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Clinical Trial Results:
A Phase II, Randomized Study of Atezolizumab (Anti−PD-L1 Antibody) Administered as Monotherapy or in Combination with Bevacizumab Versus Sunitinib in Patients with Untreated Advanced Renal Cell Carcinoma

Summary
EudraCT number	2013-003167-58
Trial protocol	CZ DE IT GB ES FR RO PL
Global end of trial date	08 Jan 2019

Results information
Results version number	v2(current)
This version publication date	18 Dec 2019
First version publication date	29 Oct 2017
Other versions	v1
Version creation reason

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

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Trial information

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Sponsor protocol code

WO29074

ISRCTN number

US NCT number

NCT01984242

WHO universal trial number (UTN)

Sponsor organisation name

F. Hoffmann-La Roche AG

Sponsor organisation address

Grenzacherstrasse 124, Basel, Switzerland, CH-4070

Public contact

Roche Trial Information Hotline, F. Hoffmann-La Roche AG, +41 61 6878333, global.trial_information@roche.com

Scientific contact

Roche Trial Information Hotline, F. Hoffmann-La Roche AG, +41 61 6878333, global.trial_information@roche.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

08 Jan 2019

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

08 Jan 2019

Was the trial ended prematurely?

Main objective of the trial

To estimate the efficacy of atezolizumab and bevacizumab combination and atezolizumab monotherapy compared with sunitinib as measured by progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) via an independent central radiologic review in the intent-to-treat (ITT) population and in participants who had detectable levels of programmed death−ligand 1 (PD-L1) expression on tumor-infiltrating immune cells (immunohistochemistry [IHC] IC1/2/3)

Protection of trial subjects

This study was conducted in full conformance with the International Council for Harmonisation (ICH) E6 guideline for Good Clinical Practice and the principles of the Declaration of Helsinki, or the laws and regulations of the country in which the research was conducted, whichever afforded the greater protection to the individual. The study protocol, Informed Consent Forms (ICFs), any information to be given to the participants, and relevant supporting information were submitted to the Institutional Review Boards (IRBs)/Ethics Committees (ECs) by the Principal Investigators and reviewed and approved by the IRB/EC before the study was initiated. In addition, any participant recruitment materials were also approved by the IRB/EC.

Background therapy

Evidence for comparator

Actual start date of recruitment

08 Jan 2014

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Czech Republic: 1

Country: Number of subjects enrolled

Spain: 8

Country: Number of subjects enrolled

France: 11

Country: Number of subjects enrolled

United Kingdom: 31

Country: Number of subjects enrolled

Germany: 3

Country: Number of subjects enrolled

Italy: 5

Country: Number of subjects enrolled

Poland: 6

Country: Number of subjects enrolled

Romania: 4

Country: Number of subjects enrolled

United States: 236

Worldwide total number of subjects

305

EEA total number of subjects

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)

192

From 65 to 84 years

109

85 years and over

Subject disposition

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Recruitment details

Screening details

Total 305 participants were enrolled in this study. Participants enrolled in atezolizumab (except European Union [EU] participants) or sunitinib group could crossover to receive atezolizumab and bevacizumab combination therapy in case of disease progression.

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

Atezolizumab and Bevacizumab

Arm description

Atezolizumab 1200 milligrams (mg) and bevacizumab 15 milligrams per kilogram (mg/kg) were administered as intravenous (IV) infusions every 3 weeks (q3w) on Day 1 and Day 22 of each 6-week cycle until disease progression.

Arm type

Experimental

Investigational medicinal product name

Atezolizumab

Investigational medicinal product code

RO5541267

Other name

Tecentriq

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

1200 mg IV q3w

Investigational medicinal product name

Bevacizumab

Investigational medicinal product code

Other name

Avastin

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

15 mg/kg IV q3w

Atezolizumab

Arm description

Atezolizumab 1200 mg was administered as IV infusion q3w on Day 1 and Day 22 of each 6-week cycle until disease progression. Upon disease progression, participants (except EU participants) could crossover to receive atezolizumab and bevacizumab combination until disease progression, lack of clinical benefit, unacceptable toxicity, withdrawal from study, or study completion or termination.

Arm type

Experimental

Investigational medicinal product name

Atezolizumab

Investigational medicinal product code

RO5541267

Other name

Tecentriq

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

1200 mg IV q3w

Sunitinib

Arm description

Sunitinib 50 mg was administered orally once daily on Days 1 to 28 of each 6-week cycle until disease progression. Upon disease progression, participants could crossover to receive atezolizumab and bevacizumab combination until disease progression, lack of clinical benefit, unacceptable toxicity, withdrawal from study, or study completion or termination.

Arm type

Active comparator

Investigational medicinal product name

Sunitinib

Investigational medicinal product code

Other name

Sutent

Pharmaceutical forms

Capsule, hard

Routes of administration

Oral use

Dosage and administration details

50 mg orally once daily for 4 weeks, followed by 2 weeks of rest

Number of subjects in period 1	Atezolizumab and Bevacizumab	Atezolizumab	Sunitinib
Started	101	103	101
Treated	100	103	100
Completed	0	0	0
Not completed	101	103	101
Consent withdrawn by subject	5	3	10
Physician decision	-	-	1
Study terminated by Sponsor	38	50	34
Death	52	50	52
Non-compliance	1	-	-
Sponsor Decision	1	-	-
Lost to follow-up	4	-	3
Disease Progression	-	-	1

Baseline characteristics

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Reporting group title

Atezolizumab and Bevacizumab

Reporting group description

Reporting group title

Atezolizumab

Reporting group description

Reporting group title

Sunitinib

Reporting group description

Reporting group values	Atezolizumab and Bevacizumab	Atezolizumab	Sunitinib	Total
Number of subjects	101	103	101	305
Age Categorical
Units: Subjects
Age Continuous
Units: years
arithmetic mean (standard deviation)	61.1 ( 10.8 )	60.1 ( 10.2 )	59.7 ( 10.8 )	-
Gender Categorical
Units: Subjects
Female	27	26	22	75
Male	74	77	79	230

Subject analysis set title

Atezolizumab (Crossover)

Subject analysis set type

Intention-to-treat

Subject analysis set description

Among the participants assigned to atezolizumab initially, those participants who upon disease progression, crossed over to receive atezolizumab and bevacizumab combination until disease progression, lack of clinical benefit, unacceptable toxicity, withdrawal from study, or study completion or termination, were included in this group. Atezolizumab 1200 mg and bevacizumab 15 mg/kg were administered as IV infusions q3w on Day 1 and Day 22 of each 6-week cycle.

Subject analysis set title

Sunitinib (Crossover)

Subject analysis set type

Intention-to-treat

Subject analysis set description

Among the participants assigned to sunitinib initially, those participants who upon disease progression, crossed over to receive atezolizumab and bevacizumab combination until disease progression, lack of clinical benefit, unacceptable toxicity, withdrawal from study, or study completion or termination, were included in this group. Atezolizumab 1200 mg and bevacizumab 15 mg/kg were administered as IV infusions q3w on Day 1 and Day 22 of each 6-week cycle.

Subject analysis sets values	Atezolizumab (Crossover)	Sunitinib (Crossover)
Number of subjects	46	63
Age Categorical
Units: Subjects
Age Continuous
Units: years
arithmetic mean (standard deviation)	59.2 ( 10.6 )	58.8 ( 12.0 )
Gender Categorical
Units: Subjects
Female	9	10
Male	35	47

End points

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Reporting group title

Atezolizumab and Bevacizumab

Reporting group description

Reporting group title

Atezolizumab

Reporting group description

Reporting group title

Sunitinib

Reporting group description

Subject analysis set title

Atezolizumab (Crossover)

Subject analysis set type

Intention-to-treat

Subject analysis set description

Subject analysis set title

Sunitinib (Crossover)

Subject analysis set type

Intention-to-treat

Subject analysis set description

Primary: Percentage of Participants with Disease Progression per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) via Independent Review Committee (IRC) Assessment or Death in Intent-to-Treat (ITT) Population

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End point title

Percentage of Participants with Disease Progression per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) via Independent Review Committee (IRC) Assessment or Death in Intent-to-Treat (ITT) Population ^[1]

End point description

Progressive Disease (PD): at least a 20 percent (%) increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, including baseline, and an absolute increase of at least 5 millimeters (mm); appearance of one or more new target or non-target lesions; or unequivocal progression of existing non-target lesions. Intent-to-treat (ITT) population included all randomized participants regardless of whether they received any study drug.

End point type

Primary

End point timeframe

From randomization until disease progression or death due to any cause (until data cut-off date 17 October 2016, up to approximately 2.75 years)

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analysis was planned for this endpoint.

End point values	Atezolizumab and Bevacizumab	Atezolizumab	Sunitinib
Number of subjects analysed	101	103	101
Units: percentage of participants
number (not applicable)	66.3	59.2	58.4

No statistical analyses for this end point

Primary: Progression-Free Survival (PFS) per RECIST v1.1 via IRC Assessment in ITT Population

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End point title

Progression-Free Survival (PFS) per RECIST v1.1 via IRC Assessment in ITT Population

End point description

End point type

Primary

End point timeframe

From randomization until disease progression or death due to any cause (until data cut-off date 17 October 2016, up to approximately 2.75 years)

End point values	Atezolizumab and Bevacizumab	Atezolizumab	Sunitinib
Number of subjects analysed	101	103	101
Units: months
median (confidence interval 95%)	11.7 (8.4 to 17.3)	6.1 (5.4 to 13.6)	8.4 (7.0 to 14.0)

Statistical Analysis 1

Comparison groups

Atezolizumab and Bevacizumab v Sunitinib

Number of subjects included in analysis

202

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9819

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

0.69

upper limit

1.45

Statistical Analysis 2

Comparison groups

Atezolizumab v Sunitinib

Number of subjects included in analysis

204

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.358

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

1.19

Confidence interval

level

95%

sides

2-sided

lower limit

0.82

upper limit

1.71

Primary: Percentage of Participants with Disease Progression per RECIST v1.1 via IRC Assessment or Death in Immune Cell 1/2/3 (IC1/2/3) Population

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End point title

Percentage of Participants with Disease Progression per RECIST v1.1 via IRC Assessment or Death in Immune Cell 1/2/3 (IC1/2/3) Population ^[2]

End point description

PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, including baseline, and an absolute increase of at least 5 mm; appearance of one or more new target or non-target lesions; or unequivocal progression of existing non-target lesions. IC1/2/3 population included ITT participants with PD-L1 expression of greater than or equal to (>=) 1% on tumor-infiltrating immune cells.

End point type

Primary

End point timeframe

From randomization until disease progression or death due to any cause (until data cut-off date 17 October 2016, up to approximately 2.75 years)

Notes
[2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analysis was planned for this endpoint.

End point values	Atezolizumab and Bevacizumab	Atezolizumab	Sunitinib
Number of subjects analysed	50	54	60
Units: percentage of participants
number (not applicable)	58.0	59.3	68.3

No statistical analyses for this end point

Primary: PFS per RECIST v1.1 via IRC Assessment in IC1/2/3 Population

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End point title

PFS per RECIST v1.1 via IRC Assessment in IC1/2/3 Population

End point description

End point type

Primary

End point timeframe

From randomization until disease progression or death due to any cause (until data cut-off date 17 October 2016, up to approximately 2.75 years)

End point values	Atezolizumab and Bevacizumab	Atezolizumab	Sunitinib
Number of subjects analysed	50	54	60
Units: months
median (confidence interval 95%)	14.7 (8.2 to 25.1)	5.5 (3.0 to 13.9)	7.8 (3.8 to 10.8)

Statistical Analysis 1

Comparison groups

Atezolizumab and Bevacizumab v Sunitinib

Number of subjects included in analysis

110

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0952

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.64

Confidence interval

level

95%

sides

2-sided

lower limit

0.38

upper limit

1.08

Statistical Analysis 2

Comparison groups

Atezolizumab v Sunitinib

Number of subjects included in analysis

114

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9172

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

1.03

Confidence interval

level

95%

sides

2-sided

lower limit

0.63

upper limit

1.67

Secondary: Percentage of Participants with Disease Progression per RECIST v1.1 via IRC Assessment or Death in Participants who Have Tumors with Higher Than Median Expression of an Immune Gene Signature

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End point title

Percentage of Participants with Disease Progression per RECIST v1.1 via IRC Assessment or Death in Participants who Have Tumors with Higher Than Median Expression of an Immune Gene Signature

End point description

PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, including baseline, and an absolute increase of at least 5 mm; appearance of one or more new target or non-target lesions; or unequivocal progression of existing non-target lesions. Biomarker evaluable population included ITT participants whose tumor samples had sufficient material available for gene signature expression analyses. Participants with higher than median expression of an immune gene signature were included in this analysis.

End point type

Secondary

End point timeframe

From randomization until disease progression or death due to any cause (until data cut-off date 17 October 2016, up to approximately 2.75 years)

End point values	Atezolizumab and Bevacizumab	Atezolizumab	Sunitinib
Number of subjects analysed	45	44	42
Units: percentage of participants
number (not applicable)	55.6	61.4	73.8

No statistical analyses for this end point

Secondary: PFS per RECIST v1.1 via IRC Assessment in Participants who Have Tumors with Higher Than Median Expression of an Immune Gene Signature

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End point title

PFS per RECIST v1.1 via IRC Assessment in Participants who Have Tumors with Higher Than Median Expression of an Immune Gene Signature

End point description

PFS was defined as the time from randomization to the first occurrence of PD or death due to any cause. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, including baseline, and an absolute increase of at least 5 mm; appearance of one or more new target or non-target lesions; or unequivocal progression of existing non-target lesions. Kaplan-Meier methodology was used to estimate PFS. Biomarker evaluable population. Participants with higher than median expression of an immune gene signature were included in this analysis. ‘99999’ indicates that data could not be estimated due to high number of censored participants.

End point type

Secondary

End point timeframe

From randomization until disease progression or death due to any cause (until data cut-off date 17 October 2016, up to approximately 2.75 years)

End point values	Atezolizumab and Bevacizumab	Atezolizumab	Sunitinib
Number of subjects analysed	45	44	42
Units: months
median (confidence interval 95%)	17.5 (10.3 to 99999)	5.7 (3.2 to 16.7)	7.1 (4.2 to 8.7)

Statistical Analysis 1

Comparison groups

Atezolizumab and Bevacizumab v Sunitinib

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0153

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.48

Confidence interval

level

95%

sides

2-sided

lower limit

0.26

upper limit

0.87

Statistical Analysis 2

Comparison groups

Atezolizumab v Sunitinib

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5545

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.84

Confidence interval

level

95%

sides

2-sided

lower limit

0.48

upper limit

1.46

Secondary: Percentage of Participants with Disease Progression per RECIST v1.1 via Investigator Assessment or Death in Participants who Have Tumors with Higher Than Median Expression of an Immune Gene Signature

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End point title

Percentage of Participants with Disease Progression per RECIST v1.1 via Investigator Assessment or Death in Participants who Have Tumors with Higher Than Median Expression of an Immune Gene Signature

End point description

PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, including baseline, and an absolute increase of at least 5 mm; appearance of one or more new target or non-target lesions; or unequivocal progression of existing non-target lesions. Biomarker evaluable population. Participants with higher than median expression of an immune gene signature were included in this analysis.

End point type

Secondary

End point timeframe

From randomization until disease progression or death due to any cause (until data cut-off date 17 October 2016, up to approximately 2.75 years)

End point values	Atezolizumab and Bevacizumab	Atezolizumab	Sunitinib
Number of subjects analysed	45	44	42
Units: percentage of participants
number (not applicable)	57.8	77.3	83.3

No statistical analyses for this end point

Secondary: PFS per RECIST v1.1 via Investigator Assessment in Participants who Have Tumors with Higher Than Median Expression of an Immune Gene Signature

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End point title

PFS per RECIST v1.1 via Investigator Assessment in Participants who Have Tumors with Higher Than Median Expression of an Immune Gene Signature

End point description

End point type

Secondary

End point timeframe

From randomization until disease progression or death due to any cause (until data cut-off date 17 October 2016, up to approximately 2.75 years)

End point values	Atezolizumab and Bevacizumab	Atezolizumab	Sunitinib
Number of subjects analysed	45	44	42
Units: months
median (confidence interval 95%)	16.6 (8.2 to 99999)	5.5 (3.0 to 11.1)	6.8 (5.4 to 8.7)

Statistical Analysis 1

Comparison groups

Atezolizumab and Bevacizumab v Sunitinib

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0086

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.49

Confidence interval

level

95%

sides

2-sided

lower limit

0.28

upper limit

0.84

Statistical Analysis 2

Comparison groups

Atezolizumab v Sunitinib

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.7675

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.93

Confidence interval

level

95%

sides

2-sided

lower limit

0.56

upper limit

1.53

Secondary: Percentage of Participants with Disease Progression per RECIST v1.1 via IRC Assessment or Death in Participants who Have Tumors with Higher Than the 33rd Percentile Expression of an Immune Gene Signature

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End point title

Percentage of Participants with Disease Progression per RECIST v1.1 via IRC Assessment or Death in Participants who Have Tumors with Higher Than the 33rd Percentile Expression of an Immune Gene Signature

End point description

PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, including baseline, and an absolute increase of at least 5 mm; appearance of one or more new target or non-target lesions; or unequivocal progression of existing non-target lesions. Biomarker evaluable population. Participants with higher than the 33rd percentile expression of an immune gene signature were included in this analysis.

