negative subset in FAS used. "N" = participants evaluable for this endpoint. "n" signifies number of participants evaluable for specified rows. “99999” = values were not estimable due to insufficient number of participants with event.

End point type

Secondary

End point timeframe

From documentation of OR until date of first documentation of PD or death due to any cause, whichever occurred first (maximum up to approximately 26 months)

End point values	Avelumab + Axitinib	Sunitinib
Number of subjects analysed	211	108
Units: Months
median (confidence interval 95%)
PD-L1 Positive Tumors (n=149,74)	99999 (99999 to 99999)	99999 (10.9 to 99999)
PD-L1 Negative Tumors (n=62,34)	99999 (11.1 to 99999)	99999 (9.0 to 99999)

No statistical analyses for this end point

Secondary: Time to Symptom Deterioration (TTD) for Functional Assessment of Cancer Therapy (FACT)-Kidney Symptom Index - Disease Related Symptoms (FKSI-DRS)

Top of page

End point title

Time to Symptom Deterioration (TTD) for Functional Assessment of Cancer Therapy (FACT)-Kidney Symptom Index - Disease Related Symptoms (FKSI-DRS)

End point description

TTD was defined as the time from date of randomization to the first time the participant’s score showed a 3-point or greater decrease in FKSI-DRS. FKSI was used to assess symptoms and quality of life (QoL) for those diagnosed with advanced kidney cancer and it consisted of 19 questions. A 9-item subscale of the FKSI known as FKSI-Disease Related Symptoms subscale (FKSI-DRS). This subscale included 9 items: lack of energy, pain, losing weight, bone pain, fatigue, shortness of breath, coughing, bothered by fevers, and hematuria. Each of the 9 items was answered on a 5-point Likert-type scale ranging from 0 to 4 (0= not at all, 1= a little bit, 2= somewhat, 3= quite a bit, 4= very much). Total FKSI-DRS score = sum of the 9 item scores; total range: 0 - 36; 0 (no symptoms) to 36 (very much); higher score indicated greater presence of symptoms. FAS included all randomized participants.

End point type

Secondary

End point timeframe

Date of randomization to the first time the participant’s score showed a 3-point or greater decrease in FKSI-DRS (maximum up to approximately 26 months)

End point values	Avelumab + Axitinib	Sunitinib
Number of subjects analysed	442	444
Units: Months
median (full range (min-max))	4.2 (4.2 to 5.7)	6.3 (5.5 to 8.3)

No statistical analyses for this end point

Secondary: Change From Baseline in European Quality of Life (EuroQol) 5-Dimension 5 Levels (EQ-5D-5L) Utility Score

Top of page

End point title

Change From Baseline in European Quality of Life (EuroQol) 5-Dimension 5 Levels (EQ-5D-5L) Utility Score

End point description

EQ-5D-5L is 5-item participant-completed questionnaire designed to assess health status in terms of a single utility score. EQ-5D health state profile is comprised of 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: 1=no problems, 2=slight problems, 3=moderate problems, 4=severe problems, and 5=extreme problems. Overall scores ranged from 0 to 1, with low scores representing higher level of dysfunction. Published UK weights were used to create single summary utility score. Utility scores range from -0.594 to 1, with higher scores=health status. FAS included all randomized participants. All participants reported under "N" contributed data to table; however, may not have evaluable data for every row. "n" signifies number of participants evaluable for specified rows. "99999"= SD could not be calculated as only 1 participant was analyzed. “88888” mean and SD could not be calculated as 0 participant was analyzed.

End point type

Secondary

End point timeframe

Baseline, Day 1 of Cycle 2 to Cycle 60, End of treatment (any Day from Day 1 of dosing; maximum up to approximately 89 months)

End point values	Avelumab + Axitinib	Sunitinib
Number of subjects analysed	442	444
Units: Units on a scale
arithmetic mean (standard deviation)
Cycle 2 (Day 1) (n=381,355)	-0.034 ( 0.1743 )	0.001 ( 0.1632 )
Cycle 3 (Day 1) (n=356,317)	-0.023 ( 0.1826 )	-0.017 ( 0.1804 )
Cycle 4 (Day 1) (n=335,283)	-0.029 ( 0.1829 )	-0.022 ( 0.1667 )
Cycle 5 (Day 1) (n=324,260)	-0.019 ( 0.1622 )	-0.016 ( 0.1826 )
Cycle 6 (Day 1) (n=300,229)	-0.025 ( 0.1787 )	-0.003 ( 0.1967 )
Cycle 7 (Day 1) (n=276,202)	-0.018 ( 0.1651 )	0.008 ( 0.1618 )
Cycle 8 (Day 1) (n=264,177)	-0.029 ( 0.1848 )	0.002 ( 0.1731 )
Cycle 9 (Day 1) (n=249,155)	-0.029 ( 0.2021 )	-0.011 ( 0.1662 )
Cycle 10 (Day 1) (n=236,152)	-0.025 ( 0.1935 )	-0.018 ( 0.1617 )
Cycle 11 (Day 1) (n=228,138)	-0.020 ( 0.1854 )	0.004 ( 0.1642 )
Cycle 12 (Day 1) (n=209,123)	-0.026 ( 0.1875 )	-0.016 ( 0.1712 )
Cycle 13 (Day 1) (n=208,111)	-0.026 ( 0.1777 )	-0.017 ( 0.1549 )
Cycle 14 (Day 1) (n=197,102)	-0.036 ( 0.1938 )	-0.006 ( 0.1600 )
Cycle 15 (Day 1) (n=192,102)	-0.036 ( 0.1892 )	0.018 ( 0.1487 )
Cycle 16 (Day 1) (n=175,95)	-0.044 ( 0.1757 )	0.020 ( 0.1663 )
Cycle 17 (Day 1) (n=168,89)	-0.050 ( 0.1950 )	-0.000 ( 0.1675 )
Cycle 18 (Day 1) (n=160,81)	-0.040 ( 0.1667 )	-0.027 ( 0.1765 )
Cycle 19 (Day 1) (n=148,78)	-0.059 ( 0.1959 )	0.003 ( 0.1665 )
Cycle 20 (Day 1) (n=143,71)	-0.050 ( 0.1942 )	0.001 ( 0.1538 )
Cycle 21 (Day 1) (n=135,67)	-0.048 ( 0.1902 )	-0.004 ( 0.1904 )
Cycle 22 (Day 1) (n=129,60)	0.037 ( 0.1919 )	0.002 ( 0.1561 )
Cycle 23 (Day 1) (n=118,58)	-0.033 ( 0.2021 )	-0.028 ( 0.1729 )
Cycle 24 (Day 1) (n=116,54)	-0.036 ( 0.1982 )	0.004 ( 0.1618 )
Cycle 25 (Day 1) (n=112,54)	-0.019 ( 0.1825 )	-0.007 ( 0.1678 )
Cycle 26 (Day 1) (n=111,48)	-0.039 ( 0.1927 )	-0.009 ( 0.1471 )
Cycle 27 (Day 1) (n=107,45)	-0.046 ( 0.2233 )	0.014 ( 0.1492 )
Cycle 28 (Day 1) (n=99,40)	-0.039 ( 0.2060 )	-0.007 ( 0.1639 )
Cycle 29 (Day 1) (n=99,38)	-0.019 ( 0.2095 )	0.017 ( 0.1601 )
Cycle 30 (Day 1) (n=94,36)	-0.032 ( 0.2244 )	-0.003 ( 0.1557 )
Cycle 31 (Day 1) (n=90,35)	-0.042 ( 0.2246 )	-0.009 ( 0.1508 )
Cycle 32 (Day 1) (n=86,31)	-0.044 ( 0.2095 )	0.032 ( 0.1255 )
Cycle 33 (Day 1) (n=80,29)	-0.051 ( 0.2294 )	-0.060 ( 0.3550 )
Cycle 34 (Day 1) (n=77,26)	-0.029 ( 0.1776 )	0.038 ( 0.1558 )
Cycle 35 (Day 1) (n=66,26)	-0.010 ( 0.1442 )	-0.002 ( 0.1610 )
Cycle 36 (Day 1) (n=65,24)	-0.016 ( 0.1599 )	0.030 ( 0.1551 )
Cycle 37 (Day 1) (n=64,22)	-0.027 ( 0.1507 )	0.052 ( 0.1601 )
Cycle 38 (Day 1) (n=59,21)	-0.016 ( 0.1459 )	0.057 ( 0.1666 )
Cycle 39 (Day 1) (n=56,18)	-0.042 ( 0.1569 )	0.052 ( 0.1386 )
Cycle 40 (Day 1) (n=55,18)	-0.021 ( 0.1484 )	0.060 ( 0.1232 )
Cycle 41 (Day 1) (n=51,17)	-0.030 ( 0.1492 )	0.056 ( 0.1853 )
Cycle 42 (Day 1) (n=48,17)	-0.021 ( 0.1634 )	0.034 ( 0.1585 )
Cycle 43 (Day 1) (n=45,16)	-0.031 ( 0.1334 )	0.011 ( 0.2062 )
Cycle 44 (Day 1) (n=48,16)	-0.028 ( 0.1300 )	0.016 ( 0.2114 )
Cycle 45 (Day 1) (n=45,15)	-0.050 ( 0.1442 )	0.007 ( 0.2191 )
Cycle 46 (Day 1) (n=43,15)	-0.042 ( 0.1380 )	-0.007 ( 0.2495 )
Cycle 47 (Day 1) (n=39,13)	-0.019 ( 0.1240 )	-0.015 ( 0.2335 )
Cycle 48 (Day 1) (n=39,12)	-0.025 ( 0.1566 )	0.009 ( 0.2833 )
Cycle 49 (Day 1) (n=36,12)	-0.028 ( 0.1356 )	0.010 ( 0.1873 )
Cycle 50 (Day 1) (n=34,12)	-0.028 ( 0.1359 )	0.028 ( 0.2507 )
Cycle 51 (Day 1) (n=26,11)	-0.011 ( 0.1304 )	-0.010 ( 0.2594 )
Cycle 52 (Day 1) (n=25,11)	-0.036 ( 0.1265 )	-0.035 ( 0.2524 )
Cycle 53 (Day 1) (n=18,9)	-0.084 ( 0.1437 )	0.048 ( 0.1308 )
Cycle 54 (Day 1) (n=18,8)	-0.040 ( 0.1425 )	0.078 ( 0.1157 )
Cycle 55 (Day 1) (n=14,5)	-0.046 ( 0.1121 )	0.051 ( 0.1060 )
Cycle 56 (Day 1) (n=9,2)	-0.083 ( 0.1081 )	0.025 ( 0.1796 )
Cycle 57 (Day 1) (n=8,1)	-0.104 ( 0.1347 )	0.031 ( 99999 )
Cycle 58 (Day 1) (n=7,1)	-0.078 ( 0.1408 )	0.031 ( 99999 )
Cycle 59 (Day 1) (n=5,0)	-0.106 ( 0.1053 )	88888 ( 88888 )
Cycle 60 (Day 1) (n=3,0)	-0.040 ( 0.1167 )	88888 ( 88888 )
End of Treatment (n=275,297	-0.111 ( 0.2464 )	-0.069 ( 0.2375 )

