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Clinical Trial Results:
A Double-Blind, Randomized, Two Arm Phase 2 Study of Nivolumab in Combination with Ipilimumab versus Nivolumab in Combination with Ipilimumab Placebo In Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck (SCCHN) (CheckMate 714: CHECKpoint pathway and nivoluMAb clinical Trial Evaluation 714)

Summary
EudraCT number	2016-001645-64
Trial protocol	CZ ES IE BE NL SE NO GB FI IT
Global end of trial date	11 Mar 2022

Results information
Results version number	v1(current)
This version publication date	28 Mar 2023
First version publication date	28 Mar 2023
Other versions

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

CA209-714

ISRCTN number

US NCT number

NCT02823574

WHO universal trial number (UTN)

Sponsor organisation name

Bristol-Myers Squibb

Sponsor organisation address

Chaussee de la Hulpe 185, Brussels, Belgium, 1170

Public contact

EU Study Start-Up Unit, Bristol-Myers Squibb International Corporation, Clinical.Trials@bms.com

Scientific contact

Bristol-Myers Squibb Study Director, Bristol-Myers Squibb, Clinical.Trials@bms.gov

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

22 Apr 2022

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

11 Mar 2022

Was the trial ended prematurely?

Main objective of the trial

To compare the ORR and assess the DOR of the treatment of nivolumab in combination with ipilimumab vs nivolumab in combination with ipilimumab placebo, as determined by a blinded independent central review (BICR) using Response Evaluation Criteria In Solid Tumors (RECIST 1.1) criteria, for first-line treatment of recurrent or metastatic SCCHN in the platinum refractory setting.

Protection of trial subjects

The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization Good Clinical Practice Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were followed.

Background therapy

Evidence for comparator

Actual start date of recruitment

22 Sep 2016

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Argentina: 1

Country: Number of subjects enrolled

Belgium: 12

Country: Number of subjects enrolled

Brazil: 45

Country: Number of subjects enrolled

Canada: 46

Country: Number of subjects enrolled

Chile: 1

Country: Number of subjects enrolled

Finland: 2

Country: Number of subjects enrolled

France: 79

Country: Number of subjects enrolled

Ireland: 10

Country: Number of subjects enrolled

Italy: 1

Country: Number of subjects enrolled

Mexico: 13

Country: Number of subjects enrolled

Netherlands: 13

Country: Number of subjects enrolled

Norway: 20

Country: Number of subjects enrolled

Romania: 37

Country: Number of subjects enrolled

Russian Federation: 10

Country: Number of subjects enrolled

South Africa: 1

Country: Number of subjects enrolled

Spain: 22

Country: Number of subjects enrolled

Sweden: 1

Country: Number of subjects enrolled

Turkey: 3

Country: Number of subjects enrolled

United Kingdom: 19

Country: Number of subjects enrolled

United States: 69

Country: Number of subjects enrolled

Czechia: 20

Worldwide total number of subjects

425

EEA total number of subjects

217

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)

301

From 65 to 84 years

122

85 years and over

Subject disposition

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Recruitment details

Screening details

425 randomized and 423 participants treated.

Period 1 title

Randomization

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Investigator, Subject

Are arms mutually exclusive

Yes

Treatment A - Platinum Refractory Subgroup

Arm description

Participants with histologically confirmed Squamous Cell Carcinoma of the Head and Neck (SCCHN) that has recurred during or less than 6 months after completion of previous platinum-based chemotherapy. Treated with Nivolumab 3 mg/kg Q2W + Ipilimumab 1 mg/kg Q6W

Arm type

Experimental

Investigational medicinal product name

nivolumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

100mg (10mg/mL)

Investigational medicinal product name

ipilimumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

200mg (5mg/mL)

Treatment B - Platinum Refractory Subgroup

Arm description

Arm type

Experimental

Investigational medicinal product name

placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

(0.9% sodium chloride injection or 5% dextrose injection

Investigational medicinal product name

nivolumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

100mg (10mg/mL)