End point type

Secondary

End point timeframe

From randomization until disease progression or death due to any cause (until data cut-off date 17 October 2016, up to approximately 2.75 years)

End point values	Atezolizumab and Bevacizumab	Atezolizumab	Sunitinib
Number of subjects analysed	61	55	60
Units: percentage of participants
number (not applicable)	59.0	58.2	65.0

No statistical analyses for this end point

Secondary: PFS per RECIST v1.1 via IRC Assessment in Participants who Have Tumors with Higher Than the 33rd Percentile Expression of an Immune Gene Signature

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End point title

PFS per RECIST v1.1 via IRC Assessment in Participants who Have Tumors with Higher Than the 33rd Percentile Expression of an Immune Gene Signature

End point description

PFS was defined as the time from randomization to the first occurrence of PD or death due to any cause. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, including baseline, and an absolute increase of at least 5 mm; appearance of one or more new target or non-target lesions; or unequivocal progression of existing non-target lesions. Kaplan-Meier methodology was used to estimate PFS. Biomarker evaluable population. Participants with higher than the 33rd percentile expression of an immune gene signature were included in this analysis.

End point type

Secondary

End point timeframe

From randomization until disease progression or death due to any cause (until data cut-off date 17 October 2016, up to approximately 2.75 years)

End point values	Atezolizumab and Bevacizumab	Atezolizumab	Sunitinib
Number of subjects analysed	61	55	60
Units: months
median (confidence interval 95%)	13.8 (8.3 to 25.1)	5.7 (5.4 to 17.3)	8.2 (5.7 to 11.4)

Statistical Analysis 1

Comparison groups

Atezolizumab and Bevacizumab v Sunitinib

Number of subjects included in analysis

121

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1973

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.72

Confidence interval

level

95%

sides

2-sided

lower limit

0.44

upper limit

1.18

Statistical Analysis 2

Comparison groups

Atezolizumab v Sunitinib

Number of subjects included in analysis

115

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.7738

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

1.07

Confidence interval

level

95%

sides

2-sided

lower limit

0.65

upper limit

1.76

Secondary: Percentage of Participants with Disease Progression per RECIST v1.1 via Investigator Assessment or Death in Participants who Have Tumors with Higher Than the 33rd Percentile Expression of an Immune Gene Signature

Top of page

End point title

Percentage of Participants with Disease Progression per RECIST v1.1 via Investigator Assessment or Death in Participants who Have Tumors with Higher Than the 33rd Percentile Expression of an Immune Gene Signature

End point description

PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, including baseline, and an absolute increase of at least 5 mm; appearance of one or more new target or non-target lesions; or unequivocal progression of existing non-target lesions. Biomarker evaluable population. Participants with higher than the 33rd percentile expression of an immune gene signature were included in this analysis.

End point type

Secondary

End point timeframe

From randomization until disease progression or death due to any cause (until data cut-off date 17 October 2016, up to approximately 2.75 years)

End point values	Atezolizumab and Bevacizumab	Atezolizumab	Sunitinib
Number of subjects analysed	61	55	60
Units: percentage of participants
number (not applicable)	63.9	76.4	78.3

No statistical analyses for this end point

Secondary: PFS per RECIST v1.1 via Investigator Assessment in Participants who Have Tumors with Higher Than the 33rd Percentile Expression of an Immune Gene Signature

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End point title

PFS per RECIST v1.1 via Investigator Assessment in Participants who Have Tumors with Higher Than the 33rd Percentile Expression of an Immune Gene Signature

End point description

PFS was defined as the time from randomization to the first occurrence of PD or death due to any cause. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, including baseline, and an absolute increase of at least 5 mm; appearance of one or more new target or non-target lesions; or unequivocal progression of existing non-target lesions. Kaplan-Meier methodology was used to estimate PFS. Biomarker evaluable population. Participants with higher than the 33rd percentile expression of an immune gene signature were included in this analysis.

End point type

Secondary

End point timeframe

From randomization until disease progression or death due to any cause (until data cut-off date 17 October 2016, up to approximately 2.75 years)

End point values	Atezolizumab and Bevacizumab	Atezolizumab	Sunitinib
Number of subjects analysed	61	55	60
Units: months
median (confidence interval 95%)	11.1 (8.1 to 19.3)	5.5 (3.0 to 10.9)	7.1 (5.8 to 11.3)

Statistical Analysis 1

Comparison groups

Atezolizumab and Bevacizumab v Sunitinib

Number of subjects included in analysis

121

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.083

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.68

Confidence interval

level

95%

sides

2-sided

lower limit

0.43

upper limit

1.06

Statistical Analysis 2

Comparison groups

Atezolizumab v Sunitinib

Number of subjects included in analysis

115

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.7141

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

1.09

Confidence interval

level

95%

sides

2-sided

lower limit

0.7

upper limit

1.69

Secondary: Percentage of Participants with Disease Progression per RECIST v1.1 via Investigator Assessment or Death in ITT Population

Top of page

End point title

Percentage of Participants with Disease Progression per RECIST v1.1 via Investigator Assessment or Death in ITT Population

End point description

End point type

Secondary

End point timeframe

From randomization until disease progression or death due to any cause (until data cut-off date 17 October 2016, up to approximately 2.75 years)

End point values	Atezolizumab and Bevacizumab	Atezolizumab	Sunitinib
Number of subjects analysed	101	103	101
Units: percentage of participants
number (not applicable)	71.3	75.7	75.2

No statistical analyses for this end point

Secondary: PFS per RECIST v1.1 via Investigator Assessment in ITT Population

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End point title

PFS per RECIST v1.1 via Investigator Assessment in ITT Population

End point description

End point type

Secondary

End point timeframe

From randomization until disease progression or death due to any cause (until data cut-off date 17 October 2016, up to approximately 2.75 years)

End point values	Atezolizumab and Bevacizumab	Atezolizumab	Sunitinib
Number of subjects analysed	101	103	101
Units: months
median (confidence interval 95%)	11.1 (8.2 to 13.5)	5.5 (3.0 to 8.4)	7.8 (5.7 to 11.2)

Statistical Analysis 1

Comparison groups

Atezolizumab and Bevacizumab v Sunitinib

Number of subjects included in analysis

202

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2541

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.82

Confidence interval

level

95%

sides

2-sided

lower limit

0.59

upper limit

1.15

Statistical Analysis 2

Comparison groups

Atezolizumab v Sunitinib

Number of subjects included in analysis

204

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3103

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

1.18

Confidence interval

level

95%

sides

2-sided

lower limit

0.86

upper limit

1.63

Secondary: Percentage of Participants with Disease Progression per RECIST v1.1 via Investigator Assessment or Death in IC1/2/3 Population

Top of page

End point title

Percentage of Participants with Disease Progression per RECIST v1.1 via Investigator Assessment or Death in IC1/2/3 Population

End point description

End point type

Secondary

End point timeframe

From randomization until disease progression or death due to any cause (until data cut-off date 17 October 2016, up to approximately 2.75 years)

End point values	Atezolizumab and Bevacizumab	Atezolizumab	Sunitinib
Number of subjects analysed	50	54	60
Units: percentage of participants
number (not applicable)	66.0	74.1	81.7

No statistical analyses for this end point

Secondary: PFS per RECIST v1.1 via Investigator Assessment in IC1/2/3 Population

Top of page

End point title

PFS per RECIST v1.1 via Investigator Assessment in IC1/2/3 Population

End point description

End point type

Secondary

End point timeframe

From randomization until disease progression or death due to any cause (until data cut-off date 17 October 2016, up to approximately 2.75 years)

End point values	Atezolizumab and Bevacizumab	Atezolizumab	Sunitinib
Number of subjects analysed	50	54	60
Units: months
median (confidence interval 95%)	11.1 (8.1 to 16.7)	5.5 (3.0 to 10.9)	7.0 (5.6 to 11.2)

Statistical Analysis 1

Comparison groups

Atezolizumab and Bevacizumab v Sunitinib

Number of subjects included in analysis

110

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0351

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.6

Confidence interval

level

95%

sides

2-sided

lower limit

0.37

upper limit

0.97

Statistical Analysis 2

Comparison groups

Atezolizumab v Sunitinib

Number of subjects included in analysis

114

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9769

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.99

Confidence interval

level

95%

sides

2-sided

lower limit

0.64

upper limit

1.54

Secondary: Percentage of Participants with Objective Response (Complete Response [CR] or Partial Response [PR]) per RECIST v1.1 via IRC Assessment in ITT Population

Top of page

End point title

Percentage of Participants with Objective Response (Complete Response [CR] or Partial Response [PR]) per RECIST v1.1 via IRC Assessment in ITT Population

End point description

Objective Response was defined as CR or PR. CR: disappearance of all target and non-target lesions and (if applicable) normalization of tumor marker level; or reduction in short axis of any pathological lymph nodes (whether target or non-target) to less than (<) 10 mm. PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters; or persistence of one or more non-target lesion(s) and/or (if applicable) maintenance of tumor marker level above the normal limits. ITT population.

End point type

Secondary

End point timeframe

From randomization until disease progression or death due to any cause (until data cut-off date 17 October 2016, up to approximately 2.75 years)

End point values	Atezolizumab and Bevacizumab	Atezolizumab	Sunitinib
Number of subjects analysed	101	103	101
Units: percentage of participants
number (confidence interval 95%)	31.7 (22.78 to 41.69)	25.2 (17.20 to 34.76)	28.7 (20.15 to 38.57)

Statistical Analysis 1

Comparison groups

Atezolizumab and Bevacizumab v Sunitinib

Number of subjects included in analysis

202

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.6492

Method

Cochran-Mantel-Haenszel

Parameter type

Difference in response rates

Point estimate

2.97

Confidence interval

level

95%

sides

2-sided

lower limit

-10.68

upper limit

16.62

Statistical Analysis 2

Comparison groups

Atezolizumab v Sunitinib

Number of subjects included in analysis

204

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5433

Method

Cochran-Mantel-Haenszel

Parameter type

Difference in response rates

Point estimate

-3.47

Confidence interval

level

95%

sides

2-sided

lower limit

-16.63

upper limit

9.69

Secondary: Percentage of Participants with Objective Response per RECIST v1.1 via IRC Assessment in IC1/2/3 Population

Top of page

End point title

Percentage of Participants with Objective Response per RECIST v1.1 via IRC Assessment in IC1/2/3 Population

End point description

Objective Response was defined as CR or PR. CR: disappearance of all target and non-target lesions and (if applicable) normalization of tumor marker level; or reduction in short axis of any pathological lymph nodes (whether target or non-target) to <10 mm. PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters; or persistence of one or more non-target lesion(s) and/or (if applicable) maintenance of tumor marker level above the normal limits. IC1/2/3 population.

End point type

Secondary

End point timeframe

From randomization until disease progression or death due to any cause (until data cut-off date 17 October 2016, up to approximately 2.75 years)

End point values	Atezolizumab and Bevacizumab	Atezolizumab	Sunitinib
Number of subjects analysed	50	54	60
Units: percentage of participants
number (confidence interval 95%)	46.0 (31.81 to 60.68)	27.8 (16.46 to 41.64)	26.7 (16.07 to 39.66)

Statistical Analysis 1

Comparison groups

Atezolizumab and Bevacizumab v Sunitinib

Number of subjects included in analysis

110

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0141

Method

Cochran-Mantel-Haenszel

Parameter type

Difference in response rates

Point estimate

19.33

Confidence interval

level

95%

sides

2-sided

lower limit

-0.28

upper limit

38.94

Statistical Analysis 2

Comparison groups

Atezolizumab v Sunitinib

Number of subjects included in analysis

114

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8719

Method

Cochran-Mantel-Haenszel

Parameter type

Difference in response rates

Point estimate

1.11

Confidence interval

level

95%

sides

2-sided

lower limit

-17.02

upper limit

19.24

Secondary: Percentage of Participants with Objective Response per RECIST v1.1 via Investigator Assessment in ITT Population

Top of page

End point title

Percentage of Participants with Objective Response per RECIST v1.1 via Investigator Assessment in ITT Population

End point description

Objective Response was defined as CR or PR. CR: disappearance of all target and non-target lesions and (if applicable) normalization of tumor marker level; or reduction in short axis of any pathological lymph nodes (whether target or non-target) to <10 mm. PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters; or persistence of one or more non-target lesion(s) and/or (if applicable) maintenance of tumor marker level above the normal limits. ITT population.

End point type

Secondary

End point timeframe

From randomization until disease progression or death due to any cause (until data cut-off date 17 October 2016, up to approximately 2.75 years)

End point values	Atezolizumab and Bevacizumab	Atezolizumab	Sunitinib
Number of subjects analysed	101	103	101
Units: percentage of participants
number (confidence interval 95%)	34.7 (25.46 to 44.77)	23.3 (15.54 to 32.66)	32.7 (23.67 to 42.72)

Statistical Analysis 1

Comparison groups

Atezolizumab and Bevacizumab v Sunitinib

Number of subjects included in analysis

202

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8068

Method

Cochran-Mantel-Haenszel

Parameter type

Difference in response rates

Point estimate

1.98

Confidence interval

level

95%

sides

2-sided

lower limit

-12.04

upper limit

Statistical Analysis 2

Comparison groups

Atezolizumab v Sunitinib

Number of subjects included in analysis

204

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1321

Method

Cochran-Mantel-Haenszel

Parameter type

Difference in response rates

Point estimate

-9.37

Confidence interval

level

95%

sides

2-sided

lower limit

-22.61

upper limit

3.87

Secondary: Percentage of Participants with Objective Response per RECIST v1.1 via Investigator Assessment in IC1/2/3 Population

Top of page

End point title

Percentage of Participants with Objective Response per RECIST v1.1 via Investigator Assessment in IC1/2/3 Population

End point description

Objective Response was defined as CR or PR. CR: disappearance of all target and non-target lesions and (if applicable) normalization of tumor marker level; or reduction in short axis of any pathological lymph nodes (whether target or non-target) to <10 mm. PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters; or persistence of one or more non-target lesion(s) and/or (if applicable) maintenance of tumor marker level above the normal limits. IC1/2/3 population.

End point type

Secondary

End point timeframe

From randomization until disease progression or death due to any cause (until data cut-off date 17 October 2016, up to approximately 2.75 years)

End point values	Atezolizumab and Bevacizumab	Atezolizumab	Sunitinib
Number of subjects analysed	50	54	60
Units: percentage of participants
number (confidence interval 95%)	48.0 (33.66 to 62.58)	25.9 (14.96 to 39.65)	28.3 (17.45 to 41.44)

Statistical Analysis 1

Comparison groups

Atezolizumab and Bevacizumab v Sunitinib

Number of subjects included in analysis

110

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0199

Method

Cochran-Mantel-Haenszel

Parameter type

Difference in response rates

Point estimate

19.67

Confidence interval

level

95%

sides

2-sided

lower limit

-0.1

upper limit

39.44

Statistical Analysis 2

Comparison groups

Atezolizumab v Sunitinib

Number of subjects included in analysis

114

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.7836

Method

Cochran-Mantel-Haenszel

Parameter type

Difference in response rates

Point estimate

-2.41

Confidence interval

level

95%

sides

2-sided

lower limit

-20.5

upper limit

15.68

Secondary: Percentage of Participants with Objective Response per Modified RECIST via Investigator Assessment in ITT Population

Top of page

End point title

Percentage of Participants with Objective Response per Modified RECIST via Investigator Assessment in ITT Population

End point description

Objective Response was defined as CR or PR. CR: disappearance of all target and non-target lesions; or reduction in short axis of any pathological lymph nodes (whether target or non-target) to <10 mm. PR: at least a 30% decrease in the sum of diameters of target and all new measurable lesions, taking as reference the baseline sum of diameters, in absence of CR. ITT population.

End point type

Secondary

End point timeframe

From randomization until disease progression or death due to any cause (until data cut-off date 17 October 2016, up to approximately 2.75 years)

End point values	Atezolizumab and Bevacizumab	Atezolizumab	Sunitinib
Number of subjects analysed	101	103	101
Units: percentage of participants
number (confidence interval 95%)	37.6 (28.18 to 47.82)	25.2 (17.20 to 34.76)	33.7 (24.56 to 43.75)

Statistical Analysis 1

Comparison groups

Atezolizumab and Bevacizumab v Sunitinib

Number of subjects included in analysis

202

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.6231

Method

Cochran-Mantel-Haenszel

Parameter type

Difference in response rates

Point estimate

3.96

Confidence interval

level

95%

sides

2-sided

lower limit

-10.23

upper limit

18.15

Statistical Analysis 2

Comparison groups

Atezolizumab v Sunitinib

Number of subjects included in analysis

204

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1816

Method

Cochran-Mantel-Haenszel

Parameter type

Difference in response rates

Point estimate

-8.42

Confidence interval

level

95%

sides

2-sided

lower limit

-21.86

upper limit

5.02

Secondary: Percentage of Participants with Objective Response per Modified RECIST via Investigator Assessment in IC1/2/3 Population

Top of page

End point title

Percentage of Participants with Objective Response per Modified RECIST via Investigator Assessment in IC1/2/3 Population

End point description

End point type

Secondary

End point timeframe

From randomization until disease progression or death due to any cause (until data cut-off date 17 October 2016, up to approximately 2.75 years)

End point values	Atezolizumab and Bevacizumab	Atezolizumab	Sunitinib
Number of subjects analysed	50	54	60
Units: percentage of participants
number (confidence interval 95%)	52.0 (37.42 to 66.34)	27.8 (16.46 to 41.64)	30.0 (18.85 to 43.21)

Statistical Analysis 1

Comparison groups

Atezolizumab and Bevacizumab v Sunitinib

Number of subjects included in analysis

110

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0111

Method

Cochran-Mantel-Haenszel

Parameter type

Difference in response rates

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

2.11

upper limit

41.89

Statistical Analysis 2

Comparison groups

Atezolizumab v Sunitinib

Number of subjects included in analysis

114

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8209

Method

Cochran-Mantel-Haenszel

Parameter type

Difference in response rates

Point estimate

-2.22

Confidence interval

level

95%

sides

2-sided

lower limit

-20.63

upper limit

16.19

Secondary: Percentage of Participants with Disease Progression per Modified RECIST via Investigator Assessment or Death in ITT Population

Top of page

End point title

Percentage of Participants with Disease Progression per Modified RECIST via Investigator Assessment or Death in ITT Population

End point description

PD: at least a 20% increase in the sum of diameters of all target and new measurable lesions, taking as reference the smallest sum on study, including baseline, and an absolute increase of at least 5 mm. ITT population.