No statistical analyses for this end point

Secondary: Number of Participants With Positive Anti-Drug Antibodies (ADA) and Neutralizing Antibodies (nAb) of Avelumab When Used in Combination With Axitinib

Top of page

End point title

Number of Participants With Positive Anti-Drug Antibodies (ADA) and Neutralizing Antibodies (nAb) of Avelumab When Used in Combination With Axitinib ^[14]

End point description

Immunogenicity analysis set included all participants who received at least one dose of study drug and who had at least one ADA/nAb sample collected for avelumab in “Avelumab + Axitinib” arm. Here "Participants Analyzed" signifies participants evaluable for this endpoint. This endpoint was not planned to be analyzed for ‘’Sunitinib’’ reporting group.

End point type

Secondary

End point timeframe

From start of treatment until 30 days after the end of avelumab treatment (maximum up to approximately 90 months)

Notes
[14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint is specific to Avelumab and Axitinib; hence, only arm for Avelumab and Axitinib was included.

End point values	Avelumab + Axitinib
Number of subjects analysed	433
Units: Participants
ADA Positive	77
nAb Positive	51

No statistical analyses for this end point

Secondary: Change From Baseline in EQ-5D Visual Analogue Scale (VAS) Score

Top of page

End point title

Change From Baseline in EQ-5D Visual Analogue Scale (VAS) Score

End point description

EQ-VAS records the participant’s self-rated health status from 0 (worst imaginable health status) to 100 (best imaginable health status), where higher scores indicated better health status. FAS included all randomized participants. All participants reported under "Participants Analyzed" contributed data to the table; however, may not have evaluable data for every row. "n" signifies number of participants evaluable for the specified rows. "99999"= SD could not be calculated as only 1 participant was analyzed. “88888” mean and SD could not be calculated as 0 participant was analyzed.

End point type

Secondary

End point timeframe

Baseline, Day 1 of Cycle 2 to Cycle 60, End of treatment (any Day from Day 1 of dosing; maximum up to approximately 89 months)

End point values	Avelumab + Axitinib	Sunitinib
Number of subjects analysed	442	444
Units: Units on a scale
arithmetic mean (standard deviation)
Cycle 2 (Day 1) (n=381,347)	-0.9 ( 16.12 )	-0.2 ( 15.85 )
Cycle 3 (Day 1) (n=355,312)	-0.4 ( 16.39 )	0.4 ( 16.44 )
Cycle 4 (Day 1) (n=333,278)	-0.1 ( 17.23 )	0.7 ( 17.26 )
Cycle 5 (Day 1) (n=322,258)	0.4 ( 16.66 )	1.8 ( 16.16 )
Cycle 6 (Day 1) (n=296,224)	1.3 ( 16.05 )	2.6 ( 15.35 )
Cycle 7 (Day 1) (n=275,197)	1.2 ( 16.34 )	3.3 ( 14.91 )
Cycle 8 (Day 1) (n=266,174)	1.4 ( 16.54 )	2.9 ( 13.84 )
Cycle 9 (Day 1) (n=246,154)	2.0 ( 16.06 )	3.3 ( 13.77 )
Cycle 10 (Day 1) (n=233,150)	1.6 ( 15.12 )	2.4 ( 14.46 )
Cycle 11 (Day 1) (n=225,135)	2.5 ( 15.70 )	4.1 ( 12.91 )
Cycle 12 (Day 1) (n=207,121)	2.1 ( 14.72 )	2.6 ( 14.59 )
Cycle 13 (Day 1) (n=205,110)	3.0 ( 14.39 )	2.7 ( 14.29 )
Cycle 14 (Day 1) (n=196,101)	2.7 ( 15.07 )	3.0 ( 13.98 )
Cycle 15 (Day 1) (n=192,101)	3.1 ( 14.97 )	4.7 ( 13.63 )
Cycle 16 (Day 1) (n=175,94)	2.9 ( 15.08 )	3.6 ( 14.02 )
Cycle 17 (Day 1) (n=167,88)	3.0 ( 15.44 )	3.2 ( 12.88 )
Cycle 18 (Day 1) (n=162,82)	3.2 ( 15.31 )	2.0 ( 13.69 )
Cycle 19 (Day 1) (n=147,78)	4.5 ( 15.61 )	3.0 ( 13.10 )
Cycle 20 (Day 1) (n=142,71)	3.9 ( 15.15 )	3.1 ( 12.58 )
Cycle 21 (Day 1) (n=132,67)	3.7 ( 16.30 )	2.1 ( 13.00 )
Cycle 22 (Day 1) (n=128,60)	4.3 ( 16.43 )	2.6 ( 12.82 )
Cycle 23 (Day 1) (n=117,58)	3.7 ( 16.90 )	1.3 ( 15.16 )
Cycle 24 (Day 1) (n=115,55)	3.3 ( 18.70 )	4.5 ( 13.45 )
Cycle 25 (Day 1) (n=113,54)	4.6 ( 15.28 )	4.2 ( 14.42 )
Cycle 26 (Day 1) (n=111,48)	4.4 ( 17.10 )	3.4 ( 13.00 )
Cycle 27 (Day 1) (n=106,45)	4.7 ( 16.59 )	5.4 ( 13.43 )
Cycle 28 (Day 1) (n=98,40)	6.3 ( 16.08 )	5.0 ( 13.84 )
Cycle 29 (Day 1) (n=98,38)	4.8 ( 15.44 )	5.4 ( 14.24 )
Cycle 30 (Day 1) (n=94,36)	6.0 ( 15.78 )	5.3 ( 14.61 )
Cycle 31 (Day 1) (n=89,35)	5.7 ( 15.42 )	5.2 ( 14.88 )
Cycle 32 (Day 1) (n=85,31)	5.4 ( 16.35 )	6.0 ( 13.57 )
Cycle 33 (Day 1) (n=79,29)	5.5 ( 16.07 )	3.6 ( 20.61 )
Cycle 34 (Day 1) (n=76,26)	4.8 ( 15.25 )	6.1 ( 15.91 )
Cycle 35 (Day 1) (n=65,26)	6.0 ( 14.53 )	6.4 ( 15.61 )
Cycle 36 (Day 1) (n=64,24)	6.0 ( 15.63 )	5.2 ( 17.11 )
Cycle 37 (Day 1) (n=63,22)	5.8 ( 14.63 )	4.5 ( 15.86 )
Cycle 38 (Day 1) (n=58,20)	5.3 ( 14.58 )	4.3 ( 17.58 )
Cycle 39 (Day 1) (n=56,18)	5.3 ( 14.04 )	5.9 ( 15.75 )
Cycle 40 (Day 1) (n=54,18)	6.0 ( 15.00 )	4.7 ( 18.17 )
Cycle 41 (Day 1) (n=52,17)	5.6 ( 13.69 )	6.2 ( 18.37 )
Cycle 42 (Day 1) (n=47,17)	5.3 ( 13.68 )	5.4 ( 18.19 )
Cycle 43 (Day 1) (n=44,16)	6.6 ( 11.64 )	5.4 ( 20.14 )
Cycle 44 (Day 1) (n=47,16)	4.9 ( 13.38 )	5.1 ( 19.77 )
Cycle 45 (Day 1) (n=44,15)	6.3 ( 12.55 )	1.5 ( 17.97 )
Cycle 46 (Day 1) (n=41,15)	6.7 ( 13.25 )	0.3 ( 19.31 )
Cycle 47 (Day 1) (n=38,13)	5.4 ( 11.10 )	2.5 ( 18.07 )
Cycle 48 (Day 1) (n=38,12)	4.4 ( 11.73 )	3.5 ( 21.77 )
Cycle 49 (Day 1) (n=35,12)	4.2 ( 12.21 )	1.9 ( 21.42 )
Cycle 50 (Day 1) (n=33,12)	4.8 ( 13.07 )	2.9 ( 20.53 )
Cycle 51 (Day 1) (n=26,10)	5.8 ( 12.36 )	2.1 ( 22.93 )
Cycle 52 (Day 1) (n=25,11)	4.2 ( 11.37 )	1.5 ( 19.94 )
Cycle 53 (Day 1) (n=18,9)	3.2 ( 11.43 )	7.7 ( 16.22 )
Cycle 54 (Day 1) (n=18,8)	4.6 ( 11.54 )	7.5 ( 13.34 )
Cycle 55 (Day 1) (n=14,5)	4.6 ( 11.65 )	7.8 ( 17.89 )
Cycle 56 (Day 1) (n=9,2)	-0.6 ( 8.08 )	-6.0 ( 5.66 )
Cycle 57 (Day 1) (n=8,1)	-1.9 ( 10.67 )	-2.0 ( 99999 )
Cycle 58 (Day 1) (n=7,1)	-2.1 ( 8.59 )	-2.0 ( 99999 )
Cycle 59 (Day 1) (n=5,0)	0.0 ( 9.35 )	88888 ( 88888 )
Cycle 60 (Day 1) (n=3,0)	-1.7 ( 16.07 )	88888 ( 88888 )
End of Treatment (n=277,296)	-5.0 ( 19.92 )	-4.3 ( 19.63 )