Treatment A - Platinum Eligible Subgroup

Arm description

Participants with histologically confirmed Squamous Cell Carcinoma of the Head and Neck (SCCHN) who are platinum naive or have recurred 6 months or more after completion of previous platinum-based chemotherapy. Treated with Nivolumab 3 mg/kg Q2W + Ipilimumab 1 mg/kg Q6W

Arm type

Experimental

Investigational medicinal product name

ipilimumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

200mg (5mg/mL)

Investigational medicinal product name

nivolumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

100mg (10mg/mL)

Treatment B - Platinum Eligible Subgroup

Arm description

Arm type

Experimental

Investigational medicinal product name

placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

(0.9% sodium chloride injection or 5% dextrose injection

Investigational medicinal product name

nivolumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

100mg (10mg/mL)

Number of subjects in period 1	Treatment A - Platinum Refractory Subgroup	Treatment B - Platinum Refractory Subgroup	Treatment A - Platinum Eligible Subgroup	Treatment B - Platinum Eligible Subgroup
Started	159	82	123	61
Completed	158	82	122	61
Not completed	1	0	1	0
AE unrelated to Study Drug	1	-	-	-
Disease Progression	-	-	1	-

Period 2 title

Treatment Period

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Are arms mutually exclusive

Yes

Treatment A - Platinum Refractory Subgroup

Arm description

Arm type

Experimental

Investigational medicinal product name

ipilimumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

200mg (5mg/mL)

Investigational medicinal product name

nivolumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

100mg (10mg/mL)

Treatment B - Platinum Refractory Subgroup

Arm description

Arm type

Experimental

Investigational medicinal product name

nivolumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

100mg (10mg/mL)

Investigational medicinal product name

placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

0.9% sodium chloride injection or 5% dextrose injection

Treatment A - Platinum Eligible Subgroup

Arm description

Arm type

Experimental

Investigational medicinal product name

ipilimumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

200mg (5mg/mL)

Investigational medicinal product name

nivolumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

100mg (10mg/mL)

Treatment B - Platinum Eligible Subgroup

Arm description

Arm type

Experimental

Investigational medicinal product name

nivolumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

100mg (10mg/mL)

Investigational medicinal product name

placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

0.9% sodium chloride injection or 5% dextrose injection

Number of subjects in period 2	Treatment A - Platinum Refractory Subgroup	Treatment B - Platinum Refractory Subgroup	Treatment A - Platinum Eligible Subgroup	Treatment B - Platinum Eligible Subgroup
Started	158	82	122	61
Completed	0	0	0	0
Not completed	158	82	122	61
Adverse event, serious fatal	-	-	3	1
Participant withdrew consent	4	-	-	1
Poor/Non Compliance	1	-	-	1
Participant request to discontinue	5	-	3	2
Maximum Clinical Benefit	8	4	7	1
Adverse Event unrelated to to study Drug	10	2	9	2
Participant no longer meets study criterai	-	-	1	-
Other reasons	5	9	3	6
Study Drug Toxicity	11	2	14	4
Lost to follow-up	1	1	-	-
Disease Progression	113	64	82	43

Baseline characteristics

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Reporting group title

Treatment A - Platinum Refractory Subgroup

Reporting group description

Reporting group title

Treatment B - Platinum Refractory Subgroup

Reporting group description

Reporting group title

Treatment A - Platinum Eligible Subgroup

Reporting group description

Reporting group title

Treatment B - Platinum Eligible Subgroup

Reporting group description

Reporting group values	Treatment A - Platinum Refractory Subgroup	Treatment B - Platinum Refractory Subgroup	Treatment A - Platinum Eligible Subgroup	Treatment B - Platinum Eligible Subgroup	Total
Number of subjects	159	82	123	61	425
Age Categorical
Units: participants
<=18 years	0	0	0	0	0
Between 18 and 65 years	119	63	79	40	301
>=65 years	40	19	44	21	124
Age continuous
Units: years
arithmetic mean (full range (min-max))	58.2 (24 to 82)	57.9 (36 to 77)	61.8 (37 to 88)	60.8 (33 to 79)	-
Sex: Female, Male
Units: participants
Female	29	18	18	14	79
Male	130	64	105	47	346
Race (NIH/OMB)
Units: Subjects
American Indian or Alaska Native	0	0	0	0	0
Asian	3	1	0	1	5
Native Hawaiian or Other Pacific Islander	0	0	0	0	0
Black or African American	2	3	2	1	8
White	141	75	120	58	394
More than one race	0	0	0	0	0
Unknown or Not Reported	13	3	1	1	18
Ethnicity (NIH/OMB)
Units: Subjects
Hispanic or Latino	10	7	6	6	29
Not Hispanic or Latino	56	23	66	25	170
Unknown or Not Reported	93	52	51	30	226