End point type

Secondary

End point timeframe

From randomization until disease progression or death due to any cause (until data cut-off date 17 October 2016, up to approximately 2.75 years)

End point values	Atezolizumab and Bevacizumab	Atezolizumab	Sunitinib
Number of subjects analysed	101	103	101
Units: percentage of participants
number (not applicable)	60.4	61.2	63.4

No statistical analyses for this end point

Secondary: PFS per Modified RECIST via Investigator Assessment in ITT Population

Top of page

End point title

PFS per Modified RECIST via Investigator Assessment in ITT Population

End point description

PFS was defined as the time from randomization to the first occurrence of PD or death due to any cause. PD: at least a 20% increase in the sum of diameters of all target and new measurable lesions, taking as reference the smallest sum on study, including baseline, and an absolute increase of at least 5 mm. Kaplan-Meier methodology was used to estimate PFS. ITT population.

End point type

Secondary

End point timeframe

From randomization until disease progression or death due to any cause (until data cut-off date 17 October 2016, up to approximately 2.75 years)

End point values	Atezolizumab and Bevacizumab	Atezolizumab	Sunitinib
Number of subjects analysed	101	103	101
Units: months
median (confidence interval 95%)	16.7 (11.4 to 22.6)	10.9 (7.9 to 14.0)	9.9 (8.1 to 14.1)

Statistical Analysis 1

Comparison groups

Atezolizumab and Bevacizumab v Sunitinib

Number of subjects included in analysis

202

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0863

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.72

Confidence interval

level

95%

sides

2-sided

lower limit

0.5

upper limit

1.05

Statistical Analysis 2

Comparison groups

Atezolizumab v Sunitinib

Number of subjects included in analysis

204

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5922

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

1.1

Confidence interval

level

95%

sides

2-sided

lower limit

0.77

upper limit

1.57

Secondary: Percentage of Participants with Disease Progression per Modified RECIST via Investigator Assessment or Death in IC1/2/3 Population

Top of page

End point title

Percentage of Participants with Disease Progression per Modified RECIST via Investigator Assessment or Death in IC1/2/3 Population

End point description

End point type

Secondary

End point timeframe

From randomization until disease progression or death due to any cause (until data cut-off date 17 October 2016, up to approximately 2.75 years)

End point values	Atezolizumab and Bevacizumab	Atezolizumab	Sunitinib
Number of subjects analysed	50	54	60
Units: percentage of participants
number (not applicable)	52.0	59.3	75.0

No statistical analyses for this end point

Secondary: PFS per Modified RECIST via Investigator Assessment in IC1/2/3 Population

Top of page

End point title

PFS per Modified RECIST via Investigator Assessment in IC1/2/3 Population

End point description

End point type

Secondary

End point timeframe

From randomization until disease progression or death due to any cause (until data cut-off date 17 October 2016, up to approximately 2.75 years)

End point values	Atezolizumab and Bevacizumab	Atezolizumab	Sunitinib
Number of subjects analysed	50	54	60
Units: months
median (confidence interval 95%)	21.7 (11.1 to 99999)	10.9 (5.4 to 14.0)	8.4 (5.8 to 11.3)

Statistical Analysis 1

Comparison groups

Atezolizumab and Bevacizumab v Sunitinib

Number of subjects included in analysis

110

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0021

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.43

Confidence interval

level

95%

sides

2-sided

lower limit

0.25

upper limit

0.75

Statistical Analysis 2

Comparison groups

Atezolizumab v Sunitinib

Number of subjects included in analysis

114

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.6566

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.9

Confidence interval

level

95%

sides

2-sided

lower limit

0.56

upper limit

1.44

Secondary: Duration of Response (DOR) per RECIST v1.1 via IRC Assessment in ITT Population

Top of page

End point title

Duration of Response (DOR) per RECIST v1.1 via IRC Assessment in ITT Population

End point description

DOR was defined as the time from first observation of an objective response (CR or PR) until first observation of PD. CR, PR, and PD have been defined in previous endpoints, and are not repeated here due to space constraint. Kaplan-Meier methodology was used to estimate DOR. ITT population. ‘Number of Subjects Analyzed’=participants evaluable for this outcome measure. ‘99999’ indicates that data could not be estimated due to high number of censored participants.

End point type

Secondary

End point timeframe

From CR or PR until disease progression or death due to any cause (until data cut-off date 17 October 2016, up to approximately 2.75 years)

End point values	Atezolizumab and Bevacizumab	Atezolizumab	Sunitinib
Number of subjects analysed	32	26	29
Units: months
median (confidence interval 95%)	22.1 (19.4 to 99999)	99999 (23.4 to 99999)	99999 (99999 to 99999)

No statistical analyses for this end point

Secondary: DOR per RECIST v1.1 via Investigator Assessment in ITT Population

Top of page

End point title

DOR per RECIST v1.1 via Investigator Assessment in ITT Population

End point description

End point type

Secondary

End point timeframe

From CR or PR until disease progression or death due to any cause (until data cut-off date 17 October 2016, up to approximately 2.75 years)

End point values	Atezolizumab and Bevacizumab	Atezolizumab	Sunitinib
Number of subjects analysed	35	24	33
Units: months
median (confidence interval 95%)	99999 (19.4 to 99999)	99999 (99999 to 99999)	14.2 (13.0 to 99999)

No statistical analyses for this end point

Secondary: DOR per RECIST v1.1 via IRC Assessment in IC1/2/3 Population

Top of page

End point title

DOR per RECIST v1.1 via IRC Assessment in IC1/2/3 Population

End point description

DOR was defined as the time from first observation of an objective response (CR or PR) until first observation of PD. CR, PR, and PD have been defined in previous endpoints, and are not repeated here due to space constraint. Kaplan-Meier methodology was used to estimate DOR. IC1/2/3 population. ‘Number of Subjects Analyzed’=participants evaluable for this outcome measure. ‘99999’ indicates that data could not be estimated due to high number of censored participants.

End point type

Secondary

End point timeframe

From CR or PR until disease progression or death due to any cause (until data cut-off date 17 October 2016, up to approximately 2.75 years)

End point values	Atezolizumab and Bevacizumab	Atezolizumab	Sunitinib
Number of subjects analysed	23	15	16
Units: months
median (confidence interval 95%)	22.1 (19.4 to 99999)	99999 (23.4 to 99999)	99999 (12.0 to 99999)

No statistical analyses for this end point

Secondary: DOR per RECIST v1.1 via Investigator Assessment in IC1/2/3 Population

Top of page

End point title

DOR per RECIST v1.1 via Investigator Assessment in IC1/2/3 Population

End point description

DOR was defined as the time from first observation of an objective response (CR or PR) until first observation of PD. CR, PR, and PD have been defined in previous endpoints, and are not repeated here due to space constraint. Kaplan-Meier methodology was used to estimate DOR. IC1/2/3 population. ‘Number of Subjects Analyzed’=participants evaluable for this outcome measure. ‘99999’ indicates that data could not be estimated due to high number of censored participants.

End point type

Secondary

End point timeframe

From CR or PR until disease progression or death due to any cause (until data cut-off date 17 October 2016, up to approximately 2.75 years)

End point values	Atezolizumab and Bevacizumab	Atezolizumab	Sunitinib
Number of subjects analysed	24	14	17
Units: months
median (confidence interval 95%)	22.4 (13.8 to 99999)	99999 (99999 to 99999)	14.1 (11.1 to 99999)

No statistical analyses for this end point

Secondary: DOR per Modified RECIST via Investigator Assessment in ITT Population

Top of page

End point title

DOR per Modified RECIST via Investigator Assessment in ITT Population

End point description

End point type

Secondary

End point timeframe

From CR or PR until disease progression or death due to any cause (until data cut-off date 17 October 2016, up to approximately 2.75 years)

End point values	Atezolizumab and Bevacizumab	Atezolizumab	Sunitinib
Number of subjects analysed	38	26	34
Units: months
median (confidence interval 95%)	99999 (19.8 to 99999)	99999 (99999 to 99999)	16.6 (13.6 to 99999)

No statistical analyses for this end point

Secondary: DOR per Modified RECIST via Investigator Assessment in IC1/2/3 Population

Top of page

End point title

DOR per Modified RECIST via Investigator Assessment in IC1/2/3 Population

End point description

DOR was defined as the time from first observation of an objective response (CR or PR) until first observation of PD. CR, PR, and PD have been defined in previous endpoints, and are not repeated here due to space constraint. Kaplan-Meier methodology was used to estimate DOR. IC1/2/3 population. ‘Number of Subjects Analyzed’=participants evaluable for this outcome measure. ‘99999’ indicates that data could not be estimated due to high number of censored participants.

End point type

Secondary

End point timeframe

From CR or PR until disease progression or death due to any cause (until data cut-off date 17 October 2016, up to approximately 2.75 years)

End point values	Atezolizumab and Bevacizumab	Atezolizumab	Sunitinib
Number of subjects analysed	26	15	18
Units: months
median (confidence interval 95%)	22.4 (19.4 to 99999)	99999 (99999 to 99999)	16.6 (11.3 to 99999)

No statistical analyses for this end point

Secondary: Percentage of Participants who Died in ITT Population

Top of page

End point title

Percentage of Participants who Died in ITT Population

End point description

ITT population.

End point type

Secondary

End point timeframe

Randomization until death due to any cause (until data cut-off date 17 October 2016, up to approximately 2.75 years)

End point values	Atezolizumab and Bevacizumab	Atezolizumab	Sunitinib
Number of subjects analysed	101	103	101
Units: percentage of participants
number (not applicable)	38.6	35.0	30.7

No statistical analyses for this end point

Secondary: Overall Survival (OS) in ITT Population

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End point title

Overall Survival (OS) in ITT Population

End point description

OS was defined as the time from the date of randomization to the date of death due to any cause. Kaplan-Meier methodology was used to estimate OS. ITT population. ‘99999’ indicates that data could not be estimated due to high number of censored participants.

End point type

Secondary

End point timeframe

Randomization until death due to any cause (until data cut-off date 17 October 2016, up to approximately 2.75 years)

End point values	Atezolizumab and Bevacizumab	Atezolizumab	Sunitinib
Number of subjects analysed	101	103	101
Units: months
median (confidence interval 95%)	99999 (23.9 to 99999)	99999 (30.2 to 99999)	99999 (27.2 to 99999)

Statistical Analysis 1

Comparison groups

Atezolizumab and Bevacizumab v Sunitinib

Number of subjects included in analysis

202

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2867

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

1.3

Confidence interval

level

95%

sides

2-sided

lower limit

0.8

upper limit

2.13

Statistical Analysis 2

Comparison groups

Atezolizumab v Sunitinib

Number of subjects included in analysis

204

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8039

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

1.06

Confidence interval

level

95%

sides

2-sided

lower limit

0.65

upper limit

1.73

Secondary: Percentage of Participants who Died in IC1/2/3 Population

Top of page

End point title

Percentage of Participants who Died in IC1/2/3 Population

End point description

IC1/2/3 population.

End point type

Secondary

End point timeframe

Randomization until death due to any cause (until data cut-off date 17 October 2016, up to approximately 2.75 years)

End point values	Atezolizumab and Bevacizumab	Atezolizumab	Sunitinib
Number of subjects analysed	50	54	60
Units: percentage of participants
number (not applicable)	38.0	39.8	35.0

No statistical analyses for this end point

Secondary: OS in IC1/2/3 Population

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End point title

OS in IC1/2/3 Population

End point description

OS was defined as the time from the date of randomization to the date of death due to any cause. Kaplan-Meier methodology was used to estimate OS. IC1/2/3 population. ‘99999’ indicates that data could not be estimated due to high number of censored participants.

End point type

Secondary

End point timeframe

Randomization until death due to any cause (until data cut-off date 17 October 2016, up to approximately 2.75 years)

End point values	Atezolizumab and Bevacizumab	Atezolizumab	Sunitinib
Number of subjects analysed	50	54	60
Units: months
median (confidence interval 95%)	27.3 (24.6 to 99999)	30.2 (23.3 to 99999)	99999 (22.4 to 99999)

Statistical Analysis 1

Comparison groups

Atezolizumab and Bevacizumab v Sunitinib

Number of subjects included in analysis

110

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.7879

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.91

Confidence interval

level

95%

sides

2-sided

lower limit

0.47

upper limit

1.78

Statistical Analysis 2

Comparison groups

Atezolizumab v Sunitinib

Number of subjects included in analysis

114

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9065

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.96

Confidence interval

level

95%

sides

2-sided

lower limit

0.52

upper limit

1.8

Secondary: Percentage of Participants with Objective Response per RECIST v1.1 via Investigator Assessment in Crossover Population

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End point title

Percentage of Participants with Objective Response per RECIST v1.1 via Investigator Assessment in Crossover Population

End point description

Objective Response was defined as CR or PR. CR: disappearance of all target and non-target lesions and (if applicable) normalization of tumor marker level; or reduction in short axis of any pathological lymph nodes (whether target or non-target) to <10 mm. PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters; or persistence of one or more non-target lesion(s) and/or (if applicable) maintenance of tumor marker level above the normal limits. Crossover population included participants in atezolizumab or sunitinib arms who had crossed over to the atezolizumab and bevacizumab arm. ‘Number of Subjects Analyzed’=participants evaluable for this outcome measure.

End point type

Secondary

End point timeframe

From start of crossover treatment until disease progression or death due to any cause (until data cut-off date 17 October 2016, up to approximately 2.75 years)

End point values	Atezolizumab (Crossover)	Sunitinib (Crossover)
Number of subjects analysed	41	54
Units: percentage of participants
number (confidence interval 95%)	24.4 (12.36 to 40.30)	27.8 (16.46 to 41.64)

No statistical analyses for this end point

Secondary: DOR per RECIST v1.1 via Investigator Assessment in Crossover Population

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End point title

DOR per RECIST v1.1 via Investigator Assessment in Crossover Population

End point description

DOR was defined as the time from first observation of an objective response (CR or PR) until first observation of PD. CR, PR, and PD have been defined in previous endpoints, and are not repeated here due to space constraint. Kaplan-Meier methodology was used to estimate DOR. Crossover population. ‘Number of Subjects Analyzed’=participants evaluable for this outcome measure. ‘99999’ indicates that data could not be estimated due to high number of censored participants.

End point type

Secondary

End point timeframe

From start of crossover treatment until disease progression or death due to any cause (until data cut-off date 17 October 2016, up to approximately 2.75 years)

End point values	Atezolizumab (Crossover)	Sunitinib (Crossover)
Number of subjects analysed	10	15
Units: months
median (confidence interval 95%)	99999 (7.2 to 99999)	99999 (11.1 to 99999)

No statistical analyses for this end point

Secondary: Percentage of Participants with Disease Progression per RECIST v1.1 via Investigator Assessment or Death in Crossover Population

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End point title

Percentage of Participants with Disease Progression per RECIST v1.1 via Investigator Assessment or Death in Crossover Population

End point description

End point type

Secondary

End point timeframe

From start of crossover treatment until disease progression or death due to any cause (until data cut-off date 17 October 2016, up to approximately 2.75 years)

End point values	Atezolizumab (Crossover)	Sunitinib (Crossover)
Number of subjects analysed	44	57
Units: percentage of participants
number (not applicable)	59.1	68.4

No statistical analyses for this end point

Secondary: PFS per RECIST v1.1 via Investigator Assessment in Crossover Population

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End point title

PFS per RECIST v1.1 via Investigator Assessment in Crossover Population

End point description

End point type

Secondary

End point timeframe

From start of crossover treatment until disease progression or death due to any cause (until data cut-off date 17 October 2016, up to approximately 2.75 years)

End point values	Atezolizumab (Crossover)	Sunitinib (Crossover)
Number of subjects analysed	44	57
Units: months
median (confidence interval 95%)	12.6 (6.0 to 17.7)	8.3 (3.1 to 11.2)

No statistical analyses for this end point

Secondary: Percentage of Participants with Anti-Therapeutic Antibodies (ATA) to Atezolizumab

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End point title

Percentage of Participants with Anti-Therapeutic Antibodies (ATA) to Atezolizumab ^[3]

End point description

This outcome measure was planned to be analyzed in ‘Atezolizumab’ and ‘Atezolizumab and Bevacizumab’ arms only. ATA evaluable population included participants at baseline who had a baseline ATA sample and post-baseline participants who had at least one ATA sample and had received at least one dose of study treatment.