No statistical analyses for this end point

Adverse events

Top of page

Timeframe for reporting adverse events

From start of study treatment until 90 days after last dose of study treatment (maximum up to approximately 92 months)

Adverse event reporting additional description

Same event may appear as both non-SAE and SAE but are distinct events. An event may be categorized as serious in 1 participant and non-serious in another, or a participant may have experienced both SAE and non-SAE. For SAEs and non-SAEs safety analysis set was used. For All-cause mortality, FAS was used.

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

v27.0

Reporting group title

Sunitinib

Reporting group description

Reporting group title

Avelumab + Axitinib

Reporting group description

Serious adverse events	Sunitinib	Avelumab + Axitinib
Total subjects affected by serious adverse events
subjects affected / exposed	166 / 439 (37.81%)	231 / 434 (53.23%)
number of deaths (all causes)	296	284
number of deaths resulting from adverse events	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma of colon
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Gastric cancer
subjects affected / exposed	1 / 439 (0.23%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Bladder transitional cell carcinoma
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Breast cancer
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cancer pain
subjects affected / exposed	1 / 439 (0.23%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Colorectal cancer
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Endometrial cancer
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Basal cell carcinoma
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Invasive lobular breast carcinoma
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Lung neoplasm malignant
subjects affected / exposed	1 / 439 (0.23%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Malignant melanoma
subjects affected / exposed	1 / 439 (0.23%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Malignant neoplasm progression
subjects affected / exposed	1 / 439 (0.23%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Tumour associated fever
subjects affected / exposed	1 / 439 (0.23%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Prostate cancer
subjects affected / exposed	1 / 439 (0.23%)	4 / 434 (0.92%)
occurrences causally related to treatment / all	0 / 2	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
Renal cancer
subjects affected / exposed	1 / 439 (0.23%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Renal cell carcinoma
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Squamous cell carcinoma
subjects affected / exposed	1 / 439 (0.23%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Neoplasm progression
subjects affected / exposed	3 / 439 (0.68%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 4	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Tumour pain
subjects affected / exposed	1 / 439 (0.23%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular disorders
Aortic aneurysm
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Aortic dissection
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Arterial insufficiency
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Circulatory collapse
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Deep vein thrombosis
subjects affected / exposed	0 / 439 (0.00%)	2 / 434 (0.46%)
occurrences causally related to treatment / all	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Embolism
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Infarction
subjects affected / exposed	1 / 439 (0.23%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Haematoma
subjects affected / exposed	3 / 439 (0.68%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hypertension
subjects affected / exposed	3 / 439 (0.68%)	3 / 434 (0.69%)
occurrences causally related to treatment / all	2 / 3	2 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Hypertensive crisis
subjects affected / exposed	1 / 439 (0.23%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hypotension
subjects affected / exposed	1 / 439 (0.23%)	6 / 434 (1.38%)
occurrences causally related to treatment / all	0 / 1	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 0
Hypovolaemic shock
subjects affected / exposed	1 / 439 (0.23%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Embolism venous
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Peripheral arterial occlusive disease
subjects affected / exposed	0 / 439 (0.00%)	2 / 434 (0.46%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Thrombosis
subjects affected / exposed	1 / 439 (0.23%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Peripheral embolism
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	0 / 439 (0.00%)	4 / 434 (0.92%)
occurrences causally related to treatment / all	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Chest discomfort
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Chest pain
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Death
subjects affected / exposed	0 / 439 (0.00%)	6 / 434 (1.38%)
occurrences causally related to treatment / all	0 / 0	4 / 6
deaths causally related to treatment / all	0 / 0	0 / 0
Disease progression
subjects affected / exposed	7 / 439 (1.59%)	10 / 434 (2.30%)
occurrences causally related to treatment / all	1 / 7	0 / 10
deaths causally related to treatment / all	0 / 0	0 / 0
Fatigue
subjects affected / exposed	1 / 439 (0.23%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
General physical health deterioration
subjects affected / exposed	1 / 439 (0.23%)	3 / 434 (0.69%)
occurrences causally related to treatment / all	1 / 1	2 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Localised oedema
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Mucosal inflammation
subjects affected / exposed	1 / 439 (0.23%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Multiple organ dysfunction syndrome
subjects affected / exposed	1 / 439 (0.23%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Non-cardiac chest pain
subjects affected / exposed	4 / 439 (0.91%)	3 / 434 (0.69%)
occurrences causally related to treatment / all	2 / 4	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Oedema peripheral
subjects affected / exposed	1 / 439 (0.23%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Peripheral swelling
subjects affected / exposed	1 / 439 (0.23%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	6 / 439 (1.37%)	5 / 434 (1.15%)
occurrences causally related to treatment / all	5 / 6	3 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
Sudden death
subjects affected / exposed	0 / 439 (0.00%)	2 / 434 (0.46%)
occurrences causally related to treatment / all	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Swelling
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Immune system disorders
Anaphylactic reaction
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Reproductive system and breast disorders
Endometrial hyperplasia
subjects affected / exposed	1 / 439 (0.23%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gynaecomastia
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Bronchial obstruction
subjects affected / exposed	1 / 439 (0.23%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Acute respiratory failure
subjects affected / exposed	2 / 439 (0.46%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Atelectasis
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cough
subjects affected / exposed	1 / 439 (0.23%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	6 / 439 (1.37%)	8 / 434 (1.84%)
occurrences causally related to treatment / all	1 / 6	5 / 9
deaths causally related to treatment / all	0 / 0	0 / 0
Dyspnoea exertional
subjects affected / exposed	1 / 439 (0.23%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Epistaxis
subjects affected / exposed	3 / 439 (0.68%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	2 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Haemoptysis
subjects affected / exposed	2 / 439 (0.46%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 2	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonitis
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hypoxia
subjects affected / exposed	1 / 439 (0.23%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Interstitial lung disease
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Lung disorder
subjects affected / exposed	1 / 439 (0.23%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	2 / 439 (0.46%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 3	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Hypercapnia
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumothorax
subjects affected / exposed	2 / 439 (0.46%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	1 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	4 / 439 (0.91%)	5 / 434 (1.15%)
occurrences causally related to treatment / all	1 / 4	1 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary haemorrhage
subjects affected / exposed	1 / 439 (0.23%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary toxicity
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory failure
subjects affected / exposed	2 / 439 (0.46%)	3 / 434 (0.69%)
occurrences causally related to treatment / all	0 / 2	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Psychiatric disorders
Confusional state
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Investigations
Electrocardiogram abnormal
subjects affected / exposed	1 / 439 (0.23%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Aspartate aminotransferase increased
subjects affected / exposed	0 / 439 (0.00%)	2 / 434 (0.46%)
occurrences causally related to treatment / all	0 / 0	4 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Blood bilirubin increased
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	3 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Blood corticotrophin increased
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Blood creatinine increased
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Ejection fraction decreased
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Electrocardiogram T wave inversion
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Alanine aminotransferase increased
subjects affected / exposed	0 / 439 (0.00%)	2 / 434 (0.46%)
occurrences causally related to treatment / all	0 / 0	4 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Gamma-glutamyltransferase increased
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Myocardial necrosis marker increased
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Troponin I increased
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Troponin increased
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Injury, poisoning and procedural complications
Arterial injury
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Fall
subjects affected / exposed	1 / 439 (0.23%)	2 / 434 (0.46%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Jaw fracture
subjects affected / exposed	1 / 439 (0.23%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Femur fracture
subjects affected / exposed	1 / 439 (0.23%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Fracture
subjects affected / exposed	1 / 439 (0.23%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Humerus fracture
subjects affected / exposed	0 / 439 (0.00%)	2 / 434 (0.46%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Incisional hernia
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Infusion related reaction
subjects affected / exposed	0 / 439 (0.00%)	5 / 434 (1.15%)
occurrences causally related to treatment / all	0 / 0	5 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
Femoral neck fracture
subjects affected / exposed	1 / 439 (0.23%)	2 / 434 (0.46%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Lower limb fracture
subjects affected / exposed	1 / 439 (0.23%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Lumbar vertebral fracture