End points

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Reporting group title

Treatment A - Platinum Refractory Subgroup

Reporting group description

Reporting group title

Treatment B - Platinum Refractory Subgroup

Reporting group description

Reporting group title

Treatment A - Platinum Eligible Subgroup

Reporting group description

Reporting group title

Treatment B - Platinum Eligible Subgroup

Reporting group description

Reporting group title

Treatment A - Platinum Refractory Subgroup

Reporting group description

Reporting group title

Treatment B - Platinum Refractory Subgroup

Reporting group description

Reporting group title

Treatment A - Platinum Eligible Subgroup

Reporting group description

Reporting group title

Treatment B - Platinum Eligible Subgroup

Reporting group description

Subject analysis set title

Treatment A

Subject analysis set type

Intention-to-treat

Subject analysis set description

Participants in both Platinum Refractory Subgroup and Platinum Eligible Subgroup treated with Nivolumab 3 mg/kg Q2W + Ipilimumab 1 mg/kg Q6W

Subject analysis set title

Treatment B

Subject analysis set type

Intention-to-treat

Subject analysis set description

Participants in both Platinum Refractory Subgroup and Platinum Eligible Subgroup treated with Nivolumab 3 mg/kg Q2W + Ipilimumab-Placebo Q6W

Primary: Objective Response Rate (ORR) as determined by Blinded Independent Central Review (BIRC) - Platinum refractory subgroup

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End point title

Objective Response Rate (ORR) as determined by Blinded Independent Central Review (BIRC) - Platinum refractory subgroup ^[1]

End point description

ORR is defined as best overall response (BOR) of a complete response (CR) or partial response (PR) divided by the number of randomized participants for each treatment group. Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes(whether target or non-target) must have reduction in short axis to < 10 mm. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.

End point type

Primary

End point timeframe

Approximately up to 30 months (from FPFV to Data base lock)

Notes
[1] - 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: Endpoints are specific for subgroups not baseline period

End point values	Treatment A - Platinum Refractory Subgroup	Treatment B - Platinum Refractory Subgroup
Number of subjects analysed	159	82
Units: percentage of participants
number (confidence interval 95%)	13.2 (8.4 to 19.5)	18.3 (10.6 to 28.4)

Statistical Analysis

Statistical analysis description

Treatment A over Treatment B

Comparison groups

Treatment A - Platinum Refractory Subgroup v Treatment B - Platinum Refractory Subgroup

Number of subjects included in analysis

241

Analysis specification

Pre-specified

Analysis type

P-value

= 0.2897

Method

Mantel-Haenszel

Parameter type

Odds ratio (OR)

Point estimate

0.68

Confidence interval

level

95.5%

sides

2-sided

lower limit

0.33

upper limit

1.43

Primary: Duration of Response (DOR) as determined by Blinded Independent Central Review (BIRC) - Platinum refractory subgroup

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End point title

Duration of Response (DOR) as determined by Blinded Independent Central Review (BIRC) - Platinum refractory subgroup ^[2] ^[3]

End point description

The time between the date of first confirmed response to the date of the first documented tumor progression, or death due to any cause, whichever occurs first. Here "99999" signifies NA

End point type

Primary

End point timeframe

Approximately up to 30 months (from FPFV to Data base lock)

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: Endpoints are specific for subgroups not baseline period
[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: Endpoints are specific for subgroups not baseline period

End point values	Treatment A - Platinum Refractory Subgroup	Treatment B - Platinum Refractory Subgroup
Number of subjects analysed	21	15
Units: Months
median (confidence interval 95%)	99999 (11.01 to 99999)	11.07 (4.14 to 99999)

No statistical analyses for this end point

Primary: Time to Response (TTR) as determined by Blinded Independent Central Review (BIRC) - Platinum refractory subgroup

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End point title

Time to Response (TTR) as determined by Blinded Independent Central Review (BIRC) - Platinum refractory subgroup ^[4] ^[5]

End point description

Time to Response (TTR) for participants demonstrating a response (either CR or PR) was defined as the time from the date of randomization to the date of the first confirmed response. Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes(whether target or non-target) must have reduction in short axis to < 10 mm. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.