End point type

Secondary

End point timeframe

Cycle 1 Day 1 until treatment discontinuation (until data cut-off date 17 October 2016, up to approximately 2.75 years) (1 cycle=6 weeks)

Notes
[3] - 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: This endpoint was planned to be evaluated for the reported arms only.

End point values	Atezolizumab and Bevacizumab	Atezolizumab
Number of subjects analysed	97	96
Units: percentage of participants
number (not applicable)	34.0	25.0

No statistical analyses for this end point

Secondary: Maximum Serum Concentration (Cmax) of Atezolizumab

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End point title

Maximum Serum Concentration (Cmax) of Atezolizumab ^[4]

End point description

The pharmacokinetic (PK) evaluable population included participants who received at least one dose of study drug and had sufficient PK sample collected within the time specified in the protocol. ‘Number of Subjects Analyzed’=participants evaluable for this outcome measure.

End point type

Secondary

End point timeframe

30 minutes after end of infusion on Cycle 1 Day 1 (1 cycle=6 weeks) (infusion length for first dose=60 minutes)

Notes
[4] - 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: No statistical analysis was planned for this endpoint.

End point values	Atezolizumab and Bevacizumab	Atezolizumab	Atezolizumab (Crossover)	Sunitinib (Crossover)
Number of subjects analysed	95	93	41	53
Units: micrograms per milliliter (mcg/mL)
arithmetic mean (standard deviation)	335 ( 86.0 )	358 ( 93.1 )	418 ( 114 )	314 ( 87.1 )

No statistical analyses for this end point

Secondary: Minimum Serum Concentration (Cmin) of Atezolizumab

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End point title

Minimum Serum Concentration (Cmin) of Atezolizumab ^[5]

End point description

PK evaluable population. ‘Number of Subjects Analyzed’=participants evaluable for this outcome measure. ‘n’=participants evaluable for this outcome measure at specified timepoint for each arm respectively.

End point type

Secondary

End point timeframe

Pre-infusion (0 hour) on Day 1 of Cycles 2 and 4; Day 22 of Cycles 1, 2, and 4 (1 cycle=6 weeks) (infusion length=30-60 minutes)

Notes
[5] - 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: No statistical analysis was planned for this endpoint.

End point values	Atezolizumab and Bevacizumab	Atezolizumab	Atezolizumab (Crossover)	Sunitinib (Crossover)
Number of subjects analysed	98	94	42	52
Units: mcg/mL
arithmetic mean (standard deviation)
Cycle 1 Day 22 (n=98, 94, 42, 52)	72.6 ( 29.5 )	79.9 ( 26.1 )	174 ( 121 )	73.2 ( 31.5 )
Cycle 2 Day 1 (n=89, 88, 38, 49)	122 ( 50.4 )	125 ( 47.4 )	158 ( 101 )	106 ( 45.2 )
Cycle 2 Day 22 (n=85, 88, 38, 44)	152 ( 65.3 )	159 ( 84.6 )	164 ( 70.7 )	141 ( 85.5 )
Cycle 4 Day 1 (n=79, 66, 28, 34)	183 ( 90.5 )	192 ( 77.6 )	154 ( 62.7 )	174 ( 75.7 )
Cycle 4 Day 22 (n=71, 65, 25, 29)	190 ( 86.3 )	200 ( 90.0 )	163 ( 70.5 )	172 ( 78.8 )

No statistical analyses for this end point

Secondary: Cmax of Bevacizumab

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End point title

Cmax of Bevacizumab ^[6]

End point description

PK evaluable population. ‘Number of Subjects Analyzed’=participants evaluable for this outcome measure.

End point type

Secondary

End point timeframe

30 minutes after end of infusion on Day 1 of Cycles 1 and 2 (1 cycle=6 weeks) (infusion length=30-90 minutes)

Notes
[6] - 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: No statistical analysis was planned for this endpoint.

End point values	Atezolizumab and Bevacizumab	Atezolizumab (Crossover)	Sunitinib (Crossover)
Number of subjects analysed	86	34	44
Units: mcg/mL
arithmetic mean (standard deviation)	89.8 ( 39.4 )	433 ( 115 )	455 ( 106 )

No statistical analyses for this end point

Secondary: Cmin of Bevacizumab

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End point title

Cmin of Bevacizumab ^[7]

End point description

PK evaluable population. ‘Number of Subjects Analyzed’=participants evaluable for this outcome measure.

End point type

Secondary

End point timeframe

For Atezolizumab and Bevacizumab Arm: at First-line treatment discontinuation (up to approximately 2.75 years); For Crossover Arms: pre-infusion (0 hour) on Day 1 of Cycle 2 (1 cycle=6 weeks) (infusion length=30-90 minutes)

Notes
[7] - 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: No statistical analysis was planned for this endpoint.

End point values	Atezolizumab and Bevacizumab	Atezolizumab (Crossover)	Sunitinib (Crossover)
Number of subjects analysed	42	39	42
Units: mcg/mL
arithmetic mean (standard deviation)	75.2 ( 72.1 )	101 ( 48.7 )	95.9 ( 43.9 )

No statistical analyses for this end point

Secondary: M.D. Anderson Symptom Inventory (MDASI) Interference Score

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End point title

M.D. Anderson Symptom Inventory (MDASI) Interference Score

End point description

MDASI questionnaire comprises of 2 parts:symptoms (16 items), interference with daily life (6 items). Participants were asked to rate how much their symptoms interfered with general activity, mood, work, relations with other people, walking, enjoyment of life during last 24 hours. Each item in interference score was answered on scale of 0 (did not interfere) to 10 (interfered completely). Mean score of 6 items was reported on scale of 0 (did not interfere) to 10 (interfered completely). Patient Reported Outcome (PRO)-evaluable population: randomized participants who had non-missing baseline assessment and at least 1 post-baseline assessment. ‘Overall Number of Participants Analyzed’=participants evaluable for this outcome. ‘n’=participants evaluable for this outcome at specified timepoint for each arm, respectively. ‘999999’ indicates that standard deviation was not estimable for single participant. ‘999’ indicates that data were not estimable as there were no evaluable participants.

End point type

Secondary

End point timeframe

Days 1 and 22 of Cycles 1 to 24; Day 1 of Cycle 25; treatment discontinuation (up to approximately 2.75 years) (1 cycle=6 weeks)

End point values	Atezolizumab and Bevacizumab	Atezolizumab	Sunitinib
Number of subjects analysed	96	95	93
Units: units on a scale
arithmetic mean (standard deviation)
Cycle 1 Day 1 (n=96, 95, 93)	1.60 ( 1.97 )	1.38 ( 2.03 )	1.79 ( 2.39 )
Cycle 1 Day 22 (n=93, 88, 88)	2.08 ( 2.34 )	1.26 ( 2.07 )	3.16 ( 2.65 )
Cycle 2 Day 1 (n=86, 82, 80)	1.56 ( 1.82 )	1.20 ( 1.72 )	1.83 ( 2.19 )
Cycle 2 Day 22 (n=82, 80, 77)	1.57 ( 1.83 )	1.04 ( 1.62 )	2.50 ( 2.47 )
Cycle 3 Day 1 (n=77, 65, 69)	1.72 ( 2.15 )	0.90 ( 1.43 )	1.49 ( 2.01 )
Cycle 3 Day 22 (n=74, 63, 63)	1.66 ( 2.07 )	1.01 ( 1.58 )	2.20 ( 2.42 )
Cycle 4 Day 1 (n=72, 61, 62)	1.59 ( 2.11 )	1.24 ( 1.99 )	1.61 ( 2.24 )
Cycle 4 Day 22 (n=68, 61, 59)	1.68 ( 2.31 )	1.26 ( 1.98 )	1.92 ( 2.00 )
Cycle 5 Day 1 (n=60, 52, 53)	1.70 ( 2.29 )	0.69 ( 1.11 )	1.53 ( 1.96 )
Cycle 5 Day 22 (n=60, 50, 47)	1.80 ( 2.29 )	0.67 ( 1.33 )	1.97 ( 2.21 )
Cycle 6 Day 1 (n=57, 47, 49)	1.91 ( 2.54 )	0.64 ( 1.13 )	1.39 ( 1.76 )
Cycle 6 Day 22 (n=56, 49, 44)	1.80 ( 2.38 )	0.63 ( 1.12 )	2.00 ( 2.23 )
Cycle 7 Day 1 (n=51, 41, 41)	1.99 ( 2.49 )	0.53 ( 0.78 )	1.00 ( 1.09 )
Cycle 7 Day 22 (n=51, 40, 38)	2.01 ( 2.45 )	0.59 ( 0.93 )	1.15 ( 1.04 )
Cycle 8 Day 1 (n=50, 41, 39)	1.88 ( 2.26 )	0.55 ( 0.85 )	0.94 ( 1.04 )
Cycle 8 Day 22 (n=51, 38, 36)	1.81 ( 2.41 )	0.58 ( 0.91 )	1.34 ( 1.39 )
Cycle 9 Day 1 (n=46, 34, 33)	1.75 ( 2.24 )	0.55 ( 0.90 )	1.16 ( 1.22 )
Cycle 9 Day 22 (n=46, 32, 28)	1.64 ( 2.16 )	0.58 ( 0.89 )	1.57 ( 1.61 )
Cycle 10 Day 1 (n=45, 33, 28)	1.43 ( 1.82 )	0.81 ( 1.13 )	1.08 ( 1.40 )
Cycle 10 Day 22 (n=43, 33, 29)	1.55 ( 2.09 )	0.70 ( 1.10 )	1.49 ( 1.78 )
Cycle 11 Day 1 (n=41, 30, 29)	1.65 ( 2.13 )	0.61 ( 0.95 )	0.98 ( 1.00 )
Cycle 11 Day 22 (n=38, 28, 26)	1.35 ( 1.81 )	0.78 ( 1.07 )	1.47 ( 1.61 )
Cycle 12 Day 1 (n=39, 28, 29)	1.21 ( 1.69 )	0.68 ( 1.15 )	0.84 ( 0.83 )
Cycle 12 Day 22 (n=38, 25, 26)	1.51 ( 2.23 )	0.53 ( 0.99 )	1.41 ( 1.53 )
Cycle 13 Day 1 (n=35, 23, 24)	1.50 ( 2.16 )	0.68 ( 1.07 )	1.26 ( 1.45 )
Cycle 13 Day 22 (n=37, 23, 20)	1.45 ( 2.32 )	0.67 ( 1.10 )	1.32 ( 1.37 )
Cycle 14 Day 1 (n=35, 21, 23)	1.60 ( 2.24 )	0.67 ( 0.95 )	1.07 ( 1.31 )
Cycle 14 Day 22 (n=35, 19, 20)	1.40 ( 2.09 )	0.63 ( 0.94 )	1.50 ( 1.48 )
Cycle 15 Day 1 (n=31, 17, 21)	1.16 ( 1.74 )	0.84 ( 1.16 )	1.50 ( 1.64 )
Cycle 15 Day 22 (n=28, 13, 15)	1.48 ( 1.92 )	0.71 ( 1.10 )	2.08 ( 1.64 )
Cycle 16 Day 1 (n=25, 13, 14)	0.87 ( 0.99 )	0.85 ( 1.40 )	1.07 ( 1.22 )
Cycle 16 Day 22 (n=23, 9, 14)	0.72 ( 0.93 )	0.87 ( 1.30 )	2.04 ( 2.24 )
Cycle 17 Day 1 (n=18, 10, 8)	0.98 ( 0.99 )	0.57 ( 0.75 )	0.71 ( 0.95 )
Cycle 17 Day 22 (n=14, 8, 8)	0.73 ( 1.02 )	0.65 ( 0.97 )	1.21 ( 1.32 )
Cycle 18 Day 1 (n=12, 8, 7)	0.93 ( 1.07 )	0.71 ( 0.98 )	0.95 ( 1.15 )
Cycle 18 Day 22 (n=13, 6, 7)	0.79 ( 1.06 )	0.33 ( 0.41 )	1.05 ( 1.42 )
Cycle 19 Day 1 (n=11, 6, 7)	1.11 ( 1.25 )	0.31 ( 0.34 )	1.33 ( 1.66 )
Cycle 19 Day 22 (n=10, 5, 7)	0.97 ( 1.37 )	0.30 ( 0.41 )	1.55 ( 1.69 )
Cycle 20 Day 1 (n=8, 4, 5)	1.19 ( 1.31 )	0.21 ( 0.42 )	0.90 ( 1.07 )
Cycle 20 Day 22 (n=5, 4, 4)	1.10 ( 1.30 )	0.04 ( 0.08 )	1.67 ( 1.56 )
Cycle 21 Day 1 (n=5, 2, 3)	1.17 ( 1.42 )	0.00 ( 0.00 )	0.78 ( 1.07 )
Cycle 21 Day 22 (n=5, 1, 2)	1.23 ( 1.51 )	0.00 ( 999999 )	1.25 ( 1.53 )
Cycle 22 Day 1 (n=4, 1, 2)	0.54 ( 0.76 )	0.00 ( 999999 )	0.83 ( 0.71 )
Cycle 22 Day 22 (n=3, 1, 2)	0.94 ( 1.07 )	0.00 ( 999999 )	1.25 ( 1.53 )
Cycle 23 Day 1 (n=2, 1, 2)	1.67 ( 1.89 )	0.00 ( 999999 )	1.58 ( 2.00 )
Cycle 23 Day 22 (n=2, 1, 2)	1.25 ( 1.77 )	0.00 ( 999999 )	2.67 ( 2.36 )
Cycle 24 Day 1 (n=1, 1, 1)	2.33 ( 999999 )	0.00 ( 999999 )	1.67 ( 999999 )
Cycle 24 Day 22 (n=0, 1, 1)	999 ( 999 )	0.00 ( 999999 )	0.50 ( 999999 )
Cycle 25 Day 1 (n=0, 1, 0)	999 ( 999 )	0.00 ( 999999 )	999 ( 999 )
Treatment discontinuation (n=46, 39, 39)	2.54 ( 2.66 )	2.29 ( 2.54 )	3.49 ( 3.16 )

No statistical analyses for this end point

Secondary: Brief Fatigue Inventory (BFI) Fatigue Level Score

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End point title

Brief Fatigue Inventory (BFI) Fatigue Level Score

End point description

BFI questionnaire comprises of 2 parts: fatigue level (3 items), interference with daily life (1 item with 6 sub-items). Each items in the fatigue level score was answered on a scale of 0 (no fatigue) to 10 (as bad as you can imagine). The mean score of all 3 items was reported on the scale of 0 (no fatigue) to 10 (as bad as you can imagine). PRO-evaluable population. ‘Number of Subjects Analyzed’=participants evaluable for this outcome measure. ‘n’=participants evaluable for this outcome measure at specified timepoint for each arm respectively. ‘999999’ indicates that standard deviation was not estimable for single participant. ‘999’ indicates that data were not estimable as there were no evaluable participants.