subjects affected / exposed	1 / 439 (0.23%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Periprosthetic fracture
subjects affected / exposed	1 / 439 (0.23%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Procedural pain
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Rib fracture
subjects affected / exposed	1 / 439 (0.23%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Tibia fracture
subjects affected / exposed	1 / 439 (0.23%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Congenital, familial and genetic disorders
Hydrocele
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders
Cardiomyopathy
subjects affected / exposed	1 / 439 (0.23%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Acute myocardial infarction
subjects affected / exposed	0 / 439 (0.00%)	11 / 434 (2.53%)
occurrences causally related to treatment / all	0 / 0	3 / 11
deaths causally related to treatment / all	0 / 0	0 / 0
Angina pectoris
subjects affected / exposed	1 / 439 (0.23%)	3 / 434 (0.69%)
occurrences causally related to treatment / all	1 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Arrhythmia
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Arteriosclerosis coronary artery
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Atrial fibrillation
subjects affected / exposed	0 / 439 (0.00%)	6 / 434 (1.38%)
occurrences causally related to treatment / all	0 / 0	1 / 7
deaths causally related to treatment / all	0 / 0	0 / 0
Atrial flutter
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Autoimmune myocarditis
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Bradycardia
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac arrest
subjects affected / exposed	1 / 439 (0.23%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorder
subjects affected / exposed	1 / 439 (0.23%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac failure
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac tamponade
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac ventricular thrombosis
subjects affected / exposed	1 / 439 (0.23%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardio-respiratory arrest
subjects affected / exposed	1 / 439 (0.23%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Acute coronary syndrome
subjects affected / exposed	0 / 439 (0.00%)	6 / 434 (1.38%)
occurrences causally related to treatment / all	0 / 0	5 / 7
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiopulmonary failure
subjects affected / exposed	1 / 439 (0.23%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Coronary artery disease
subjects affected / exposed	1 / 439 (0.23%)	4 / 434 (0.92%)
occurrences causally related to treatment / all	0 / 1	1 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Coronary artery occlusion
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Coronary artery stenosis
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Left ventricular dysfunction
subjects affected / exposed	1 / 439 (0.23%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Left ventricular failure
subjects affected / exposed	1 / 439 (0.23%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Myocardial fibrosis
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Myocardial infarction
subjects affected / exposed	1 / 439 (0.23%)	4 / 434 (0.92%)
occurrences causally related to treatment / all	0 / 1	2 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
Myocardial ischaemia
subjects affected / exposed	1 / 439 (0.23%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Myocarditis
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Sinus bradycardia
subjects affected / exposed	1 / 439 (0.23%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Tachycardia
subjects affected / exposed	1 / 439 (0.23%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiovascular insufficiency
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorders
Altered state of consciousness
subjects affected / exposed	1 / 439 (0.23%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Aphasia
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Ataxia
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Brain hypoxia
subjects affected / exposed	1 / 439 (0.23%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Embolic stroke
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cerebral haematoma
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cerebral haemorrhage
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cerebrovascular accident
subjects affected / exposed	4 / 439 (0.91%)	5 / 434 (1.15%)
occurrences causally related to treatment / all	3 / 4	2 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
Diabetic neuropathy
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Dizziness
subjects affected / exposed	1 / 439 (0.23%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cerebellar haemorrhage
subjects affected / exposed	1 / 439 (0.23%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Encephalopathy
subjects affected / exposed	0 / 439 (0.00%)	2 / 434 (0.46%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Haemorrhagic stroke
subjects affected / exposed	2 / 439 (0.46%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Headache
subjects affected / exposed	1 / 439 (0.23%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Intracranial tumour haemorrhage
subjects affected / exposed	1 / 439 (0.23%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Posterior reversible encephalopathy syndrome
subjects affected / exposed	1 / 439 (0.23%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Ischaemic stroke
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Loss of consciousness
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Lumbar radiculopathy
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Polyneuropathy
subjects affected / exposed	1 / 439 (0.23%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Irregular sleep wake rhythm disorder
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Presyncope
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Seizure
subjects affected / exposed	1 / 439 (0.23%)	2 / 434 (0.46%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Spinal cord compression
subjects affected / exposed	1 / 439 (0.23%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Superficial siderosis of central nervous system
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Syncope
subjects affected / exposed	3 / 439 (0.68%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 3	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Tremor
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Transient ischaemic attack
subjects affected / exposed	1 / 439 (0.23%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	10 / 439 (2.28%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	6 / 10	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Febrile neutropenia
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pancytopenia
subjects affected / exposed	1 / 439 (0.23%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Leukocytosis
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Immune thrombocytopenia
subjects affected / exposed	1 / 439 (0.23%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Thrombocytopenia
subjects affected / exposed	3 / 439 (0.68%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	3 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Ear and labyrinth disorders
Vertigo
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Eye disorders
Cataract
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Glaucoma
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Optic neuropathy
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Autoimmune pancreatitis
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Abdominal distension
subjects affected / exposed	1 / 439 (0.23%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Abdominal hernia
subjects affected / exposed	0 / 439 (0.00%)	2 / 434 (0.46%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Abdominal incarcerated hernia
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Abdominal pain
subjects affected / exposed	12 / 439 (2.73%)	2 / 434 (0.46%)
occurrences causally related to treatment / all	5 / 18	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Abdominal pain lower
subjects affected / exposed	1 / 439 (0.23%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Abdominal pain upper
subjects affected / exposed	1 / 439 (0.23%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Aphthous ulcer
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrooesophageal reflux disease
subjects affected / exposed	1 / 439 (0.23%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal necrosis
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Haemorrhagic erosive gastritis
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Haemorrhoidal haemorrhage
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Ileus
subjects affected / exposed	1 / 439 (0.23%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Inguinal hernia
subjects affected / exposed	1 / 439 (0.23%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Intestinal obstruction
subjects affected / exposed	1 / 439 (0.23%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Colitis
subjects affected / exposed	0 / 439 (0.00%)	3 / 434 (0.69%)
occurrences causally related to treatment / all	0 / 0	2 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Constipation
subjects affected / exposed	1 / 439 (0.23%)	2 / 434 (0.46%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	3 / 439 (0.68%)	12 / 434 (2.76%)
occurrences causally related to treatment / all	2 / 3	11 / 13
deaths causally related to treatment / all	0 / 0	0 / 0
Dyspepsia
subjects affected / exposed	1 / 439 (0.23%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Enteritis
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastric haemorrhage
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastric ulcer
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal haemorrhage
subjects affected / exposed	1 / 439 (0.23%)	2 / 434 (0.46%)
occurrences causally related to treatment / all	1 / 1	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Haematochezia
subjects affected / exposed	1 / 439 (0.23%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Intestinal perforation
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Large intestine perforation
subjects affected / exposed	3 / 439 (0.68%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	2 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Lower gastrointestinal haemorrhage
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Nausea
subjects affected / exposed	3 / 439 (0.68%)	3 / 434 (0.69%)
occurrences causally related to treatment / all	3 / 3	3 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Pancreatitis
subjects affected / exposed	0 / 439 (0.00%)	2 / 434 (0.46%)
occurrences causally related to treatment / all	0 / 0	3 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Pancreatitis acute
subjects affected / exposed	1 / 439 (0.23%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pancreatitis necrotising
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumoperitoneum
subjects affected / exposed	1 / 439 (0.23%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Proctitis
subjects affected / exposed	1 / 439 (0.23%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Rectal haemorrhage
subjects affected / exposed	1 / 439 (0.23%)	2 / 434 (0.46%)
occurrences causally related to treatment / all	1 / 1	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Retroperitoneal haemorrhage
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Small intestinal haemorrhage
subjects affected / exposed	1 / 439 (0.23%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Small intestinal obstruction
subjects affected / exposed	2 / 439 (0.46%)	3 / 434 (0.69%)
occurrences causally related to treatment / all	0 / 2	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Vomiting
subjects affected / exposed	6 / 439 (1.37%)	4 / 434 (0.92%)