End point type

Primary

End point timeframe

Approximately up to 30 months (from FPFV to Data base lock)

Notes
[4] - 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: Endpoints are specific for subgroups not baseline period
[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: Endpoints are specific for subgroups not baseline period

End point values	Treatment A - Platinum Refractory Subgroup	Treatment B - Platinum Refractory Subgroup
Number of subjects analysed	21	15
Units: Months
median (full range (min-max))	2.56 (1.1 to 6.6)	1.51 (1.2 to 7.7)

No statistical analyses for this end point

Secondary: Objective Response Rate (ORR) as determined by Blinded Independent Central Review (BIRC) - Platinum Eligible subgroup

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End point title

Objective Response Rate (ORR) as determined by Blinded Independent Central Review (BIRC) - Platinum Eligible subgroup ^[6]

End point description

ORR is defined as percentage of participants with a complete response (CR) or partial response (PR) Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes(whether target or non-target) must have reduction in short axis to < 10 mm. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.

End point type

Secondary

End point timeframe

From randomization to end of study. Approximately 63 Months

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: Endpoints are specific for subgroups not baseline period

End point values	Treatment A - Platinum Eligible Subgroup	Treatment B - Platinum Eligible Subgroup
Number of subjects analysed	123	61
Units: percentage of participants
number (confidence interval 95%)	20.3 (13.6 to 28.5)	29.5 (18.5 to 42.6)

No statistical analyses for this end point

Secondary: Duration of Response (DOR) as determined by Blinded Independent Central Review (BIRC) - Platinum Eligible subgroup

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End point title

Duration of Response (DOR) as determined by Blinded Independent Central Review (BIRC) - Platinum Eligible subgroup ^[7]

End point description

The time between the date of first confirmed response to the date of the first documented tumor progression, or death due to any cause, whichever occurs first. Here "99999" signifies NA

End point type

Secondary

End point timeframe

From randomization to disease progression or death. Approximately 63 Months

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: Endpoints are specific for subgroups not baseline period

End point values	Treatment A - Platinum Eligible Subgroup	Treatment B - Platinum Eligible Subgroup
Number of subjects analysed	25	18
Units: Months
median (confidence interval 95%)	27.04 (11.01 to 99999)	24.61 (6.90 to 99999)

No statistical analyses for this end point

Secondary: Progression Free Survival (PFS) as determined by Blinded Independent Central Review (BIRC) - Platinum Refractory subgroup

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End point title

Progression Free Survival (PFS) as determined by Blinded Independent Central Review (BIRC) - Platinum Refractory subgroup ^[8]

End point description

The time from randomization to the date of first documented disease progression, or death due to any cause, whichever occurs first. Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression).

End point type

Secondary

End point timeframe

From randomization to disease progression or death. Approximately 63 Months

Notes
[8] - 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: Endpoints are specific for subgroups not baseline period

End point values	Treatment A - Platinum Refractory Subgroup	Treatment B - Platinum Refractory Subgroup
Number of subjects analysed	159	82
Units: Months
median (confidence interval 95%)	2.50 (1.45 to 2.76)	2.60 (1.54 to 3.38)

Statistical Analysis

Comparison groups

Treatment A - Platinum Refractory Subgroup v Treatment B - Platinum Refractory Subgroup

Number of subjects included in analysis

241

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Hazard ratio (HR)

Point estimate

1.05

Confidence interval

level

95%

sides

2-sided

lower limit

0.78

upper limit

1.41

Secondary: Progression Free Survival (PFS) as determined by Blinded Independent Central Review (BIRC) - Platinum Eligible subgroup

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End point title

Progression Free Survival (PFS) as determined by Blinded Independent Central Review (BIRC) - Platinum Eligible subgroup ^[9]

End point description

the time from randomization to the date of first documented disease progression, or death due to any cause, whichever occurs first. Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression).