End point type

Secondary

End point timeframe

Days 1 and 22 of Cycles 1 to 24; Day 1 of Cycle 25; treatment discontinuation (up to approximately 2.75 years) (1 cycle=6 weeks)

End point values	Atezolizumab and Bevacizumab	Atezolizumab	Sunitinib
Number of subjects analysed	95	94	93
Units: units on a scale
arithmetic mean (standard deviation)
Cycle 1 Day 1 (n=93, 93, 92)	2.80 ( 2.64 )	2.52 ( 2.72 )	2.66 ( 2.74 )
Cycle 1 Day 22 (n=90, 86, 89)	3.80 ( 2.86 )	2.55 ( 2.60 )	4.42 ( 3.09 )
Cycle 2 Day 1 (n=86, 79, 79)	3.21 ( 2.61 )	2.63 ( 2.69 )	2.86 ( 2.76 )
Cycle 2 Day 22 (n=81, 82, 78)	3.15 ( 2.61 )	2.57 ( 2.74 )	3.69 ( 2.74 )
Cycle 3 Day 1 (n=76, 64, 69)	2.91 ( 2.60 )	2.11 ( 2.42 )	2.35 ( 2.44 )
Cycle 3 Day 22 (n=74, 62, 63)	2.93 ( 2.67 )	2.31 ( 2.71 )	3.60 ( 3.09 )
Cycle 4 Day 1 (n=72, 62, 62)	3.21 ( 2.66 )	2.32 ( 2.86 )	2.39 ( 2.47 )
Cycle 4 Day 22 (n=66, 61, 59)	3.06 ( 2.68 )	2.33 ( 2.94 )	3.15 ( 2.57 )
Cycle 5 Day 1 (n=59, 51, 53)	2.97 ( 2.83 )	1.59 ( 2.03 )	2.32 ( 2.62 )
Cycle 5 Day 22 (n=60, 50, 47)	3.02 ( 2.87 )	1.34 ( 1.81 )	2.91 ( 2.86 )
Cycle 6 Day 1 (n=57, 48, 49)	3.05 ( 2.83 )	1.42 ( 1.90 )	2.22 ( 2.48 )
Cycle 6 Day 22 (n=56, 49, 44)	3.23 ( 2.94 )	1.39 ( 2.01 )	3.09 ( 2.69 )
Cycle 7 Day 1 (n=51, 40, 40)	3.16 ( 2.81 )	1.33 ( 1.91 )	1.68 ( 1.75 )
Cycle 7 Day 22 (n=51, 41, 38)	2.86 ( 2.60 )	1.24 ( 1.67 )	2.16 ( 1.87 )
Cycle 8 Day 1 (n=50, 41, 39)	2.80 ( 2.56 )	1.12 ( 1.68 )	1.72 ( 1.70 )
Cycle 8 Day 22 (n=51, 38, 36)	2.88 ( 2.80 )	1.24 ( 1.75 )	2.58 ( 2.13 )
Cycle 9 Day 1 (n=46, 35, 34)	3.09 ( 2.81 )	1.11 ( 1.55 )	2.12 ( 2.48 )
Cycle 9 Day 22 (n=46, 32, 28)	2.80 ( 2.73 )	1.19 ( 1.71 )	2.64 ( 2.57 )
Cycle 10 Day 1 (n=45, 34, 28)	2.80 ( 2.58 )	1.29 ( 1.88 )	2.11 ( 2.23 )
Cycle 10 Day 22 (n=43, 33, 29)	2.91 ( 2.83 )	1.33 ( 1.90 )	2.24 ( 2.43 )
Cycle 11 Day 1 (n=40, 30, 28)	2.98 ( 2.71 )	1.40 ( 1.96 )	1.93 ( 1.65 )
Cycle 11 Day 22 (n=37, 29, 26)	2.59 ( 2.44 )	1.72 ( 2.23 )	2.42 ( 2.12 )
Cycle 12 Day 1 (n=39, 28, 29)	2.31 ( 2.25 )	1.25 ( 1.96 )	1.66 ( 1.67 )
Cycle 12 Day 22 (n=38, 25, 26)	2.79 ( 2.46 )	1.44 ( 2.12 )	2.27 ( 2.05 )
Cycle 13 Day 1 (n=36, 23, 24)	2.69 ( 2.57 )	1.65 ( 2.17 )	2.08 ( 1.56 )
Cycle 13 Day 22 (n=37, 22, 20)	2.97 ( 2.97 )	1.55 ( 2.13 )	2.60 ( 2.28 )
Cycle 14 Day 1 (n=35, 20, 23)	2.94 ( 2.94 )	1.45 ( 2.14 )	2.30 ( 2.34 )
Cycle 14 Day 22 (n=35, 18, 20)	2.83 ( 2.85 )	1.61 ( 2.00 )	2.60 ( 2.09 )
Cycle 15 Day 1 (n=30, 17, 20)	2.73 ( 2.56 )	1.76 ( 2.19 )	2.60 ( 2.33 )
Cycle 15 Day 22 (n=28, 13, 16)	2.61 ( 2.79 )	0.92 ( 1.12 )	2.94 ( 1.61 )
Cycle 16 Day 1 (n=25, 13, 14)	1.88 ( 1.99 )	1.54 ( 2.07 )	2.21 ( 2.42 )
Cycle 16 Day 22 (n=23, 9, 13)	1.70 ( 1.61 )	2.11 ( 2.15 )	2.85 ( 2.19 )
Cycle 17 Day 1 (n=18, 10, 8)	1.78 ( 1.59 )	1.60 ( 1.96 )	1.50 ( 1.51 )
Cycle 17 Day 22 (n=14, 8, 8)	2.00 ( 1.80 )	2.13 ( 2.42 )	2.38 ( 1.60 )
Cycle 18 Day 1 (n=13, 8, 7)	2.23 ( 1.74 )	1.88 ( 2.23 )	1.71 ( 1.70 )
Cycle 18 Day 22 (n=13, 6, 7)	1.92 ( 2.14 )	1.67 ( 2.07 )	2.14 ( 2.19 )
Cycle 19 Day 1 (n=12, 6, 7)	2.17 ( 2.48 )	1.50 ( 1.97 )	2.29 ( 3.30 )
Cycle 19 Day 22 (n=10, 5, 7)	1.90 ( 2.42 )	1.40 ( 2.19 )	3.29 ( 2.43 )
Cycle 20 Day 1 (n=8, 4, 5)	3.00 ( 3.16 )	1.25 ( 2.50 )	1.80 ( 1.30 )
Cycle 20 Day 22 (n=5, 4, 4)	2.40 ( 3.05 )	1.50 ( 3.00 )	2.25 ( 2.06 )
Cycle 21 Day 1 (n=5, 2, 3)	2.60 ( 2.97 )	2.50 ( 3.54 )	1.67 ( 1.53 )
Cycle 21 Day 22 (n=5, 1, 2)	2.40 ( 1.95 )	0.00 ( 999999 )	2.00 ( 1.41 )
Cycle 22 Day 1 (n=4, 1, 2)	1.25 ( 1.89 )	0.00 ( 999999 )	2.00 ( 1.41 )
Cycle 22 Day 22 (n=3, 1, 2)	1.33 ( 2.31 )	0.00 ( 999999 )	3.00 ( 2.83 )
Cycle 23 Day 1 (n=2, 1, 2)	2.50 ( 3.54 )	0.00 ( 999999 )	2.00 ( 2.83 )
Cycle 23 Day 22 (n=2, 1, 2)	2.00 ( 2.83 )	0.00 ( 999999 )	4.50 ( 3.54 )
Cycle 24 Day 1 (n=1, 1, 1)	4.00 ( 999999 )	0.00 ( 999999 )	2.00 ( 999999 )
Cycle 24 Day 22 (n=0, 1, 1)	999 ( 999 )	0.00 ( 999999 )	0.00 ( 999999 )
Cycle 25 Day 1 (n=0, 1, 0)	999 ( 999 )	0.00 ( 999999 )	999 ( 999 )
Treatment discontinuation (n=46, 39, 40)	3.74 ( 2.82 )	3.95 ( 3.27 )	3.75 ( 3.09 )

No statistical analyses for this end point

Other pre-specified: EuroQoL 5 Dimension (EQ-5D) Questionnaire Score

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End point title

EuroQoL 5 Dimension (EQ-5D) Questionnaire Score

End point description

EQ-5D: participant rated questionnaire to assess health-related quality of life in terms of a single utility score. Health State Profile component assesses level of current health for 5 domains: mobility, self-care, usual activities, pain and discomfort, and anxiety and depression; 1 indicates better health state (no problems); 3 indicates worst health state. Scoring formula developed by EuroQol Group assigns a utility value for each domain in the profile. Score is transformed and results in a total score range -0.594 to 1.000; higher score indicates a better health state.

End point type

Other pre-specified

End point timeframe

Days 1 and 22 of Cycles 1 to 24; Day 1 of Cycle 25; treatment discontinuation (up to approximately 2.75 years) (1 cycle=6 weeks)

End point values	Atezolizumab and Bevacizumab	Atezolizumab	Sunitinib
Number of subjects analysed	0 ^[8]	0 ^[9]	0 ^[10]
Units: units on a scale
arithmetic mean (standard deviation)	( )	( )	( )

Notes
[8] - As this outcome was pre-specified as an exploratory outcome, no results are reported.
[9] - As this outcome was pre-specified as an exploratory outcome, no results are reported.
[10] - As this outcome was pre-specified as an exploratory outcome, no results are reported.

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Baseline up to approximately 60 months.

Adverse event reporting additional description

Safety-evaluable population included all participants who received at least one dose of any study medication. Adverse events were reported separately for crossed over participants.

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

21.1

Reporting group title

Atezolizumab and Bevacizumab

Reporting group description

Reporting group title

Atezolizumab

Reporting group description

Reporting group title

Sunitinib

Reporting group description

Reporting group title

Atezolizumab (Crossover)

Reporting group description

Reporting group title

Sunitinib (Crossover)