occurrences causally related to treatment / all	6 / 6	3 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Intussusception
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatobiliary disorders
Biliary dilatation
subjects affected / exposed	1 / 439 (0.23%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Biliary obstruction
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatic function abnormal
subjects affected / exposed	0 / 439 (0.00%)	2 / 434 (0.46%)
occurrences causally related to treatment / all	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Immune-mediated hepatitis
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Drug-induced liver injury
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cholelithiasis
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cholecystitis acute
subjects affected / exposed	2 / 439 (0.46%)	2 / 434 (0.46%)
occurrences causally related to treatment / all	0 / 2	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Cholecystitis
subjects affected / exposed	2 / 439 (0.46%)	4 / 434 (0.92%)
occurrences causally related to treatment / all	1 / 2	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Cholangitis acute
subjects affected / exposed	1 / 439 (0.23%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cholangitis
subjects affected / exposed	0 / 439 (0.00%)	2 / 434 (0.46%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Liver disorder
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Jaundice cholestatic
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatitis
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatitis acute
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatitis alcoholic
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatotoxicity
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gallbladder rupture
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Rash maculo-papular
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Rash papular
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Scar pain
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Skin disorder
subjects affected / exposed	1 / 439 (0.23%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Splinter haemorrhages
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Exfoliative rash
subjects affected / exposed	1 / 439 (0.23%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Renal and urinary disorders
Chronic kidney disease
subjects affected / exposed	1 / 439 (0.23%)	2 / 434 (0.46%)
occurrences causally related to treatment / all	0 / 1	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Acute kidney injury
subjects affected / exposed	9 / 439 (2.05%)	9 / 434 (2.07%)
occurrences causally related to treatment / all	6 / 9	4 / 10
deaths causally related to treatment / all	0 / 0	0 / 0
Calculus urinary
subjects affected / exposed	1 / 439 (0.23%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Haematuria
subjects affected / exposed	6 / 439 (1.37%)	5 / 434 (1.15%)
occurrences causally related to treatment / all	3 / 6	0 / 7
deaths causally related to treatment / all	0 / 0	0 / 0
Nephropathy toxic
subjects affected / exposed	1 / 439 (0.23%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Renal failure
subjects affected / exposed	1 / 439 (0.23%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Renal impairment
subjects affected / exposed	2 / 439 (0.46%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Renal injury
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary retention
subjects affected / exposed	3 / 439 (0.68%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 5	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Tubulointerstitial nephritis
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Endocrine disorders
Adrenal insufficiency
subjects affected / exposed	0 / 439 (0.00%)	6 / 434 (1.38%)
occurrences causally related to treatment / all	0 / 0	5 / 7
deaths causally related to treatment / all	0 / 0	0 / 0
Hyperparathyroidism
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hypophysitis
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hypothyroidism
subjects affected / exposed	1 / 439 (0.23%)	2 / 434 (0.46%)
occurrences causally related to treatment / all	1 / 1	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Inappropriate antidiuretic hormone secretion
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pituitary apoplexy
subjects affected / exposed	1 / 439 (0.23%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hyperthyroidism
subjects affected / exposed	0 / 439 (0.00%)	2 / 434 (0.46%)
occurrences causally related to treatment / all	0 / 0	3 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Osteoarthritis
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Arthralgia
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Arthritis
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Back pain
subjects affected / exposed	3 / 439 (0.68%)	3 / 434 (0.69%)
occurrences causally related to treatment / all	1 / 3	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Bone pain
subjects affected / exposed	3 / 439 (0.68%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 4	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Joint range of motion decreased
subjects affected / exposed	1 / 439 (0.23%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal chest pain
subjects affected / exposed	0 / 439 (0.00%)	2 / 434 (0.46%)
occurrences causally related to treatment / all	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal pain
subjects affected / exposed	1 / 439 (0.23%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Myalgia
subjects affected / exposed	0 / 439 (0.00%)	2 / 434 (0.46%)
occurrences causally related to treatment / all	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Pain in extremity
subjects affected / exposed	2 / 439 (0.46%)	2 / 434 (0.46%)
occurrences causally related to treatment / all	0 / 2	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Pathological fracture
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Rotator cuff syndrome
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Spinal pain
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
COVID-19
subjects affected / exposed	1 / 439 (0.23%)	3 / 434 (0.69%)
occurrences causally related to treatment / all	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Bronchitis
subjects affected / exposed	1 / 439 (0.23%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Biliary sepsis
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Bacterial sepsis
subjects affected / exposed	1 / 439 (0.23%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Atypical pneumonia
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Appendicitis
subjects affected / exposed	1 / 439 (0.23%)	2 / 434 (0.46%)
occurrences causally related to treatment / all	1 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Actinomycosis
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
COVID-19 pneumonia
subjects affected / exposed	3 / 439 (0.68%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 5	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Clostridium difficile colitis
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Laryngitis
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Large intestine infection
subjects affected / exposed	1 / 439 (0.23%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Influenza
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Infection
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Herpes zoster
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Coronavirus pneumonia
subjects affected / exposed	1 / 439 (0.23%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Fungal infection
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Enterocolitis infectious
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Device related infection
subjects affected / exposed	0 / 439 (0.00%)	2 / 434 (0.46%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Device related bacteraemia
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	1 / 439 (0.23%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Post procedural infection
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia viral
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia aspiration
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	6 / 439 (1.37%)	6 / 434 (1.38%)
occurrences causally related to treatment / all	1 / 6	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 0
Pharyngitis
subjects affected / exposed	1 / 439 (0.23%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Peritonsillar abscess
subjects affected / exposed	1 / 439 (0.23%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Peritonitis
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Osteomyelitis
subjects affected / exposed	1 / 439 (0.23%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Lung abscess
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Lower respiratory tract infection
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pyelonephritis
subjects affected / exposed	1 / 439 (0.23%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Liver abscess
subjects affected / exposed	1 / 439 (0.23%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Retroperitoneal abscess
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Sepsis
subjects affected / exposed	2 / 439 (0.46%)	2 / 434 (0.46%)
occurrences causally related to treatment / all	1 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Septic shock
subjects affected / exposed	1 / 439 (0.23%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Sialoadenitis
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Sinusitis
subjects affected / exposed	1 / 439 (0.23%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Skin graft infection
subjects affected / exposed	1 / 439 (0.23%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Skin infection
subjects affected / exposed	1 / 439 (0.23%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Soft tissue infection
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Tooth abscess
subjects affected / exposed	1 / 439 (0.23%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Upper respiratory tract infection
subjects affected / exposed	3 / 439 (0.68%)	2 / 434 (0.46%)
occurrences causally related to treatment / all	1 / 3	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	3 / 439 (0.68%)	5 / 434 (1.15%)
occurrences causally related to treatment / all	0 / 3	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
Varicella zoster virus infection
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Viral infection
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Viral upper respiratory tract infection
subjects affected / exposed	1 / 439 (0.23%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Wound infection
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	1 / 439 (0.23%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Dehydration
subjects affected / exposed	2 / 439 (0.46%)	5 / 434 (1.15%)
occurrences causally related to treatment / all	2 / 2	2 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
Hypokalaemia
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Diabetic ketoacidosis
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gout
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hypercalcaemia
subjects affected / exposed	2 / 439 (0.46%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hyperglycaemia
subjects affected / exposed	0 / 439 (0.00%)	4 / 434 (0.92%)
occurrences causally related to treatment / all	0 / 0	3 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Hyperglycaemic hyperosmolar nonketotic syndrome
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hypoglycaemia
subjects affected / exposed	1 / 439 (0.23%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Diabetes mellitus
subjects affected / exposed	0 / 439 (0.00%)	2 / 434 (0.46%)
occurrences causally related to treatment / all	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Hyponatraemia
subjects affected / exposed	0 / 439 (0.00%)	2 / 434 (0.46%)