End point type

Secondary

End point timeframe

From randomization to disease progression or death. Approximately 63 Months

Notes
[9] - 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: Endpoints are specific for subgroups not baseline period

End point values	Treatment A - Platinum Eligible Subgroup	Treatment B - Platinum Eligible Subgroup
Number of subjects analysed	123	61
Units: Months
median (confidence interval 95%)	2.76 (1.64 to 4.17)	2.86 (1.51 to 5.65)

Statistical Analysis

Comparison groups

Treatment A - Platinum Eligible Subgroup v Treatment B - Platinum Eligible Subgroup

Number of subjects included in analysis

184

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Hazard ratio (HR)

Point estimate

1.12

Confidence interval

level

95%

sides

2-sided

lower limit

0.8

upper limit

1.59

Secondary: Overall Survival (OS)

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End point title

Overall Survival (OS)

End point description

End point type

Secondary

End point timeframe

From randomization to death. Approximately 63 Months

End point values	Treatment A	Treatment B
Number of subjects analysed	282	143
Units: Months
median (confidence interval 95%)	9.76 (7.52 to 11.47)	11.30 (8.48 to 14.00)

Statistical Analysis

Comparison groups

Treatment A v Treatment B

Number of subjects included in analysis

425

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Hazard ratio (HR)

Point estimate

1.09

Confidence interval

level

95%

sides

2-sided

lower limit

0.87

upper limit

1.36

Secondary: Overall Survival (OS) - Platinum Refractory Subgroup

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End point title

Overall Survival (OS) - Platinum Refractory Subgroup ^[10]

End point description

End point type

Secondary

End point timeframe

From randomization to death. Approximately 63 Months

Notes
[10] - 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: Endpoints are specific for subgroups not baseline period

End point values	Treatment A - Platinum Refractory Subgroup	Treatment B - Platinum Refractory Subgroup
Number of subjects analysed	159	82
Units: Months
median (confidence interval 95%)	9.76 (6.51 to 11.37)	9.59 (7.13 to 14.26)

Statistical Analysis

Comparison groups

Treatment A - Platinum Refractory Subgroup v Treatment B - Platinum Refractory Subgroup

Number of subjects included in analysis

241

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Hazard ratio (HR)

Point estimate

1.08

Confidence interval

level

95%

sides

2-sided

lower limit

0.81

upper limit

1.45

Secondary: Overall Survival (OS) - Platinum Eligible Subgroup

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End point title

Overall Survival (OS) - Platinum Eligible Subgroup ^[11]

End point description

End point type

Secondary

End point timeframe

From randomization to death. Approximately 63 Months

Notes
[11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Endpoints are specific for subgroups not baseline period

End point values	Treatment A - Platinum Eligible Subgroup	Treatment B - Platinum Eligible Subgroup
Number of subjects analysed	123	61
Units: Months
median (confidence interval 95%)	9.71 (7.43 to 12.62)	12.91 (9.33 to 22.01)

Statistical Analysis

Comparison groups

Treatment A - Platinum Eligible Subgroup v Treatment B - Platinum Eligible Subgroup

Number of subjects included in analysis

184

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Cox proportional hazard

Point estimate

1.14

Confidence interval

level

95%

sides

2-sided

lower limit

0.81

upper limit

1.61

Secondary: ORR - Platinum Eligible Subgroup based on HPV p-16 status

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End point title

ORR - Platinum Eligible Subgroup based on HPV p-16 status ^[12]

End point description

End point type

Secondary

End point timeframe

From randomization to end of study. Approximately 63 Months

Notes
[12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Endpoints are specific for subgroups not baseline period

End point values	Treatment A - Platinum Eligible Subgroup	Treatment B - Platinum Eligible Subgroup
Number of subjects analysed	123	61
Units: percentage of participants
number (confidence interval 95%)
Positive	20.0 (8.4 to 36.9)	41.2 (18.4 to 67.1)
Negative	20.5 (12.6 to 30.4)	25.0 (13.2 to 40.3)