Reporting group description

Serious adverse events	Atezolizumab and Bevacizumab	Atezolizumab	Sunitinib	Atezolizumab (Crossover)	Sunitinib (Crossover)
Total subjects affected by serious adverse events
subjects affected / exposed	49 / 101 (48.51%)	37 / 103 (35.92%)	28 / 100 (28.00%)	15 / 46 (32.61%)	22 / 63 (34.92%)
number of deaths (all causes)	54	51	56	0	0
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Intracranial tumour haemorrhage
subjects affected / exposed	1 / 101 (0.99%)	0 / 103 (0.00%)	0 / 100 (0.00%)	0 / 46 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Squamous cell carcinoma of skin
subjects affected / exposed	0 / 101 (0.00%)	0 / 103 (0.00%)	1 / 100 (1.00%)	0 / 46 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metastases to central nervous system
subjects affected / exposed	0 / 101 (0.00%)	1 / 103 (0.97%)	0 / 100 (0.00%)	0 / 46 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Deep vein thrombosis
subjects affected / exposed	1 / 101 (0.99%)	0 / 103 (0.00%)	0 / 100 (0.00%)	0 / 46 (0.00%)	1 / 63 (1.59%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Embolism
subjects affected / exposed	0 / 101 (0.00%)	0 / 103 (0.00%)	0 / 100 (0.00%)	1 / 46 (2.17%)	1 / 63 (1.59%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haemorrhage
subjects affected / exposed	1 / 101 (0.99%)	0 / 103 (0.00%)	0 / 100 (0.00%)	0 / 46 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
Hypertension
subjects affected / exposed	4 / 101 (3.96%)	0 / 103 (0.00%)	2 / 100 (2.00%)	0 / 46 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	2 / 4	0 / 0	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypertensive crisis
subjects affected / exposed	0 / 101 (0.00%)	0 / 103 (0.00%)	0 / 100 (0.00%)	1 / 46 (2.17%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Orthostatic hypotension
subjects affected / exposed	0 / 101 (0.00%)	0 / 103 (0.00%)	0 / 100 (0.00%)	0 / 46 (0.00%)	1 / 63 (1.59%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Surgical and medical procedures
Limb operation
subjects affected / exposed	0 / 101 (0.00%)	0 / 103 (0.00%)	0 / 100 (0.00%)	1 / 46 (2.17%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Chest pain
subjects affected / exposed	0 / 101 (0.00%)	1 / 103 (0.97%)	0 / 100 (0.00%)	0 / 46 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Fatigue
subjects affected / exposed	0 / 101 (0.00%)	1 / 103 (0.97%)	1 / 100 (1.00%)	1 / 46 (2.17%)	1 / 63 (1.59%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General physical health deterioration
subjects affected / exposed	0 / 101 (0.00%)	0 / 103 (0.00%)	1 / 100 (1.00%)	0 / 46 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Mucosal inflammation
subjects affected / exposed	0 / 101 (0.00%)	1 / 103 (0.97%)	0 / 100 (0.00%)	0 / 46 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Non−cardiac chest pain
subjects affected / exposed	0 / 101 (0.00%)	0 / 103 (0.00%)	1 / 100 (1.00%)	0 / 46 (0.00%)	1 / 63 (1.59%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pain
subjects affected / exposed	1 / 101 (0.99%)	0 / 103 (0.00%)	1 / 100 (1.00%)	0 / 46 (0.00%)	3 / 63 (4.76%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 2	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	2 / 101 (1.98%)	4 / 103 (3.88%)	2 / 100 (2.00%)	0 / 46 (0.00%)	2 / 63 (3.17%)
occurrences causally related to treatment / all	1 / 2	1 / 4	1 / 2	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Sudden death
subjects affected / exposed	0 / 101 (0.00%)	0 / 103 (0.00%)	1 / 100 (1.00%)	0 / 46 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
Death
subjects affected / exposed	0 / 101 (0.00%)	0 / 103 (0.00%)	1 / 100 (1.00%)	0 / 46 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
Oedema
subjects affected / exposed	0 / 101 (0.00%)	0 / 103 (0.00%)	0 / 100 (0.00%)	1 / 46 (2.17%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Asthenia
subjects affected / exposed	0 / 101 (0.00%)	0 / 103 (0.00%)	1 / 100 (1.00%)	0 / 46 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Immune system disorders
Haemophagocytic lymphohistiocytosis
subjects affected / exposed	0 / 101 (0.00%)	1 / 103 (0.97%)	0 / 100 (0.00%)	0 / 46 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Asthma
subjects affected / exposed	0 / 101 (0.00%)	1 / 103 (0.97%)	0 / 100 (0.00%)	0 / 46 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Chronic obstructive pulmonary disease
subjects affected / exposed	1 / 101 (0.99%)	0 / 103 (0.00%)	0 / 100 (0.00%)	0 / 46 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	1 / 101 (0.99%)	4 / 103 (3.88%)	0 / 100 (0.00%)	1 / 46 (2.17%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 4	0 / 0	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haemoptysis
subjects affected / exposed	1 / 101 (0.99%)	0 / 103 (0.00%)	0 / 100 (0.00%)	0 / 46 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypoxia
subjects affected / exposed	1 / 101 (0.99%)	1 / 103 (0.97%)	2 / 100 (2.00%)	0 / 46 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	1 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Laryngeal mass
subjects affected / exposed	0 / 101 (0.00%)	0 / 103 (0.00%)	1 / 100 (1.00%)	0 / 46 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Obstructive airways disorder
subjects affected / exposed	0 / 101 (0.00%)	0 / 103 (0.00%)	1 / 100 (1.00%)	0 / 46 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	0 / 101 (0.00%)	2 / 103 (1.94%)	0 / 100 (0.00%)	0 / 46 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	3 / 101 (2.97%)	1 / 103 (0.97%)	0 / 100 (0.00%)	0 / 46 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	1 / 3	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary haemorrhage
subjects affected / exposed	0 / 101 (0.00%)	1 / 103 (0.97%)	0 / 100 (0.00%)	0 / 46 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumothorax
subjects affected / exposed	1 / 101 (0.99%)	0 / 103 (0.00%)	0 / 100 (0.00%)	0 / 46 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Confusional state
subjects affected / exposed	0 / 101 (0.00%)	0 / 103 (0.00%)	0 / 100 (0.00%)	0 / 46 (0.00%)	1 / 63 (1.59%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Depression
subjects affected / exposed	0 / 101 (0.00%)	0 / 103 (0.00%)	1 / 100 (1.00%)	0 / 46 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Mental status changes
subjects affected / exposed	0 / 101 (0.00%)	1 / 103 (0.97%)	0 / 100 (0.00%)	0 / 46 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
Blood creatinine increased
subjects affected / exposed	0 / 101 (0.00%)	0 / 103 (0.00%)	1 / 100 (1.00%)	0 / 46 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Alanine aminotransferase increased
subjects affected / exposed	0 / 101 (0.00%)	0 / 103 (0.00%)	0 / 100 (0.00%)	0 / 46 (0.00%)	1 / 63 (1.59%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Aspartate aminotransferase increased
subjects affected / exposed	0 / 101 (0.00%)	0 / 103 (0.00%)	0 / 100 (0.00%)	0 / 46 (0.00%)	1 / 63 (1.59%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood bilirubin increased
subjects affected / exposed	0 / 101 (0.00%)	0 / 103 (0.00%)	0 / 100 (0.00%)	0 / 46 (0.00%)	1 / 63 (1.59%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Fall
subjects affected / exposed	1 / 101 (0.99%)	0 / 103 (0.00%)	0 / 100 (0.00%)	0 / 46 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hip fracture
subjects affected / exposed	1 / 101 (0.99%)	0 / 103 (0.00%)	0 / 100 (0.00%)	0 / 46 (0.00%)	1 / 63 (1.59%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Incisional hernia
subjects affected / exposed	1 / 101 (0.99%)	0 / 103 (0.00%)	0 / 100 (0.00%)	0 / 46 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infusion related reaction
subjects affected / exposed	0 / 101 (0.00%)	2 / 103 (1.94%)	0 / 100 (0.00%)	0 / 46 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 0	2 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Spinal compression fracture
subjects affected / exposed	1 / 101 (0.99%)	0 / 103 (0.00%)	0 / 100 (0.00%)	0 / 46 (0.00%)	1 / 63 (1.59%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Femur fracture
subjects affected / exposed	1 / 101 (0.99%)	0 / 103 (0.00%)	0 / 100 (0.00%)	1 / 46 (2.17%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Angina pectoris
subjects affected / exposed	2 / 101 (1.98%)	0 / 103 (0.00%)	0 / 100 (0.00%)	0 / 46 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Atrial fibrillation
subjects affected / exposed	1 / 101 (0.99%)	1 / 103 (0.97%)	0 / 100 (0.00%)	1 / 46 (2.17%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac failure congestive
subjects affected / exposed	1 / 101 (0.99%)	0 / 103 (0.00%)	0 / 100 (0.00%)	0 / 46 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiomyopathy
subjects affected / exposed	0 / 101 (0.00%)	0 / 103 (0.00%)	0 / 100 (0.00%)	1 / 46 (2.17%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Myocardial infarction
subjects affected / exposed	1 / 101 (0.99%)	1 / 103 (0.97%)	0 / 100 (0.00%)	0 / 46 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tachycardia
subjects affected / exposed	1 / 101 (0.99%)	0 / 103 (0.00%)	0 / 100 (0.00%)	0 / 46 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Amnesia
subjects affected / exposed	0 / 101 (0.00%)	0 / 103 (0.00%)	1 / 100 (1.00%)	0 / 46 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Autoimmune neuropathy
subjects affected / exposed	1 / 101 (0.99%)	0 / 103 (0.00%)	0 / 100 (0.00%)	0 / 46 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Demyelination
subjects affected / exposed	0 / 101 (0.00%)	1 / 103 (0.97%)	0 / 100 (0.00%)	0 / 46 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Facial paralysis
subjects affected / exposed	0 / 101 (0.00%)	1 / 103 (0.97%)	0 / 100 (0.00%)	0 / 46 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haemorrhage intracranial
subjects affected / exposed	1 / 101 (0.99%)	1 / 103 (0.97%)	0 / 100 (0.00%)	0 / 46 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
Headache
subjects affected / exposed	2 / 101 (1.98%)	0 / 103 (0.00%)	0 / 100 (0.00%)	0 / 46 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hemiparesis
subjects affected / exposed	0 / 101 (0.00%)	1 / 103 (0.97%)	0 / 100 (0.00%)	0 / 46 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nerve root compression
subjects affected / exposed	1 / 101 (0.99%)	0 / 103 (0.00%)	0 / 100 (0.00%)	0 / 46 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Peripheral sensorimotor neuropathy
subjects affected / exposed	1 / 101 (0.99%)	0 / 103 (0.00%)	0 / 100 (0.00%)	0 / 46 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Spinal cord compression
subjects affected / exposed	0 / 101 (0.00%)	1 / 103 (0.97%)	0 / 100 (0.00%)	0 / 46 (0.00%)	1 / 63 (1.59%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Syncope
subjects affected / exposed	0 / 101 (0.00%)	1 / 103 (0.97%)	0 / 100 (0.00%)	0 / 46 (0.00%)	1 / 63 (1.59%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cerebrovascular accident
subjects affected / exposed	1 / 101 (0.99%)	0 / 103 (0.00%)	0 / 100 (0.00%)	0 / 46 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intracranial haematoma
subjects affected / exposed	1 / 101 (0.99%)	0 / 103 (0.00%)	0 / 100 (0.00%)	0 / 46 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Paresis
subjects affected / exposed	0 / 101 (0.00%)	0 / 103 (0.00%)	1 / 100 (1.00%)	0 / 46 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 101 (0.00%)	0 / 103 (0.00%)	1 / 100 (1.00%)	0 / 46 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Febrile neutropenia
subjects affected / exposed	0 / 101 (0.00%)	1 / 103 (0.97%)	0 / 100 (0.00%)	0 / 46 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Histiocytosis haematophagic
subjects affected / exposed	0 / 101 (0.00%)	1 / 103 (0.97%)	0 / 100 (0.00%)	0 / 46 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
Ear and labyrinth disorders
Vertigo
subjects affected / exposed	1 / 101 (0.99%)	0 / 103 (0.00%)	0 / 100 (0.00%)	0 / 46 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	1 / 101 (0.99%)	1 / 103 (0.97%)	0 / 100 (0.00%)	1 / 46 (2.17%)	2 / 63 (3.17%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	3 / 3	3 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ascites
subjects affected / exposed	1 / 101 (0.99%)	0 / 103 (0.00%)	0 / 100 (0.00%)	0 / 46 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Autoimmune pancreatitis
subjects affected / exposed	0 / 101 (0.00%)	1 / 103 (0.97%)	0 / 100 (0.00%)	0 / 46 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Constipation
subjects affected / exposed	0 / 101 (0.00%)	0 / 103 (0.00%)	0 / 100 (0.00%)	1 / 46 (2.17%)	2 / 63 (3.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	4 / 101 (3.96%)	0 / 103 (0.00%)	2 / 100 (2.00%)	0 / 46 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	3 / 5	0 / 0	1 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastritis
subjects affected / exposed	0 / 101 (0.00%)	0 / 103 (0.00%)	0 / 100 (0.00%)	0 / 46 (0.00%)	1 / 63 (1.59%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal haemorrhage
subjects affected / exposed	0 / 101 (0.00%)	0 / 103 (0.00%)	1 / 100 (1.00%)	0 / 46 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal inflammation
subjects affected / exposed	1 / 101 (0.99%)	0 / 103 (0.00%)	0 / 100 (0.00%)	0 / 46 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrooesophageal reflux disease
subjects affected / exposed	0 / 101 (0.00%)	0 / 103 (0.00%)	1 / 100 (1.00%)	0 / 46 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intestinal haemorrhage
subjects affected / exposed	0 / 101 (0.00%)	1 / 103 (0.97%)	1 / 100 (1.00%)	0 / 46 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
Intestinal obstruction
subjects affected / exposed	1 / 101 (0.99%)	0 / 103 (0.00%)	0 / 100 (0.00%)	0 / 46 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Mesenteric vein thrombosis
subjects affected / exposed	0 / 101 (0.00%)	1 / 103 (0.97%)	0 / 100 (0.00%)	0 / 46 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nausea
subjects affected / exposed	0 / 101 (0.00%)	0 / 103 (0.00%)	0 / 100 (0.00%)	0 / 46 (0.00%)	3 / 63 (4.76%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatic fistula
subjects affected / exposed	0 / 101 (0.00%)	0 / 103 (0.00%)	1 / 100 (1.00%)	0 / 46 (0.00%)	1 / 63 (1.59%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatitis
subjects affected / exposed	0 / 101 (0.00%)	1 / 103 (0.97%)	0 / 100 (0.00%)	0 / 46 (0.00%)	1 / 63 (1.59%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatitis acute
subjects affected / exposed	0 / 101 (0.00%)	0 / 103 (0.00%)	0 / 100 (0.00%)	1 / 46 (2.17%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Peritoneal haemorrhage
subjects affected / exposed	0 / 101 (0.00%)	0 / 103 (0.00%)	1 / 100 (1.00%)	0 / 46 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Rectal haemorrhage
subjects affected / exposed	1 / 101 (0.99%)	0 / 103 (0.00%)	0 / 100 (0.00%)	0 / 46 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Retroperitoneal haemorrhage
subjects affected / exposed	1 / 101 (0.99%)	0 / 103 (0.00%)	1 / 100 (1.00%)	0 / 46 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Small intestinal obstruction
subjects affected / exposed	0 / 101 (0.00%)	1 / 103 (0.97%)	0 / 100 (0.00%)	0 / 46 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	1 / 101 (0.99%)	1 / 103 (0.97%)	1 / 100 (1.00%)	0 / 46 (0.00%)	2 / 63 (3.17%)
occurrences causally related to treatment / all	1 / 1	0 / 1	1 / 1	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Colitis microscopic
subjects affected / exposed	1 / 101 (0.99%)	0 / 103 (0.00%)	0 / 100 (0.00%)	0 / 46 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Obstructive pancreatitis
subjects affected / exposed	1 / 101 (0.99%)	0 / 103 (0.00%)	0 / 100 (0.00%)	0 / 46 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Bile duct stenosis
subjects affected / exposed	0 / 101 (0.00%)	1 / 103 (0.97%)	0 / 100 (0.00%)	0 / 46 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cholecystitis
subjects affected / exposed	0 / 101 (0.00%)	0 / 103 (0.00%)	1 / 100 (1.00%)	0 / 46 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cholelithiasis
subjects affected / exposed	0 / 101 (0.00%)	0 / 103 (0.00%)	0 / 100 (0.00%)	0 / 46 (0.00%)	1 / 63 (1.59%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatorenal syndrome
subjects affected / exposed	1 / 101 (0.99%)	0 / 103 (0.00%)	0 / 100 (0.00%)	0 / 46 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hyperbilirubinaemia
subjects affected / exposed	0 / 101 (0.00%)	0 / 103 (0.00%)	0 / 100 (0.00%)	0 / 46 (0.00%)	1 / 63 (1.59%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Rash erythematous
subjects affected / exposed	0 / 101 (0.00%)	0 / 103 (0.00%)	0 / 100 (0.00%)	1 / 46 (2.17%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Rash maculo−papular
subjects affected / exposed	0 / 101 (0.00%)	1 / 103 (0.97%)	0 / 100 (0.00%)	0 / 46 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	1 / 101 (0.99%)	3 / 103 (2.91%)	1 / 100 (1.00%)	0 / 46 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	1 / 1	2 / 4	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haematuria
subjects affected / exposed	3 / 101 (2.97%)	2 / 103 (1.94%)	1 / 100 (1.00%)	2 / 46 (4.35%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	2 / 3	0 / 2	0 / 5	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal failure
subjects affected / exposed	0 / 101 (0.00%)	1 / 103 (0.97%)	2 / 100 (2.00%)	0 / 46 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urethral stenosis
subjects affected / exposed	1 / 101 (0.99%)	0 / 103 (0.00%)	0 / 100 (0.00%)	0 / 46 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Endocrine disorders
Adrenal insufficiency
subjects affected / exposed	1 / 101 (0.99%)	0 / 103 (0.00%)	0 / 100 (0.00%)	2 / 46 (4.35%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	1 / 101 (0.99%)	0 / 103 (0.00%)	1 / 100 (1.00%)	0 / 46 (0.00%)	5 / 63 (7.94%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bone pain
subjects affected / exposed	0 / 101 (0.00%)	0 / 103 (0.00%)	2 / 100 (2.00%)	0 / 46 (0.00%)	1 / 63 (1.59%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Chondrocalcinosis
subjects affected / exposed	0 / 101 (0.00%)	0 / 103 (0.00%)	0 / 100 (0.00%)	0 / 46 (0.00%)	1 / 63 (1.59%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Flank pain
subjects affected / exposed	0 / 101 (0.00%)	0 / 103 (0.00%)	1 / 100 (1.00%)	0 / 46 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Fracture pain
subjects affected / exposed	0 / 101 (0.00%)	0 / 103 (0.00%)	1 / 100 (1.00%)	0 / 46 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Muscle haemorrhage
subjects affected / exposed	0 / 101 (0.00%)	0 / 103 (0.00%)	1 / 100 (1.00%)	1 / 46 (2.17%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal pain
subjects affected / exposed	0 / 101 (0.00%)	0 / 103 (0.00%)	0 / 100 (0.00%)	1 / 46 (2.17%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Neck pain
subjects affected / exposed	0 / 101 (0.00%)	0 / 103 (0.00%)	0 / 100 (0.00%)	2 / 46 (4.35%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Neuropathic arthropathy
subjects affected / exposed	1 / 101 (0.99%)	0 / 103 (0.00%)	0 / 100 (0.00%)	0 / 46 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pain in extremity
subjects affected / exposed	0 / 101 (0.00%)	0 / 103 (0.00%)	0 / 100 (0.00%)	1 / 46 (2.17%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pathological fracture
subjects affected / exposed	2 / 101 (1.98%)	0 / 103 (0.00%)	0 / 100 (0.00%)	0 / 46 (0.00%)	1 / 63 (1.59%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Appendicitis
subjects affected / exposed	0 / 101 (0.00%)	0 / 103 (0.00%)	0 / 100 (0.00%)	1 / 46 (2.17%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Arthritis infective
subjects affected / exposed	1 / 101 (0.99%)	0 / 103 (0.00%)	0 / 100 (0.00%)	0 / 46 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bacteraemia
subjects affected / exposed	1 / 101 (0.99%)	0 / 103 (0.00%)	0 / 100 (0.00%)	0 / 46 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bronchitis
subjects affected / exposed	1 / 101 (0.99%)	0 / 103 (0.00%)	0 / 100 (0.00%)	1 / 46 (2.17%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	0 / 101 (0.00%)	0 / 103 (0.00%)	1 / 100 (1.00%)	0 / 46 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Chest wall abscess
subjects affected / exposed	0 / 101 (0.00%)	0 / 103 (0.00%)	1 / 100 (1.00%)	0 / 46 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diverticulitis