occurrences causally related to treatment / all	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Malnutrition
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Tumour lysis syndrome
subjects affected / exposed	2 / 439 (0.46%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Type 1 diabetes mellitus
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Type 2 diabetes mellitus
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hypophagia
subjects affected / exposed	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Sunitinib	Avelumab + Axitinib
Total subjects affected by non serious adverse events
subjects affected / exposed	433 / 439 (98.63%)	429 / 434 (98.85%)
Vascular disorders
Hypotension
subjects affected / exposed	19 / 439 (4.33%)	26 / 434 (5.99%)
occurrences all number	19	35
Hypertension
subjects affected / exposed	168 / 439 (38.27%)	236 / 434 (54.38%)
occurrences all number	274	481
General disorders and administration site conditions
Mucosal inflammation
subjects affected / exposed	64 / 439 (14.58%)	69 / 434 (15.90%)
occurrences all number	101	122
Oedema peripheral
subjects affected / exposed	58 / 439 (13.21%)	55 / 434 (12.67%)
occurrences all number	84	81
Pain
subjects affected / exposed	23 / 439 (5.24%)	22 / 434 (5.07%)
occurrences all number	25	23
Pyrexia
subjects affected / exposed	65 / 439 (14.81%)	74 / 434 (17.05%)
occurrences all number	87	104
Malaise
subjects affected / exposed	23 / 439 (5.24%)	17 / 434 (3.92%)
occurrences all number	56	24
Influenza like illness
subjects affected / exposed	22 / 439 (5.01%)	34 / 434 (7.83%)
occurrences all number	32	50
Fatigue
subjects affected / exposed	194 / 439 (44.19%)	205 / 434 (47.24%)
occurrences all number	333	497
Chills
subjects affected / exposed	38 / 439 (8.66%)	75 / 434 (17.28%)
occurrences all number	45	90
Chest pain
subjects affected / exposed	12 / 439 (2.73%)	22 / 434 (5.07%)
occurrences all number	13	26
Asthenia
subjects affected / exposed	83 / 439 (18.91%)	83 / 434 (19.12%)
occurrences all number	183	200
Respiratory, thoracic and mediastinal disorders
Nasal congestion
subjects affected / exposed	20 / 439 (4.56%)	28 / 434 (6.45%)
occurrences all number	24	34
Epistaxis
subjects affected / exposed	54 / 439 (12.30%)	48 / 434 (11.06%)
occurrences all number	78	66
Dyspnoea exertional
subjects affected / exposed	21 / 439 (4.78%)	33 / 434 (7.60%)
occurrences all number	28	53
Dyspnoea
subjects affected / exposed	68 / 439 (15.49%)	106 / 434 (24.42%)
occurrences all number	94	193
Dysphonia
subjects affected / exposed	20 / 439 (4.56%)	148 / 434 (34.10%)
occurrences all number	23	225
Cough
subjects affected / exposed	103 / 439 (23.46%)	147 / 434 (33.87%)
occurrences all number	146	251
Rhinorrhoea
subjects affected / exposed	14 / 439 (3.19%)	37 / 434 (8.53%)
occurrences all number	20	47
Productive cough
subjects affected / exposed	15 / 439 (3.42%)	23 / 434 (5.30%)
occurrences all number	17	34
Oropharyngeal pain
subjects affected / exposed	38 / 439 (8.66%)	57 / 434 (13.13%)
occurrences all number	44	66
Psychiatric disorders
Insomnia
subjects affected / exposed	37 / 439 (8.43%)	51 / 434 (11.75%)
occurrences all number	43	62
Anxiety
subjects affected / exposed	24 / 439 (5.47%)	38 / 434 (8.76%)
occurrences all number	25	41
Investigations
Alanine aminotransferase increased
subjects affected / exposed	50 / 439 (11.39%)	94 / 434 (21.66%)
occurrences all number	91	219
Amylase increased
subjects affected / exposed	16 / 439 (3.64%)	34 / 434 (7.83%)
occurrences all number	33	57
Aspartate aminotransferase increased
subjects affected / exposed	59 / 439 (13.44%)	83 / 434 (19.12%)
occurrences all number	112	164
Blood alkaline phosphatase increased
subjects affected / exposed	24 / 439 (5.47%)	21 / 434 (4.84%)
occurrences all number	32	40
Blood bilirubin increased
subjects affected / exposed	20 / 439 (4.56%)	22 / 434 (5.07%)
occurrences all number	28	44
Blood cholesterol increased
subjects affected / exposed	16 / 439 (3.64%)	23 / 434 (5.30%)
occurrences all number	41	58
Blood corticotrophin increased
subjects affected / exposed	2 / 439 (0.46%)	23 / 434 (5.30%)
occurrences all number	4	26
Blood creatine phosphokinase increased
subjects affected / exposed	14 / 439 (3.19%)	26 / 434 (5.99%)
occurrences all number	24	52
Blood creatinine increased
subjects affected / exposed	37 / 439 (8.43%)	64 / 434 (14.75%)
occurrences all number	63	131
Blood thyroid stimulating hormone increased
subjects affected / exposed	25 / 439 (5.69%)	37 / 434 (8.53%)
occurrences all number	29	46
Eastern Cooperative Oncology Group performance status worsened
subjects affected / exposed	23 / 439 (5.24%)	13 / 434 (3.00%)
occurrences all number	33	26
Ejection fraction decreased
subjects affected / exposed	17 / 439 (3.87%)	48 / 434 (11.06%)
occurrences all number	21	74
Gamma-glutamyltransferase increased
subjects affected / exposed	21 / 439 (4.78%)	39 / 434 (8.99%)
occurrences all number	39	96
Lipase increased
subjects affected / exposed	27 / 439 (6.15%)	53 / 434 (12.21%)
occurrences all number	59	114
Neutrophil count decreased
subjects affected / exposed	47 / 439 (10.71%)	5 / 434 (1.15%)
occurrences all number	325	10
Platelet count decreased
subjects affected / exposed	63 / 439 (14.35%)	10 / 434 (2.30%)
occurrences all number	186	22
Weight decreased
subjects affected / exposed	46 / 439 (10.48%)	112 / 434 (25.81%)
occurrences all number	64	192
White blood cell count decreased
subjects affected / exposed	38 / 439 (8.66%)	4 / 434 (0.92%)
occurrences all number	191	9
Injury, poisoning and procedural complications
Contusion
subjects affected / exposed	13 / 439 (2.96%)	26 / 434 (5.99%)
occurrences all number	16	28
Infusion related reaction
subjects affected / exposed	0 / 439 (0.00%)	54 / 434 (12.44%)
occurrences all number	0	70
Nervous system disorders
Taste disorder
subjects affected / exposed	48 / 439 (10.93%)	24 / 434 (5.53%)
occurrences all number	57	28
Paraesthesia
subjects affected / exposed	19 / 439 (4.33%)	25 / 434 (5.76%)
occurrences all number	26	27
Headache
subjects affected / exposed	85 / 439 (19.36%)	122 / 434 (28.11%)
occurrences all number	127	154
Dysgeusia
subjects affected / exposed	107 / 439 (24.37%)	48 / 434 (11.06%)
occurrences all number	153	58
Dizziness
subjects affected / exposed	52 / 439 (11.85%)	72 / 434 (16.59%)
occurrences all number	70	97
Blood and lymphatic system disorders
Thrombocytopenia
subjects affected / exposed	89 / 439 (20.27%)	17 / 434 (3.92%)
occurrences all number	259	41
Neutropenia
subjects affected / exposed	90 / 439 (20.50%)	9 / 434 (2.07%)
occurrences all number	528	13
Leukopenia
subjects affected / exposed	27 / 439 (6.15%)	1 / 434 (0.23%)
occurrences all number	56	3
Anaemia
subjects affected / exposed	116 / 439 (26.42%)	41 / 434 (9.45%)
occurrences all number	331	75
Gastrointestinal disorders
Dyspepsia
subjects affected / exposed	87 / 439 (19.82%)	51 / 434 (11.75%)
occurrences all number	119	66
Dry mouth
subjects affected / exposed	25 / 439 (5.69%)	42 / 434 (9.68%)
occurrences all number	29	54
Diarrhoea
subjects affected / exposed	228 / 439 (51.94%)	303 / 434 (69.82%)
occurrences all number	581	1475
Constipation
subjects affected / exposed	73 / 439 (16.63%)	97 / 434 (22.35%)
occurrences all number	102	144
Abdominal pain upper
subjects affected / exposed	36 / 439 (8.20%)	34 / 434 (7.83%)
occurrences all number	46	47
Gastrooesophageal reflux disease
subjects affected / exposed	44 / 439 (10.02%)	22 / 434 (5.07%)
occurrences all number	59	27
Abdominal pain
subjects affected / exposed	57 / 439 (12.98%)	90 / 434 (20.74%)
occurrences all number	83	119
Toothache
subjects affected / exposed	12 / 439 (2.73%)	25 / 434 (5.76%)
occurrences all number	13	32
Stomatitis
subjects affected / exposed	113 / 439 (25.74%)	117 / 434 (26.96%)
occurrences all number	207	237
Oral pain
subjects affected / exposed	21 / 439 (4.78%)	33 / 434 (7.60%)
occurrences all number	26	57
Nausea
subjects affected / exposed	185 / 439 (42.14%)	186 / 434 (42.86%)
occurrences all number	320	322
Haemorrhoids
subjects affected / exposed	31 / 439 (7.06%)	21 / 434 (4.84%)
occurrences all number	41	23
Vomiting
subjects affected / exposed	99 / 439 (22.55%)	101 / 434 (23.27%)
occurrences all number	177	196
Skin and subcutaneous tissue disorders
Palmar-plantar erythrodysaesthesia syndrome
subjects affected / exposed	162 / 439 (36.90%)	160 / 434 (36.87%)
occurrences all number	431	558
Erythema
subjects affected / exposed	17 / 439 (3.87%)	24 / 434 (5.53%)
occurrences all number	20	31
Dry skin
subjects affected / exposed	52 / 439 (11.85%)	60 / 434 (13.82%)
occurrences all number	64	93
Alopecia
subjects affected / exposed	17 / 439 (3.87%)	22 / 434 (5.07%)
occurrences all number	19	22
Yellow skin
subjects affected / exposed	28 / 439 (6.38%)	1 / 434 (0.23%)
occurrences all number	30	1
Skin exfoliation
subjects affected / exposed	23 / 439 (5.24%)	16 / 434 (3.69%)
occurrences all number	35	16
Rash pruritic
subjects affected / exposed	15 / 439 (3.42%)	27 / 434 (6.22%)
occurrences all number	19	30
Rash maculo-papular
subjects affected / exposed	11 / 439 (2.51%)	29 / 434 (6.68%)
occurrences all number	13	50
Rash
subjects affected / exposed	54 / 439 (12.30%)	74 / 434 (17.05%)
occurrences all number	74	117
Pruritus
subjects affected / exposed	29 / 439 (6.61%)	96 / 434 (22.12%)
occurrences all number	36	146
Hair colour changes
subjects affected / exposed	29 / 439 (6.61%)	2 / 434 (0.46%)
occurrences all number	30	2
Renal and urinary disorders
Proteinuria
subjects affected / exposed	19 / 439 (4.33%)	35 / 434 (8.06%)
occurrences all number	39	89
Pollakiuria
subjects affected / exposed	9 / 439 (2.05%)	23 / 434 (5.30%)
occurrences all number	10	25
Haematuria
subjects affected / exposed	25 / 439 (5.69%)	17 / 434 (3.92%)
occurrences all number	45	22
Endocrine disorders
Hypothyroidism
subjects affected / exposed	89 / 439 (20.27%)	135 / 434 (31.11%)
occurrences all number	102	159
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	83 / 439 (18.91%)	157 / 434 (36.18%)
occurrences all number	133	298
Back pain
subjects affected / exposed	80 / 439 (18.22%)	118 / 434 (27.19%)
occurrences all number	106	174
Bone pain
subjects affected / exposed	18 / 439 (4.10%)	23 / 434 (5.30%)
occurrences all number	23	30
Muscle spasms
subjects affected / exposed	20 / 439 (4.56%)	28 / 434 (6.45%)
occurrences all number	38	40
Musculoskeletal chest pain
subjects affected / exposed	22 / 439 (5.01%)	36 / 434 (8.29%)
occurrences all number	25	44
Myalgia
subjects affected / exposed	32 / 439 (7.29%)	59 / 434 (13.59%)
occurrences all number	35	100
Neck pain
subjects affected / exposed	11 / 439 (2.51%)	27 / 434 (6.22%)
occurrences all number	12	31
Pain in extremity
subjects affected / exposed	63 / 439 (14.35%)	87 / 434 (20.05%)
occurrences all number	86	132
Infections and infestations
Nasopharyngitis
subjects affected / exposed	38 / 439 (8.66%)	58 / 434 (13.36%)
occurrences all number	48	94
Upper respiratory tract infection
subjects affected / exposed	19 / 439 (4.33%)	40 / 434 (9.22%)
occurrences all number	26	80
Urinary tract infection
subjects affected / exposed	15 / 439 (3.42%)	32 / 434 (7.37%)
occurrences all number	18	49
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	144 / 439 (32.80%)	141 / 434 (32.49%)
occurrences all number	211	242
Dehydration
subjects affected / exposed	7 / 439 (1.59%)	24 / 434 (5.53%)
occurrences all number	12	34
Hyperglycaemia
subjects affected / exposed	21 / 439 (4.78%)	31 / 434 (7.14%)
occurrences all number	33	56
Hyperkalaemia
subjects affected / exposed	25 / 439 (5.69%)	25 / 434 (5.76%)
occurrences all number	43	40
Hypertriglyceridaemia
subjects affected / exposed	31 / 439 (7.06%)	49 / 434 (11.29%)
occurrences all number	97	158
Hypokalaemia
subjects affected / exposed	25 / 439 (5.69%)	26 / 434 (5.99%)
occurrences all number	45	81
Hypomagnesaemia
subjects affected / exposed	25 / 439 (5.69%)	35 / 434 (8.06%)
occurrences all number	75	57
Hyponatraemia
subjects affected / exposed	28 / 439 (6.38%)	29 / 434 (6.68%)
occurrences all number	43	43
Hypophosphataemia
subjects affected / exposed	41 / 439 (9.34%)	49 / 434 (11.29%)
occurrences all number	111	112