No statistical analyses for this end point

Secondary: ORR - Platinum Eligible Subgroup based on Tumor Mutation Burden (TMB) Biomarker

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End point title

ORR - Platinum Eligible Subgroup based on Tumor Mutation Burden (TMB) Biomarker ^[13]

End point description

ORR is defined as percentage of participants with a complete response (CR) or partial response (PR) Tumor Mutational Burden (TMB) refers to the number of nonsynonymous somatic mutations that exist within a tumor’s genome as measured by the Foundation One CDx panel at Foundation Medicine. The analysis was done on subjects with baseline tumor mutation burden by a cutoff of 7 mutations/megabase (mut/Mb) and 10 mut/Mb Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes(whether target or non-target) must have reduction in short axis to < 10 mm. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.

End point type

Secondary

End point timeframe

From randomization to end of study. Approximately 63 Months

Notes
[13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Endpoints are specific for subgroups not baseline period

End point values	Treatment A - Platinum Eligible Subgroup	Treatment B - Platinum Eligible Subgroup
Number of subjects analysed	123	61
Units: percentage of participants
number (confidence interval 95%)
TMB < 7	10.2 (3.8 to 20.8)	30.8 (14.3 to 51.8)
TMB ≥ 7	34.2 (19.6 to 51.4)	28.6 (11.3 to 52.2)
TMB < 10	17.3 (9.8 to 27.3)	28.6 (14.6 to 46.3)
TMB ≥ 10	31.3 (11.0 to 58.7)	33.3 (9.9 to 65.1)
TMB Not Reported	23.1 (9.0 to 43.6)	28.6 (8.4 to 58.1)

No statistical analyses for this end point

Secondary: ORR - Platinum Refractory Subgroup based on HPV p-16 Status

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End point title

ORR - Platinum Refractory Subgroup based on HPV p-16 Status ^[14]

End point description

End point type

Secondary

End point timeframe

From randomization to end of study. Approximately 63 Months

Notes
[14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Endpoints are specific for subgroups not baseline period

End point values	Treatment A - Platinum Refractory Subgroup	Treatment B - Platinum Refractory Subgroup
Number of subjects analysed	159	82
Units: percentage of participants
number (confidence interval 95%)
OROPHARYNGEAL HPV P-16 POSITIVE	23.3 (9.9 to 42.3)	37.5 (15.2 to 64.6)
OROPHARYNGEAL HPV P-16 NEGATIVE/ NON-OROPHARYNGEAL	12.4 (7.3 to 19.4)	16.7 (8.6 to 27.9)

No statistical analyses for this end point

Secondary: ORR - Platinum Refractory Subgroup based on Tumor Mutation Burden (TMB) Biomarker

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End point title

ORR - Platinum Refractory Subgroup based on Tumor Mutation Burden (TMB) Biomarker ^[15]

End point description

End point type

Secondary

End point timeframe

From randomization to end of study. Approximately 63 Months

Notes
[15] - 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: Endpoints are specific for subgroups not baseline period

End point values	Treatment A - Platinum Refractory Subgroup	Treatment B - Platinum Refractory Subgroup
Number of subjects analysed	159	82
Units: percentage of participants
number (confidence interval 95%)
TMB < 7	9.0 (3.4 to 18.5)	20.5 (9.3 to 36.5)
TMB ≥ 7	23.3 (11.8 to 38.6)	19.0 (5.4 to 41.9)
TMB < 10	11.0 (5.4 to 19.3)	22.4 (11.8 to 36.6)
TMB ≥ 10	31.6 (12.6 to 56.6)	18.2 (2.3 to 51.8)
TMB Not Reported	14.3 (5.9 to 27.2)	18.2 (5.2 to 40.3)

No statistical analyses for this end point

Secondary: Duration of Response (DOR) - Platinum Refractory subgroup based on HPV p-16 Status

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End point title

Duration of Response (DOR) - Platinum Refractory subgroup based on HPV p-16 Status ^[16]