subjects affected / exposed	3 / 101 (2.97%)	0 / 103 (0.00%)	0 / 100 (0.00%)	1 / 46 (2.17%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	1 / 3	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	2 / 101 (1.98%)	0 / 103 (0.00%)	0 / 100 (0.00%)	0 / 46 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Influenza
subjects affected / exposed	1 / 101 (0.99%)	0 / 103 (0.00%)	0 / 100 (0.00%)	0 / 46 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lower respiratory tract infection
subjects affected / exposed	0 / 101 (0.00%)	3 / 103 (2.91%)	0 / 100 (0.00%)	0 / 46 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 3	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
Meningitis viral
subjects affected / exposed	0 / 101 (0.00%)	1 / 103 (0.97%)	0 / 100 (0.00%)	0 / 46 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Necrotising fasciitis
subjects affected / exposed	1 / 101 (0.99%)	0 / 103 (0.00%)	0 / 100 (0.00%)	0 / 46 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatic abscess
subjects affected / exposed	0 / 101 (0.00%)	0 / 103 (0.00%)	1 / 100 (1.00%)	0 / 46 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Paronychia
subjects affected / exposed	0 / 101 (0.00%)	1 / 103 (0.97%)	0 / 100 (0.00%)	0 / 46 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Peritonitis bacterial
subjects affected / exposed	1 / 101 (0.99%)	0 / 103 (0.00%)	0 / 100 (0.00%)	0 / 46 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	3 / 101 (2.97%)	2 / 103 (1.94%)	1 / 100 (1.00%)	0 / 46 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 2	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
Sinusitis
subjects affected / exposed	0 / 101 (0.00%)	0 / 103 (0.00%)	0 / 100 (0.00%)	0 / 46 (0.00%)	1 / 63 (1.59%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Spinal cord infection
subjects affected / exposed	0 / 101 (0.00%)	0 / 103 (0.00%)	0 / 100 (0.00%)	0 / 46 (0.00%)	1 / 63 (1.59%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Staphylococcal infection
subjects affected / exposed	1 / 101 (0.99%)	0 / 103 (0.00%)	0 / 100 (0.00%)	0 / 46 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	1 / 101 (0.99%)	1 / 103 (0.97%)	0 / 100 (0.00%)	0 / 46 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Wound infection
subjects affected / exposed	1 / 101 (0.99%)	0 / 103 (0.00%)	0 / 100 (0.00%)	0 / 46 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Abscess
subjects affected / exposed	1 / 101 (0.99%)	0 / 103 (0.00%)	0 / 100 (0.00%)	0 / 46 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Biliary sepsis
subjects affected / exposed	1 / 101 (0.99%)	0 / 103 (0.00%)	0 / 100 (0.00%)	0 / 46 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Osteomyelitis
subjects affected / exposed	0 / 101 (0.00%)	0 / 103 (0.00%)	0 / 100 (0.00%)	0 / 46 (0.00%)	1 / 63 (1.59%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Psoas abscess
subjects affected / exposed	0 / 101 (0.00%)	0 / 103 (0.00%)	0 / 100 (0.00%)	0 / 46 (0.00%)	1 / 63 (1.59%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	1 / 101 (0.99%)	0 / 103 (0.00%)	0 / 100 (0.00%)	1 / 46 (2.17%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skin infection
subjects affected / exposed	0 / 101 (0.00%)	0 / 103 (0.00%)	0 / 100 (0.00%)	0 / 46 (0.00%)	1 / 63 (1.59%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	1 / 101 (0.99%)	1 / 103 (0.97%)	0 / 100 (0.00%)	0 / 46 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dehydration
subjects affected / exposed	2 / 101 (1.98%)	1 / 103 (0.97%)	2 / 100 (2.00%)	0 / 46 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	1 / 2	1 / 1	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diabetes mellitus
subjects affected / exposed	1 / 101 (0.99%)	0 / 103 (0.00%)	0 / 100 (0.00%)	0 / 46 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypercalcaemia
subjects affected / exposed	0 / 101 (0.00%)	2 / 103 (1.94%)	0 / 100 (0.00%)	0 / 46 (0.00%)	3 / 63 (4.76%)
occurrences causally related to treatment / all	0 / 0	1 / 2	0 / 0	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hyperglycaemia
subjects affected / exposed	0 / 101 (0.00%)	1 / 103 (0.97%)	0 / 100 (0.00%)	0 / 46 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hyperkalaemia
subjects affected / exposed	0 / 101 (0.00%)	0 / 103 (0.00%)	2 / 100 (2.00%)	0 / 46 (0.00%)	1 / 63 (1.59%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 2	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hyponatraemia
subjects affected / exposed	4 / 101 (3.96%)	1 / 103 (0.97%)	0 / 100 (0.00%)	0 / 46 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	2 / 6	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Atezolizumab and Bevacizumab	Atezolizumab	Sunitinib	Atezolizumab (Crossover)	Sunitinib (Crossover)
Total subjects affected by non serious adverse events
subjects affected / exposed	99 / 101 (98.02%)	94 / 103 (91.26%)	99 / 100 (99.00%)	44 / 46 (95.65%)	57 / 63 (90.48%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumour pain
subjects affected / exposed	0 / 101 (0.00%)	0 / 103 (0.00%)	0 / 100 (0.00%)	3 / 46 (6.52%)	0 / 63 (0.00%)
occurrences all number	0	0	0	3	0
Vascular disorders
Hypertension
subjects affected / exposed	38 / 101 (37.62%)	10 / 103 (9.71%)	34 / 100 (34.00%)	12 / 46 (26.09%)	13 / 63 (20.63%)
occurrences all number	62	18	52	15	26
General disorders and administration site conditions
Asthenia
subjects affected / exposed	7 / 101 (6.93%)	8 / 103 (7.77%)	7 / 100 (7.00%)	1 / 46 (2.17%)	7 / 63 (11.11%)
occurrences all number	10	9	30	1	11
Chest pain
subjects affected / exposed	7 / 101 (6.93%)	5 / 103 (4.85%)	6 / 100 (6.00%)	4 / 46 (8.70%)	1 / 63 (1.59%)
occurrences all number	7	5	6	5	1
Chills
subjects affected / exposed	5 / 101 (4.95%)	8 / 103 (7.77%)	13 / 100 (13.00%)	0 / 46 (0.00%)	0 / 63 (0.00%)
occurrences all number	6	8	15	0	0
Fatigue
subjects affected / exposed	62 / 101 (61.39%)	52 / 103 (50.49%)	70 / 100 (70.00%)	19 / 46 (41.30%)	27 / 63 (42.86%)
occurrences all number	125	76	159	40	44
Influenza like illness
subjects affected / exposed	8 / 101 (7.92%)	6 / 103 (5.83%)	3 / 100 (3.00%)	0 / 46 (0.00%)	0 / 63 (0.00%)
occurrences all number	11	7	3	0	0
Mucosal inflammation
subjects affected / exposed	18 / 101 (17.82%)	4 / 103 (3.88%)	33 / 100 (33.00%)	6 / 46 (13.04%)	4 / 63 (6.35%)
occurrences all number	30	5	67	13	8
Oedema peripheral
subjects affected / exposed	20 / 101 (19.80%)	12 / 103 (11.65%)	10 / 100 (10.00%)	8 / 46 (17.39%)	10 / 63 (15.87%)
occurrences all number	28	14	12	17	12
Pain
subjects affected / exposed	16 / 101 (15.84%)	7 / 103 (6.80%)	10 / 100 (10.00%)	0 / 46 (0.00%)	0 / 63 (0.00%)
occurrences all number	20	8	12	0	0
Pyrexia
subjects affected / exposed	19 / 101 (18.81%)	23 / 103 (22.33%)	10 / 100 (10.00%)	6 / 46 (13.04%)	10 / 63 (15.87%)
occurrences all number	23	25	13	7	15
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	24 / 101 (23.76%)	26 / 103 (25.24%)	25 / 100 (25.00%)	14 / 46 (30.43%)	12 / 63 (19.05%)
occurrences all number	33	48	31	19	21
Dysphonia
subjects affected / exposed	18 / 101 (17.82%)	2 / 103 (1.94%)	4 / 100 (4.00%)	9 / 46 (19.57%)	8 / 63 (12.70%)
occurrences all number	19	2	4	9	10
Dyspnoea
subjects affected / exposed	19 / 101 (18.81%)	18 / 103 (17.48%)	18 / 100 (18.00%)	8 / 46 (17.39%)	10 / 63 (15.87%)
occurrences all number	31	20	30	11	11
Dyspnoea exertional
subjects affected / exposed	5 / 101 (4.95%)	7 / 103 (6.80%)	8 / 100 (8.00%)	3 / 46 (6.52%)	2 / 63 (3.17%)
occurrences all number	5	8	10	4	2
Epistaxis
subjects affected / exposed	29 / 101 (28.71%)	2 / 103 (1.94%)	12 / 100 (12.00%)	13 / 46 (28.26%)	5 / 63 (7.94%)
occurrences all number	37	4	17	17	6
Nasal congestion
subjects affected / exposed	12 / 101 (11.88%)	11 / 103 (10.68%)	3 / 100 (3.00%)	5 / 46 (10.87%)	4 / 63 (6.35%)
occurrences all number	18	15	3	8	4
Oropharyngeal pain
subjects affected / exposed	12 / 101 (11.88%)	11 / 103 (10.68%)	3 / 100 (3.00%)	6 / 46 (13.04%)	0 / 63 (0.00%)
occurrences all number	14	14	4	6	0
Productive cough
subjects affected / exposed	0 / 101 (0.00%)	0 / 103 (0.00%)	0 / 100 (0.00%)	5 / 46 (10.87%)	2 / 63 (3.17%)
occurrences all number	0	0	0	8	3
Rhinorrhoea
subjects affected / exposed	6 / 101 (5.94%)	6 / 103 (5.83%)	3 / 100 (3.00%)	3 / 46 (6.52%)	1 / 63 (1.59%)
occurrences all number	6	8	3	3	3
Sinus Congestion
subjects affected / exposed	7 / 101 (6.93%)	2 / 103 (1.94%)	2 / 100 (2.00%)	0 / 46 (0.00%)	0 / 63 (0.00%)
occurrences all number	7	2	2	0	0
Psychiatric disorders
Anxiety
subjects affected / exposed	8 / 101 (7.92%)	6 / 103 (5.83%)	6 / 100 (6.00%)	1 / 46 (2.17%)	6 / 63 (9.52%)
occurrences all number	10	6	7	1	6
Depression
subjects affected / exposed	9 / 101 (8.91%)	5 / 103 (4.85%)	7 / 100 (7.00%)	2 / 46 (4.35%)	4 / 63 (6.35%)
occurrences all number	11	5	12	3	4
Insomnia
subjects affected / exposed	10 / 101 (9.90%)	7 / 103 (6.80%)	12 / 100 (12.00%)	3 / 46 (6.52%)	8 / 63 (12.70%)
occurrences all number	11	8	14	3	8
Investigations
Alanine aminotransferase increased
subjects affected / exposed	14 / 101 (13.86%)	7 / 103 (6.80%)	15 / 100 (15.00%)	0 / 46 (0.00%)	0 / 63 (0.00%)
occurrences all number	25	12	23	0	0
Aspartate aminotransferase increased
subjects affected / exposed	10 / 101 (9.90%)	7 / 103 (6.80%)	17 / 100 (17.00%)	0 / 46 (0.00%)	0 / 63 (0.00%)
occurrences all number	14	14	27	0	0
Blood alkaline phosphatase increased
subjects affected / exposed	8 / 101 (7.92%)	3 / 103 (2.91%)	6 / 100 (6.00%)	0 / 46 (0.00%)	0 / 63 (0.00%)
occurrences all number	14	4	9	0	0
Blood creatinine increased
subjects affected / exposed	13 / 101 (12.87%)	17 / 103 (16.50%)	14 / 100 (14.00%)	10 / 46 (21.74%)	8 / 63 (12.70%)
occurrences all number	21	29	29	21	16
Platelet count decreased
subjects affected / exposed	2 / 101 (1.98%)	2 / 103 (1.94%)	6 / 100 (6.00%)	3 / 46 (6.52%)	0 / 63 (0.00%)
occurrences all number	2	4	11	7	0
Weight decreased
subjects affected / exposed	18 / 101 (17.82%)	5 / 103 (4.85%)	10 / 100 (10.00%)	2 / 46 (4.35%)	6 / 63 (9.52%)
occurrences all number	23	6	13	2	6
Blood lactate dehydrogenase increased
subjects affected / exposed	0 / 101 (0.00%)	0 / 103 (0.00%)	0 / 100 (0.00%)	3 / 46 (6.52%)	3 / 63 (4.76%)
occurrences all number	0	0	0	4	8
Protein total increased
subjects affected / exposed	0 / 101 (0.00%)	0 / 103 (0.00%)	0 / 100 (0.00%)	3 / 46 (6.52%)	1 / 63 (1.59%)
occurrences all number	0	0	0	8	3
Injury, poisoning and procedural complications
Contusion
subjects affected / exposed	0 / 101 (0.00%)	0 / 103 (0.00%)	0 / 100 (0.00%)	3 / 46 (6.52%)	2 / 63 (3.17%)
occurrences all number	0	0	0	3	2
Nervous system disorders
Dizziness
subjects affected / exposed	13 / 101 (12.87%)	9 / 103 (8.74%)	13 / 100 (13.00%)	4 / 46 (8.70%)	6 / 63 (9.52%)
occurrences all number	16	13	18	4	7
Dysgeusia
subjects affected / exposed	12 / 101 (11.88%)	3 / 103 (2.91%)	30 / 100 (30.00%)	0 / 46 (0.00%)	0 / 63 (0.00%)
occurrences all number	14	4	51	0	0
Headache
subjects affected / exposed	35 / 101 (34.65%)	16 / 103 (15.53%)	23 / 100 (23.00%)	7 / 46 (15.22%)	13 / 63 (20.63%)
occurrences all number	70	24	40	10	19
Neuropathy peripheral
subjects affected / exposed	5 / 101 (4.95%)	1 / 103 (0.97%)	5 / 100 (5.00%)	0 / 46 (0.00%)	0 / 63 (0.00%)
occurrences all number	5	1	5	0	0
Paraesthesia
subjects affected / exposed	8 / 101 (7.92%)	8 / 103 (7.77%)	11 / 100 (11.00%)	1 / 46 (2.17%)	4 / 63 (6.35%)
occurrences all number	10	8	13	1	5
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	11 / 101 (10.89%)	19 / 103 (18.45%)	18 / 100 (18.00%)	2 / 46 (4.35%)	9 / 63 (14.29%)
occurrences all number	21	31	29	5	11
Leukopenia
subjects affected / exposed	0 / 101 (0.00%)	0 / 103 (0.00%)	9 / 100 (9.00%)	0 / 46 (0.00%)	0 / 63 (0.00%)
occurrences all number	0	0	38	0	0
Neutropenia
subjects affected / exposed	2 / 101 (1.98%)	1 / 103 (0.97%)	12 / 100 (12.00%)	0 / 46 (0.00%)	0 / 63 (0.00%)
occurrences all number	5	1	51	0	0
Thrombocytopenia
subjects affected / exposed	6 / 101 (5.94%)	1 / 103 (0.97%)	15 / 100 (15.00%)	2 / 46 (4.35%)	4 / 63 (6.35%)
occurrences all number	12	1	30	2	8
Eye disorders
Dry eye
subjects affected / exposed	0 / 101 (0.00%)	0 / 103 (0.00%)	0 / 100 (0.00%)	3 / 46 (6.52%)	0 / 63 (0.00%)
occurrences all number	0	0	0	3	0
Gastrointestinal disorders
Abdominal distension
subjects affected / exposed	8 / 101 (7.92%)	2 / 103 (1.94%)	3 / 100 (3.00%)	0 / 46 (0.00%)	0 / 63 (0.00%)
occurrences all number	8	2	6	0	0
Abdominal pain
subjects affected / exposed	17 / 101 (16.83%)	8 / 103 (7.77%)	16 / 100 (16.00%)	5 / 46 (10.87%)	7 / 63 (11.11%)
occurrences all number	22	9	18	6	9
Abdominal pain upper
subjects affected / exposed	4 / 101 (3.96%)	2 / 103 (1.94%)	9 / 100 (9.00%)	0 / 46 (0.00%)	0 / 63 (0.00%)
occurrences all number	4	2	10	0	0
Constipation
subjects affected / exposed	30 / 101 (29.70%)	16 / 103 (15.53%)	30 / 100 (30.00%)	10 / 46 (21.74%)	15 / 63 (23.81%)
occurrences all number	45	19	37	17	30
Diarrhoea
subjects affected / exposed	36 / 101 (35.64%)	20 / 103 (19.42%)	62 / 100 (62.00%)	13 / 46 (28.26%)	19 / 63 (30.16%)
occurrences all number	67	28	180	30	46
Dry mouth
subjects affected / exposed	12 / 101 (11.88%)	12 / 103 (11.65%)	9 / 100 (9.00%)	5 / 46 (10.87%)	5 / 63 (7.94%)
occurrences all number	13	12	11	6	5
Dyspepsia
subjects affected / exposed	8 / 101 (7.92%)	4 / 103 (3.88%)	20 / 100 (20.00%)	3 / 46 (6.52%)	4 / 63 (6.35%)
occurrences all number	11	7	30	3	4
Gastrooesophageal reflux disease
subjects affected / exposed	7 / 101 (6.93%)	3 / 103 (2.91%)	13 / 100 (13.00%)	0 / 46 (0.00%)	0 / 63 (0.00%)
occurrences all number	8	4	16	0	0
Gingival bleeding
subjects affected / exposed	7 / 101 (6.93%)	0 / 103 (0.00%)	1 / 100 (1.00%)	3 / 46 (6.52%)	2 / 63 (3.17%)
occurrences all number	8	0	5	3	3
Nausea
subjects affected / exposed	40 / 101 (39.60%)	19 / 103 (18.45%)	46 / 100 (46.00%)	14 / 46 (30.43%)	21 / 63 (33.33%)
occurrences all number	61	30	87	20	31
Oral pain
subjects affected / exposed	4 / 101 (3.96%)	0 / 103 (0.00%)	7 / 100 (7.00%)	0 / 46 (0.00%)	0 / 63 (0.00%)
occurrences all number	7	0	8	0	0
Stomatitis
subjects affected / exposed	15 / 101 (14.85%)	3 / 103 (2.91%)	25 / 100 (25.00%)	14 / 46 (30.43%)	21 / 63 (33.33%)
occurrences all number	20	4	50	20	31
Vomiting
subjects affected / exposed	20 / 101 (19.80%)	8 / 103 (7.77%)	21 / 100 (21.00%)	6 / 46 (13.04%)	16 / 63 (25.40%)
occurrences all number	25	14	30	8	27
Skin and subcutaneous tissue disorders
Dry skin
subjects affected / exposed	13 / 101 (12.87%)	15 / 103 (14.56%)	10 / 100 (10.00%)	5 / 46 (10.87%)	2 / 63 (3.17%)
occurrences all number	18	16	15	8	4
Night sweats
subjects affected / exposed	8 / 101 (7.92%)	5 / 103 (4.85%)	7 / 100 (7.00%)	4 / 46 (8.70%)	3 / 63 (4.76%)
occurrences all number	10	6	7	5	4
Palmar−plantar erythrodysaesthesia syndrome
subjects affected / exposed	3 / 101 (2.97%)	0 / 103 (0.00%)	41 / 100 (41.00%)	0 / 46 (0.00%)	0 / 63 (0.00%)
occurrences all number	12	0	133	0	0
Pruritus
subjects affected / exposed	27 / 101 (26.73%)	18 / 103 (17.48%)	10 / 100 (10.00%)	8 / 46 (17.39%)	7 / 63 (11.11%)
occurrences all number	40	40	15	16	12
Rash
subjects affected / exposed	28 / 101 (27.72%)	24 / 103 (23.30%)	14 / 100 (14.00%)	12 / 46 (26.09%)	7 / 63 (11.11%)
occurrences all number	48	38	22	23	14
Ecchymosis
subjects affected / exposed	0 / 101 (0.00%)	0 / 103 (0.00%)	0 / 100 (0.00%)	3 / 46 (6.52%)	0 / 63 (0.00%)
occurrences all number	0	0	0	3	0
Hyperhidrosis
subjects affected / exposed	0 / 101 (0.00%)	0 / 103 (0.00%)	0 / 100 (0.00%)	0 / 46 (0.00%)	4 / 63 (6.35%)
occurrences all number	0	0	0	0	4
Rash erythematous
subjects affected / exposed	0 / 101 (0.00%)	0 / 103 (0.00%)	0 / 100 (0.00%)	3 / 46 (6.52%)	1 / 63 (1.59%)
occurrences all number	0	0	0	4	1
Renal and urinary disorders
Dysuria
subjects affected / exposed	1 / 101 (0.99%)	7 / 103 (6.80%)	2 / 100 (2.00%)	0 / 46 (0.00%)	0 / 63 (0.00%)
occurrences all number	1	7	2	0	0
Haematuria
subjects affected / exposed	3 / 101 (2.97%)	10 / 103 (9.71%)	9 / 100 (9.00%)	4 / 46 (8.70%)	4 / 63 (6.35%)
occurrences all number	4	18	9	7	11
Proteinuria
subjects affected / exposed	38 / 101 (37.62%)	10 / 103 (9.71%)	9 / 100 (9.00%)	21 / 46 (45.65%)	25 / 63 (39.68%)
occurrences all number	89	17	10	64	55
Acute kidney injury
subjects affected / exposed	0 / 101 (0.00%)	0 / 103 (0.00%)	0 / 100 (0.00%)	3 / 46 (6.52%)	2 / 63 (3.17%)
occurrences all number	0	0	0	3	2
Nocturia
subjects affected / exposed	6 / 101 (5.94%)	2 / 103 (1.94%)	4 / 100 (4.00%)	3 / 46 (6.52%)	1 / 63 (1.59%)
occurrences all number	6	2	4	3	1
Endocrine disorders
Hypothyroidism
subjects affected / exposed	19 / 101 (18.81%)	12 / 103 (11.65%)	20 / 100 (20.00%)	8 / 46 (17.39%)	7 / 63 (11.11%)
occurrences all number	19	15	21	9	9
Adrenal insufficiency
subjects affected / exposed	0 / 101 (0.00%)	0 / 103 (0.00%)	0 / 100 (0.00%)	3 / 46 (6.52%)	0 / 63 (0.00%)
occurrences all number	0	0	0	3	0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	40 / 101 (39.60%)	19 / 103 (18.45%)	19 / 100 (19.00%)	17 / 46 (36.96%)	15 / 63 (23.81%)
occurrences all number	73	34	24	22	25
Back pain
subjects affected / exposed	19 / 101 (18.81%)	18 / 103 (17.48%)	20 / 100 (20.00%)	8 / 46 (17.39%)	11 / 63 (17.46%)
occurrences all number	22	24	28	9	12
Muscle spasms
subjects affected / exposed	8 / 101 (7.92%)	2 / 103 (1.94%)	6 / 100 (6.00%)	4 / 46 (8.70%)	1 / 63 (1.59%)
occurrences all number	8	2	7	4	1
Musculoskeletal pain
subjects affected / exposed	22 / 101 (21.78%)	10 / 103 (9.71%)	6 / 100 (6.00%)	9 / 46 (19.57%)	5 / 63 (7.94%)
occurrences all number	29	13	7	11	7
Myalgia
subjects affected / exposed	12 / 101 (11.88%)	10 / 103 (9.71%)	15 / 100 (15.00%)	3 / 46 (6.52%)	7 / 63 (11.11%)
occurrences all number	16	14	15	3	9
Neck pain
subjects affected / exposed	10 / 101 (9.90%)	5 / 103 (4.85%)	8 / 100 (8.00%)	3 / 46 (6.52%)	1 / 63 (1.59%)
occurrences all number	11	5	8	3	1
Pain in extremity
subjects affected / exposed	17 / 101 (16.83%)	8 / 103 (7.77%)	17 / 100 (17.00%)	9 / 46 (19.57%)	6 / 63 (9.52%)
occurrences all number	25	12	24	12	9
Flank pain
subjects affected / exposed	0 / 101 (0.00%)	0 / 103 (0.00%)	0 / 100 (0.00%)	3 / 46 (6.52%)	2 / 63 (3.17%)
occurrences all number	0	0	0	3	2
Infections and infestations
Nasopharyngitis
subjects affected / exposed	11 / 101 (10.89%)	8 / 103 (7.77%)	2 / 100 (2.00%)	0 / 46 (0.00%)	0 / 63 (0.00%)
occurrences all number	13	11	2	0	0
Rhinitis
subjects affected / exposed	8 / 101 (7.92%)	6 / 103 (5.83%)	1 / 100 (1.00%)	0 / 46 (0.00%)	0 / 63 (0.00%)
occurrences all number	8	6	1	0	0
Sinusitis
subjects affected / exposed	15 / 101 (14.85%)	5 / 103 (4.85%)	3 / 100 (3.00%)	4 / 46 (8.70%)	4 / 63 (6.35%)
occurrences all number	22	6	4	5	4
Upper respiratory tract infection
subjects affected / exposed	14 / 101 (13.86%)	11 / 103 (10.68%)	5 / 100 (5.00%)	8 / 46 (17.39%)	2 / 63 (3.17%)
occurrences all number	16	16	6	12	2
Urinary tract infection
subjects affected / exposed	10 / 101 (9.90%)	8 / 103 (7.77%)	3 / 100 (3.00%)	1 / 46 (2.17%)	4 / 63 (6.35%)
occurrences all number	12	31	3	1	4
Pneumonia
subjects affected / exposed	0 / 101 (0.00%)	0 / 103 (0.00%)	0 / 100 (0.00%)	3 / 46 (6.52%)	1 / 63 (1.59%)
occurrences all number	0	0	0	3	1
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	23 / 101 (22.77%)	11 / 103 (10.68%)	30 / 100 (30.00%)	4 / 46 (8.70%)	15 / 63 (23.81%)
occurrences all number	32	15	54	7	18
Dehydration
subjects affected / exposed	11 / 101 (10.89%)	5 / 103 (4.85%)	4 / 100 (4.00%)	3 / 46 (6.52%)	6 / 63 (9.52%)
occurrences all number	12	10	8	3	7
Hypercalcaemia
subjects affected / exposed	10 / 101 (9.90%)	4 / 103 (3.88%)	4 / 100 (4.00%)	0 / 46 (0.00%)	0 / 63 (0.00%)
occurrences all number	20	4	6	0	0
Hyperglycaemia
subjects affected / exposed	8 / 101 (7.92%)	13 / 103 (12.62%)	5 / 100 (5.00%)	5 / 46 (10.87%)	5 / 63 (7.94%)
occurrences all number	14	30	6	15	11
Hyperkalaemia
subjects affected / exposed	15 / 101 (14.85%)	6 / 103 (5.83%)	6 / 100 (6.00%)	4 / 46 (8.70%)	4 / 63 (6.35%)
occurrences all number	22	15	9	8	7
Hypoalbuminaemia
subjects affected / exposed	6 / 101 (5.94%)	2 / 103 (1.94%)	5 / 100 (5.00%)	3 / 46 (6.52%)	4 / 63 (6.35%)
occurrences all number	16	5	7	3	5
Hypomagnesaemia
subjects affected / exposed	10 / 101 (9.90%)	2 / 103 (1.94%)	6 / 100 (6.00%)	2 / 46 (4.35%)	4 / 63 (6.35%)
occurrences all number	19	2	8	2	9
Hyponatraemia
subjects affected / exposed	12 / 101 (11.88%)	5 / 103 (4.85%)	7 / 100 (7.00%)	5 / 46 (10.87%)	10 / 63 (15.87%)
occurrences all number	34	5	10	9	26
Hypophosphataemia
subjects affected / exposed	6 / 101 (5.94%)	11 / 103 (10.68%)	11 / 100 (11.00%)	4 / 46 (8.70%)	4 / 63 (6.35%)
occurrences all number	10	45	22	10	6