More information

Top of page

Were there any global substantial amendments to the protocol? Yes

22 Oct 2015

Amendment 1: As per FDA request: Schedule of Activities (SoA) table and footnotes were updated as follow: Creatinine kinase and troponin measurements have been added. They will be performed along with any clinically indicated ECG assessment performed beyond Cycle 1. Section 7.1.5 and Table 9 were updated accordingly. Extend the duration of tumor assessment monitoring using the 6-week interval up to 18 months after randomization. Sections 3.1.2 and 7.7 were updated accordingly. Add PRO assessments also during Follow-Up. Sections 7.2.1 and 7.2.2 were updated accordingly. Section 9.3.2 language was updated to clarify how the analysis will be performed.

24 May 2016

Amendment 2: As per FDA request, clarification about the treatment of symptoms of avelumab infusion-related reactions was added to Section 5.4.6.7. Details on the type and dosages of medications recommended for the treatment of avelumab infusion-related reactions were added to Appendix 8. As per the requests from the EUcountries participating in the Voluntary Harmonisation Procedure, the following sections were amended: Sections 1.2.2.2. Axitinib and 1.2.2.3. Sunitinib Malate were updated indicating that Reference Safety Information (RSI) can be found in Section 7.8 of the respective Investigators Brochures. Location of RSI for avelumab was also specified (Section 1.2.2.1). Section 12.1. Institutional Review Board/Ethics Committee text was updated to clarify that only changes of study documents classified as “substantial” should be prospectively approved by IRBs/ECs. Section 12.2 Ethical Conduct of the Study. The version of the Declaration of Helsinki was updated.

30 Aug 2016

Amendment 3: As per the requests from the EU countries participating in the Voluntary Harmonisation Procedure, the following sections were amended: Sections 1.2.3 Rationale for Studying Avelumab in Combination with Axitinib, and 1.3 Summary of Risk/Benefit Assessment. Text was updated to include preliminary data from the ongoing Phase 1b study of axitinib in combination with avelumab in aRCC (Study B9991002). Section 2 Study Objectives and Endpoints. The assessment of PFS on next-line therapy (PFS2), time to treatment discontinuation/failure due to toxicity, and proportion of patients who discontinued treatment due to toxicity were added to secondary objectives in Section 2.1, and associated endpoints were added to the secondary endpoints Section 2.2. Sections 9.3.2 Analysis of Secondary Endpoints and 9.5 Safety Analysis were updated accordingly.

08 Dec 2016

Amendment 4: Exclusion Criterion (EC) No.19 was updated and new ECs (EC No. 20 and 21) were added to exclude patients with pre-existing cardiac conditions within 12 months prior to enrollment, or evidence of cardiac involvement with tumor, to better discriminate between drug-related toxicity and underlying heart disease. An independent cardiac events adjudication committee was also established to review selected cardiac adverse events reported in the study in order to confirm the diagnosis and relationship to study treatment. This will enable a comprehensive evaluation of the cardiac safety profile of the combination of avelumab and axitinib. Based on a recent publication (Johnson et al, N Engl J Med 2016; 375:1749-55), cardiac enzyme evaluation was extended up to Cycle 3.

12 Jun 2017

Amendment 5: The primary objective of the study was changed to demonstrate superiority of avelumab in combination with axitinib compared to sunitinib alone based on Progression Free Survival (PFS) by Blinded Independent Central Review (BICR) or Overall Survival (OS) in PD-L1 positive patients based on recent publications (Motzer RJ et al, N Engl J Med 2015; 373:1803-13; McDermott D et al, J Clin Oncol 35, 2017, suppl 6S; abstract 431). Protocol Summary, Sections 1.2.3 (Rationale for testing avelumab in combination with axitinib in RCC), 2 (Objectives & Endpoints), 6.4 (End of the Study) and Data Analysis /Statistical Sections 9.1, 9.2, 9.3, 9.3.1, 9.3.2, 9.6 were updated.

26 Jun 2018

Amendment 6: Interim Analysis (IA): IA3 for OS was added to occur 15 months after the primary analysis for PFS (IA2 for OS) due to the fact that the aggregate number of deaths observed in the study as of the date of this amendment is substantially lower than that expected per protocol, leading to a substantially longer duration between the originally expected timing of the primary analysis for PFS (IA2 for OS) and the primary analysis for OS. Protocol summary, Section 9.1 (Sample Size Determination) and Section 9.6 (Interim Analysis).

04 Sep 2018

Amendment 7: Schedule of Activities (SoA) for Screening/Study Treatment Period was updated specifying blood samples for avelumab pharmacokinetics (PK) and for testing avelumab immunogenicity (ie, anti-avelumab antibodies and neutralizing antibodies) will be collected up to Cycle 16 and not thereafter since samples collected so far are sufficient to properly characterize avelumab PK and assess immunogenicity. SoA Footnotes 24 and 28 were updated accordingly.