End point description

The time between the date of first confirmed response to the date of the first documented tumor progression, or death due to any cause, whichever occurs first. Here "99999" signifies NA

End point type

Secondary

End point timeframe

From randomization to disease progression or death. Approximately 63 Months

Notes
[16] - 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: Endpoints are specific for subgroups not baseline period

End point values	Treatment A - Platinum Refractory Subgroup	Treatment B - Platinum Refractory Subgroup
Number of subjects analysed	21	15
Units: Months
median (confidence interval 95%)
HPV p-16 Positive	99999 (6.87 to 99999)	11.10 (4.17 to 14.9)
HPV p-16 Negative	39.43 (26.71 to 99999)	8.34 (2.79 to 99999)

No statistical analyses for this end point

Secondary: Duration of Response (DOR) - Platinum Refractory subgroup based on Tumor Mutation Burden (TMB) Status

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End point title

Duration of Response (DOR) - Platinum Refractory subgroup based on Tumor Mutation Burden (TMB) Status ^[17]

End point description

The time between the date of first confirmed response to the date of the first documented tumor progression, or death due to any cause, whichever occurs first. Here "99999" signifies NA Tumor Mutational Burden (TMB) refers to the number of nonsynonymous somatic mutations that exist within a tumor’s genome as measured by the Foundation One CDx panel at Foundation Medicine. The analysis was done on subjects with baseline tumor mutation burden by a cutoff of 7 mutations/megabase (mut/Mb) and 10 mut/Mb

End point type

Secondary

End point timeframe

From randomization to disease progression or death. Approximately 63 Months

Notes
[17] - 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: Endpoints are specific for subgroups not baseline period

End point values	Treatment A - Platinum Refractory Subgroup	Treatment B - Platinum Refractory Subgroup
Number of subjects analysed	21	15
Units: Months
median (confidence interval 95%)
TMB: <7	99999 (11.01 to 99999)	11.14 (2.69 to 99999)
TMB ≥ 7	38.67 (3.06 to 39.43)	8.59 (2.79 to 99999)
TMB: <10	99999 (3.06 to 99999)	11.14 (4.17 to 99999)
TMB: ≥ 10	38.67 (6.87 to 38.67)	7.54 (2.79 to 12.29)
TMB: Not Reported	26.71 (6.93 to 26.71)	8.21 (4.14 to 14.29)

No statistical analyses for this end point

Secondary: Progression Free Survival (PFS) - Platinum Refractory subgroup based on HPV p-16 Status

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End point title

Progression Free Survival (PFS) - Platinum Refractory subgroup based on HPV p-16 Status ^[18]

End point description

End point type

Secondary

End point timeframe

From randomization to disease progression or death. Approximately 63 Months

Notes
[18] - 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: Endpoints are specific for subgroups not baseline period

End point values	Treatment A - Platinum Refractory Subgroup	Treatment B - Platinum Refractory Subgroup
Number of subjects analysed	159	82
Units: Months
median (confidence interval 95%)
Postive	4.11 (1.81 to 8.31)	6.70 (1.28 to 13.67)
Negative	1.84 (1.41 to 2.63)	1.94 (1.41 to 3.02)

No statistical analyses for this end point

Secondary: Progression Free Survival (PFS) - Platinum Refractory subgroup Based on Tumor Mutation Burden (TMB) Status

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End point title

Progression Free Survival (PFS) - Platinum Refractory subgroup Based on Tumor Mutation Burden (TMB) Status ^[19]

End point description

the time from randomization to the date of first documented disease progression, or death due to any cause, whichever occurs first. Tumor Mutational Burden (TMB) refers to the number of nonsynonymous somatic mutations that exist within a tumor’s genome as measured by the Foundation One CDx panel at Foundation Medicine. The analysis was done on subjects with baseline tumor mutation burden by a cutoff of 7 mutations/megabase (mut/Mb) and 10 mut/Mb Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression).