More information

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Were there any global substantial amendments to the protocol? Yes

23 Oct 2013

Protocol was amended primarily to allow investigators to use an alternate atezolizumab drug formulation (a Phase 3 formulation). In addition, further rationale for conducting fresh tumor biopsy was listed.

25 Feb 2014

Protocol was amended in response to the Voluntary Harmonisation Procedure (VHP), and the major clarifications were as follows: The term “immune related” as it pertains to tumor assessments was clarified and the term “modified RECIST” was used instead; Participants in Europe, including in France, Italy, the United Kingdom, Romania, Spain, Germany, Ukraine, the Czech Republic, and Poland, who were enrolled in atezolizumab monotherapy arm were not be allowed to cross over to combination therapy arm following disease progression; The exclusion criterion for participants with a positive human immunodeficiency virus (HIV) test was updated; The timing of vital signs measurements for participants in atezolizumab monotherapy was clarified.

21 Aug 2014

Protocol was amended to allow enrollment of approximately 300 participants (~100 participants in each treatment arm) in order to obtain the same level of precision in estimating the treatment effect for this subpopulation. Eligible renal cell carcinoma participants were to be enrolled regardless of IHC status; participants were randomized in one of three treatment arms, stratified in part by PD-L1 status. The study objective text was updated to reflect IHC 1/2/3. PFS and other efficacy endpoints were to be evaluated in the ITT population as well as in renal cell carcinoma participants with IHC 1/2/3 status.

31 Oct 2014

The protocol was amended, as requested by European health authority via VHP, to change the window for pregnancy testing from 28 days prior to Cycle 1, Day 1 to 7 days prior to Cycle 1, Day 1.

06 Feb 2015

The protocol was primarily amended to clarify the frequency of tumor assessments and to revise the tumor assessment schedule for participants who had treatment delays or interruptions.

28 Oct 2015

As per the more defined guidelines for the management of immune-mediated toxicity outlined in the updated atezolizumab Investigator’s Brochure, management of gastrointestinal, dermatologic, endocrine, pulmonary toxicity, hepatotoxicity, potential pancreatic or eye toxicity and other immune-mediated adverse events was updated; The use of any live vaccine was updated to be prohibited within 90 days following administration of last dose of study drug in addition to 4 weeks prior and during study treatment; Systemic immune activation (SIA) was identified as a potential risk of atezolizumab when given in combination with other immunomodulating agents; Clarification of childbearing potential was added; Acceptable non-hormonal contraceptive methods were added; Bevacizumab dosing was clarified with 15 mg/kg administered every 3 weeks on Days 1 and 22 of each 6-week cycle; Participants who crossed over to treatment with atezolizumab and bevacizumab combination should have a new baseline tumor assessment within 28 days prior to crossover Cycle 1, Day 1; A revised blood and serum biomarker sampling schedule was provided; The reportable non-serious adverse effects of special interest (AESI) were updated.

21 Jan 2016

Protocol was amended to incorporate multi-European Competent Authorities recommendation following assessment through the VHP as follows: The list of non-hormonal contraceptive methods was removed because these methods were not considered highly effective when used alone.

30 Jul 2016

This protocol amendment reflected changes to the primary and secondary endpoints and the analysis plan of the study. Clinical data supporting these changes 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

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Clinical trials

Clinical Trial Results: A Phase II, Randomized Study of Atezolizumab (Anti−PD-L1 Antibody) Administered as Monotherapy or in Combination with Bevacizumab Versus Sunitinib in Patients with Untreated Advanced Renal Cell Carcinoma

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Percentage of Participants with Disease Progression per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) via Independent Review Committee (IRC) Assessment or Death in Intent-to-Treat (ITT) Population

Primary: Percentage of Participants with Disease Progression per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) via Independent Review Committee (IRC) Assessment or Death in Intent-to-Treat (ITT) Population

Primary: Progression-Free Survival (PFS) per RECIST v1.1 via IRC Assessment in ITT Population

Primary: Progression-Free Survival (PFS) per RECIST v1.1 via IRC Assessment in ITT Population

Primary: Percentage of Participants with Disease Progression per RECIST v1.1 via IRC Assessment or Death in Immune Cell 1/2/3 (IC1/2/3) Population

Primary: Percentage of Participants with Disease Progression per RECIST v1.1 via IRC Assessment or Death in Immune Cell 1/2/3 (IC1/2/3) Population

Primary: PFS per RECIST v1.1 via IRC Assessment in IC1/2/3 Population

Primary: PFS per RECIST v1.1 via IRC Assessment in IC1/2/3 Population

Secondary: Percentage of Participants with Disease Progression per RECIST v1.1 via IRC Assessment or Death in Participants who Have Tumors with Higher Than Median Expression of an Immune Gene Signature

Secondary: Percentage of Participants with Disease Progression per RECIST v1.1 via IRC Assessment or Death in Participants who Have Tumors with Higher Than Median Expression of an Immune Gene Signature

Secondary: PFS per RECIST v1.1 via IRC Assessment in Participants who Have Tumors with Higher Than Median Expression of an Immune Gene Signature

Secondary: PFS per RECIST v1.1 via IRC Assessment in Participants who Have Tumors with Higher Than Median Expression of an Immune Gene Signature

Secondary: Percentage of Participants with Disease Progression per RECIST v1.1 via Investigator Assessment or Death in Participants who Have Tumors with Higher Than Median Expression of an Immune Gene Signature

Secondary: Percentage of Participants with Disease Progression per RECIST v1.1 via Investigator Assessment or Death in Participants who Have Tumors with Higher Than Median Expression of an Immune Gene Signature

Secondary: PFS per RECIST v1.1 via Investigator Assessment in Participants who Have Tumors with Higher Than Median Expression of an Immune Gene Signature

Secondary: PFS per RECIST v1.1 via Investigator Assessment in Participants who Have Tumors with Higher Than Median Expression of an Immune Gene Signature

Secondary: Percentage of Participants with Disease Progression per RECIST v1.1 via IRC Assessment or Death in Participants who Have Tumors with Higher Than the 33rd Percentile Expression of an Immune Gene Signature

Secondary: Percentage of Participants with Disease Progression per RECIST v1.1 via IRC Assessment or Death in Participants who Have Tumors with Higher Than the 33rd Percentile Expression of an Immune Gene Signature

Secondary: PFS per RECIST v1.1 via IRC Assessment in Participants who Have Tumors with Higher Than the 33rd Percentile Expression of an Immune Gene Signature

Secondary: PFS per RECIST v1.1 via IRC Assessment in Participants who Have Tumors with Higher Than the 33rd Percentile Expression of an Immune Gene Signature

Secondary: Percentage of Participants with Disease Progression per RECIST v1.1 via Investigator Assessment or Death in Participants who Have Tumors with Higher Than the 33rd Percentile Expression of an Immune Gene Signature

Secondary: Percentage of Participants with Disease Progression per RECIST v1.1 via Investigator Assessment or Death in Participants who Have Tumors with Higher Than the 33rd Percentile Expression of an Immune Gene Signature

Secondary: PFS per RECIST v1.1 via Investigator Assessment in Participants who Have Tumors with Higher Than the 33rd Percentile Expression of an Immune Gene Signature

Secondary: PFS per RECIST v1.1 via Investigator Assessment in Participants who Have Tumors with Higher Than the 33rd Percentile Expression of an Immune Gene Signature

Secondary: Percentage of Participants with Disease Progression per RECIST v1.1 via Investigator Assessment or Death in ITT Population

Secondary: Percentage of Participants with Disease Progression per RECIST v1.1 via Investigator Assessment or Death in ITT Population

Secondary: PFS per RECIST v1.1 via Investigator Assessment in ITT Population

Secondary: PFS per RECIST v1.1 via Investigator Assessment in ITT Population

Secondary: Percentage of Participants with Disease Progression per RECIST v1.1 via Investigator Assessment or Death in IC1/2/3 Population

Secondary: Percentage of Participants with Disease Progression per RECIST v1.1 via Investigator Assessment or Death in IC1/2/3 Population

Secondary: PFS per RECIST v1.1 via Investigator Assessment in IC1/2/3 Population

Secondary: PFS per RECIST v1.1 via Investigator Assessment in IC1/2/3 Population

Secondary: Percentage of Participants with Objective Response (Complete Response [CR] or Partial Response [PR]) per RECIST v1.1 via IRC Assessment in ITT Population

Secondary: Percentage of Participants with Objective Response (Complete Response [CR] or Partial Response [PR]) per RECIST v1.1 via IRC Assessment in ITT Population

Secondary: Percentage of Participants with Objective Response per RECIST v1.1 via IRC Assessment in IC1/2/3 Population

Secondary: Percentage of Participants with Objective Response per RECIST v1.1 via IRC Assessment in IC1/2/3 Population

Secondary: Percentage of Participants with Objective Response per RECIST v1.1 via Investigator Assessment in ITT Population

Secondary: Percentage of Participants with Objective Response per RECIST v1.1 via Investigator Assessment in ITT Population

Secondary: Percentage of Participants with Objective Response per RECIST v1.1 via Investigator Assessment in IC1/2/3 Population

Secondary: Percentage of Participants with Objective Response per RECIST v1.1 via Investigator Assessment in IC1/2/3 Population

Secondary: Percentage of Participants with Objective Response per Modified RECIST via Investigator Assessment in ITT Population

Secondary: Percentage of Participants with Objective Response per Modified RECIST via Investigator Assessment in ITT Population

Secondary: Percentage of Participants with Objective Response per Modified RECIST via Investigator Assessment in IC1/2/3 Population

Secondary: Percentage of Participants with Objective Response per Modified RECIST via Investigator Assessment in IC1/2/3 Population

Secondary: Percentage of Participants with Disease Progression per Modified RECIST via Investigator Assessment or Death in ITT Population

Secondary: Percentage of Participants with Disease Progression per Modified RECIST via Investigator Assessment or Death in ITT Population

Secondary: PFS per Modified RECIST via Investigator Assessment in ITT Population

Secondary: PFS per Modified RECIST via Investigator Assessment in ITT Population

Secondary: Percentage of Participants with Disease Progression per Modified RECIST via Investigator Assessment or Death in IC1/2/3 Population

Secondary: Percentage of Participants with Disease Progression per Modified RECIST via Investigator Assessment or Death in IC1/2/3 Population

Secondary: PFS per Modified RECIST via Investigator Assessment in IC1/2/3 Population

Secondary: PFS per Modified RECIST via Investigator Assessment in IC1/2/3 Population

Secondary: Duration of Response (DOR) per RECIST v1.1 via IRC Assessment in ITT Population

Secondary: Duration of Response (DOR) per RECIST v1.1 via IRC Assessment in ITT Population

Secondary: DOR per RECIST v1.1 via Investigator Assessment in ITT Population

Secondary: DOR per RECIST v1.1 via Investigator Assessment in ITT Population

Secondary: DOR per RECIST v1.1 via IRC Assessment in IC1/2/3 Population

Secondary: DOR per RECIST v1.1 via IRC Assessment in IC1/2/3 Population

Secondary: DOR per RECIST v1.1 via Investigator Assessment in IC1/2/3 Population

Secondary: DOR per RECIST v1.1 via Investigator Assessment in IC1/2/3 Population

Secondary: DOR per Modified RECIST via Investigator Assessment in ITT Population

Secondary: DOR per Modified RECIST via Investigator Assessment in ITT Population

Secondary: DOR per Modified RECIST via Investigator Assessment in IC1/2/3 Population

Secondary: DOR per Modified RECIST via Investigator Assessment in IC1/2/3 Population

Secondary: Percentage of Participants who Died in ITT Population

Secondary: Percentage of Participants who Died in ITT Population

Secondary: Overall Survival (OS) in ITT Population

Secondary: Overall Survival (OS) in ITT Population

Secondary: Percentage of Participants who Died in IC1/2/3 Population

Secondary: Percentage of Participants who Died in IC1/2/3 Population

Clinical Trial Results:
A Phase II, Randomized Study of Atezolizumab (Anti−PD-L1 Antibody) Administered as Monotherapy or in Combination with Bevacizumab Versus Sunitinib in Patients with Untreated Advanced Renal Cell Carcinoma