02 Jan 2020

Amendment 8: Reduction of safety assessments: The safety profile of the combination avelumab plus axitinib is generally tolerable, manageable, and consistent with the known safety profiles of avelumab and axitinib when administered as monotherapies, per interim analysis (IA) 1 and 2 results (cut off dates: 20 June 2018 and 28 January 2019). All patients who are still receiving treatment with study drug/s, have been on treatment for more than 1.8 years. . As per above and in order to reduce the burden to participants and sites, the frequency of safety assessments was reduced. A new Schedule of Activities (SoA) table, and a new table for laboratory tests “Laboratories Safety Assessments” were added.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

Select Country:	Select Age Range:
Select Trial Status:	Select Trial Phase:
Select Gender:
Select Date Range: to
Select Rare Disease:
IMP with orphan designation in the indication
Orphan Designation Number:
Results Status:
Clear advanced search filters

Austria
Belgium
Bulgaria
Croatia
Cyprus
Czechia
Denmark
Estonia
Finland
France
Germany
Greece
Hungary
Iceland
Ireland
Italy
Latvia
Liechtenstein
Lithuania
Luxembourg
Malta
Netherlands
Norway
Poland
Portugal
Romania
Slovakia
Slovenia
Spain
Sweden
United Kingdom
Outside EU/EEA

Clinical trials

Clinical Trial Results: A Phase 3, Multinational, Randomized, Open-Label, Parallel-Arm study of Avelumab (MSB0010718C) in Combination With Axitinib (Inlyta) Versus Sunitinib (Sutent) Monotherapy in the First-Line Treatment of Patients With Advanced Renal Cell Carcinoma

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Progression Free Survival (PFS) as Assessed by Blinded Independent Central Review (BICR) in Programmed Death-Ligand 1 (PD-L1) Positive Participants

Primary: Progression Free Survival (PFS) as Assessed by Blinded Independent Central Review (BICR) in Programmed Death-Ligand 1 (PD-L1) Positive Participants

Primary: Overall Survival (OS) in PD-L1 Positive Participants

Primary: Overall Survival (OS) in PD-L1 Positive Participants

Secondary: PFS as Assessed by BICR in Participants Irrespective of PD-L1 Expression

Secondary: PFS as Assessed by BICR in Participants Irrespective of PD-L1 Expression

Secondary: OS in Participants Irrespective of PD-L1 Expression

Secondary: OS in Participants Irrespective of PD-L1 Expression

Secondary: Percentage of Participants With OR as Assessed by Investigator Irrespective of PD-L1 Expression

Secondary: Percentage of Participants With OR as Assessed by Investigator Irrespective of PD-L1 Expression

Secondary: Percentage of Participants With Objective Response (OR) as Assessed by BICR Irrespective of PD-L1 Expression

Secondary: Percentage of Participants With Objective Response (OR) as Assessed by BICR Irrespective of PD-L1 Expression

Secondary: Percentage of Participants With DC as Assessed by Investigator Irrespective of PD-L1 Expression

Secondary: Percentage of Participants With DC as Assessed by Investigator Irrespective of PD-L1 Expression

Secondary: Percentage of Participants With Disease Control (DC) as Assessed by BICR Irrespective of PD-L1 Expression

Secondary: Percentage of Participants With Disease Control (DC) as Assessed by BICR Irrespective of PD-L1 Expression

Secondary: TTR as Assessed by Investigator in Participants Irrespective of PD-L1 Expression

Secondary: TTR as Assessed by Investigator in Participants Irrespective of PD-L1 Expression

Secondary: Time to Tumor Response (TTR) as Assessed by BICR in Participants Irrespective of PD-L1 Expression

Secondary: Time to Tumor Response (TTR) as Assessed by BICR in Participants Irrespective of PD-L1 Expression

Secondary: PFS as Assessed by Investigator in Participants Irrespective of PD-L1 Expression

Secondary: PFS as Assessed by Investigator in Participants Irrespective of PD-L1 Expression

Secondary: DR as Assessed by Investigator in Participants Irrespective of PD-L1 Expression

Secondary: DR as Assessed by Investigator in Participants Irrespective of PD-L1 Expression

Secondary: Duration of Response (DR) as Assessed by BICR in Participants Irrespective of PD-L1 Expression

Secondary: Duration of Response (DR) as Assessed by BICR in Participants Irrespective of PD-L1 Expression

Secondary: Number of Participants With Treatment-Emergent Adverse Events (AEs) Graded Based on National Cancer Institute -Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version (V) 4.03

Secondary: Number of Participants With Treatment-Emergent Adverse Events (AEs) Graded Based on National Cancer Institute -Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version (V) 4.03

Secondary: Progression-Free Survival on Next-line Therapy (PFS2) in Participants Irrespective of PD-L1 Expression

Secondary: Progression-Free Survival on Next-line Therapy (PFS2) in Participants Irrespective of PD-L1 Expression

Secondary: Number of Participants According to Grade Shift in Hematology Parameters

Secondary: Number of Participants According to Grade Shift in Hematology Parameters

Secondary: Number of Participants According to Grade Shift in Chemistry Parameters

Secondary: Number of Participants According to Grade Shift in Chemistry Parameters

Secondary: Change From Baseline in Vital Signs - Blood Pressure at Day 1 of Cycle 2, 3, 4, 5, 6, 7 and End of Treatment (EOT) Visit

Secondary: Change From Baseline in Vital Signs - Blood Pressure at Day 1 of Cycle 2, 3, 4, 5, 6, 7 and End of Treatment (EOT) Visit

Secondary: Change From Baseline in Vital Signs - Pulse Rate at Day 1 of Cycle 2, 3, 4, 5, 6, 7 and EOT Visit

Secondary: Change From Baseline in Vital Signs - Pulse Rate at Day 1 of Cycle 2, 3, 4, 5, 6, 7 and EOT Visit

Secondary: Number of Participants who Discontinued Treatment due to Toxicity

Secondary: Number of Participants who Discontinued Treatment due to Toxicity

Secondary: Trough Plasma Concentration (Ctrough) of Avelumab

Secondary: Trough Plasma Concentration (Ctrough) of Avelumab

Secondary: Time to Treatment Discontinuation/Failure Due to Toxicity

Secondary: Time to Treatment Discontinuation/Failure Due to Toxicity

Secondary: Maximum Plasma Concentration (Cmax) of Axitinib

Secondary: Maximum Plasma Concentration (Cmax) of Axitinib

Secondary: Ctrough of Axitinib

Secondary: Ctrough of Axitinib

Secondary: PFS in PD-L1 Biomarker-Positive and PD-L1 Biomarker-Negative Subgroups

Secondary: PFS in PD-L1 Biomarker-Positive and PD-L1 Biomarker-Negative Subgroups

Secondary: Percentage of Participants With OR in PD-L1 Biomarker-Positive and PD-L1 Biomarker-Negative Subgroups

Secondary: Percentage of Participants With OR in PD-L1 Biomarker-Positive and PD-L1 Biomarker-Negative Subgroups

Secondary: Number of Participants With Positive PD-L1 Biomarker Expression in Pre-treatment Tumor Tissue

Secondary: Number of Participants With Positive PD-L1 Biomarker Expression in Pre-treatment Tumor Tissue

Secondary: Percentage of Participants With DC in Biomarker-Positive Subgroup

Secondary: Percentage of Participants With DC in Biomarker-Positive Subgroup

Secondary: TTR in Biomarker-Positive Subgroup

Secondary: TTR in Biomarker-Positive Subgroup

Secondary: DR in PD-L1 Biomarker-Positive and PD-L1 Biomarker-Negative Subgroups

Secondary: DR in PD-L1 Biomarker-Positive and PD-L1 Biomarker-Negative Subgroups

Secondary: Time to Symptom Deterioration (TTD) for Functional Assessment of Cancer Therapy (FACT)-Kidney Symptom Index - Disease Related Symptoms (FKSI-DRS)

Secondary: Time to Symptom Deterioration (TTD) for Functional Assessment of Cancer Therapy (FACT)-Kidney Symptom Index - Disease Related Symptoms (FKSI-DRS)

Secondary: Change From Baseline in European Quality of Life (EuroQol) 5-Dimension 5 Levels (EQ-5D-5L) Utility Score

Secondary: Change From Baseline in European Quality of Life (EuroQol) 5-Dimension 5 Levels (EQ-5D-5L) Utility Score

Secondary: Number of Participants With Positive Anti-Drug Antibodies (ADA) and Neutralizing Antibodies (nAb) of Avelumab When Used in Combination With Axitinib

Secondary: Number of Participants With Positive Anti-Drug Antibodies (ADA) and Neutralizing Antibodies (nAb) of Avelumab When Used in Combination With Axitinib

Secondary: Change From Baseline in EQ-5D Visual Analogue Scale (VAS) Score

Secondary: Change From Baseline in EQ-5D Visual Analogue Scale (VAS) Score

Adverse events

Adverse events

Clinical Trial Results:
A Phase 3, Multinational, Randomized, Open-Label, Parallel-Arm study of Avelumab (MSB0010718C) in Combination With Axitinib (Inlyta) Versus Sunitinib (Sutent) Monotherapy in the First-Line Treatment of Patients With Advanced Renal Cell Carcinoma