End point type

Secondary

End point timeframe

From randomization to disease progression or death. Approximately 63 Months

Notes
[19] - 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: Endpoints are specific for subgroups not baseline period

End point values	Treatment A - Platinum Refractory Subgroup	Treatment B - Platinum Refractory Subgroup
Number of subjects analysed	159	82
Units: Months
median (confidence interval 95%)
TMB: < 7	1.45 (1.38 to 2.60)	2.50 (1.41 to 5.26)
TMB: ≥ 7	2.76 (1.45 to 4.11)	1.54 (1.25 to 4.07)
TMB: < 10	1.68 (1.41 to 2.60)	2.50 (1.41 to 4.24)
TMB: ≥ 10	2.81 (1.38 to 9.69)	1.41 (1.25 to 4.07)
TMB: Not Reported	2.66 (1.45 to 2.92)	2.92 (1.28 to 7.00)

No statistical analyses for this end point

Secondary: Overall Survival (OS) - Platinum Refractory Subgroup based on HPV p-16 status

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End point title

Overall Survival (OS) - Platinum Refractory Subgroup based on HPV p-16 status ^[20]

End point description

End point type

Secondary

End point timeframe

From randomization to death. Approximately 63 Months

Notes
[20] - 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: Endpoints are specific for subgroups not baseline period

End point values	Treatment A - Platinum Refractory Subgroup	Treatment B - Platinum Refractory Subgroup
Number of subjects analysed	159	82
Units: Months
median (confidence interval 95%)
Positive	13.93 (5.98 to 33.81)	14.32 (6.28 to 44.88)
Negative	9.36 (5.98 to 10.87)	9.59 (6.93 to 13.40)

No statistical analyses for this end point

Secondary: Overall Survival (OS) - Platinum Refractory Subgroup based on Tumor Mutation Burden (TMB) status

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End point title

Overall Survival (OS) - Platinum Refractory Subgroup based on Tumor Mutation Burden (TMB) status ^[21]

End point description

Overall survival was defined as the time from randomization to the date of death from any cause. Participants were censored at the date they were last known to be alive and at the date of randomization if they were randomized but had no follow-up. Tumor Mutational Burden (TMB) refers to the number of nonsynonymous somatic mutations that exist within a tumor’s genome as measured by the Foundation One CDx panel at Foundation Medicine. The analysis was done on subjects with baseline tumor mutation burden by a cutoff of 7 mutations/megabase (mut/Mb) and 10 mut/Mb

End point type

Secondary

End point timeframe

From randomization to death. Approximately 63 Months

Notes
[21] - 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: Endpoints are specific for subgroups not baseline period

End point values	Treatment A - Platinum Refractory Subgroup	Treatment B - Platinum Refractory Subgroup
Number of subjects analysed	159	82
Units: Months
median (confidence interval 95%)
TMB: <7	5.78 (3.45 to 9.76)	8.77 (4.14 to 16.66)
TMB: ≥ 7	11.37 (6.41 to 16.95)	7.16 (6.28 to 12.29)
TMB: < 10	7.52 (4.96 to 11.27)	8.31 (4.90 to 13.04)
TMB: ≥10	6.51 (2.50 to 41.33)	9.26 (1.35 to 17.51)
Not Reported	13.86 (9.53 to 17318)	20.01 (7.56 to 23.46)

No statistical analyses for this end point

Secondary: Overall Survival (OS) - Platinum Eligible Subgroup based on HPV p-16 status

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End point title

Overall Survival (OS) - Platinum Eligible Subgroup based on HPV p-16 status ^[22]

End point description

End point type

Secondary

End point timeframe

From randomization to death. Approximately 63 Months

Notes
[22] - 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: Endpoints are specific for subgroups not baseline period

End point values	Treatment A - Platinum Eligible Subgroup	Treatment B - Platinum Eligible Subgroup
Number of subjects analysed	123	61
Units: Months
median (confidence interval 95%)
Positive	16.66 (8.54 to 28.06)	33.74 (12.91 to 99999)
Negative	7.79 (5.06 to 12.39)	9.46 (5.32 to 14.00)

No statistical analyses for this end point

Secondary: Overall Survival (OS) - Platinum Eligible Subgroup based on Tumor Mutation Burden (TMB) status

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End point title

Overall Survival (OS) - Platinum Eligible Subgroup based on Tumor Mutation Burden (TMB) status ^[23]

End point description

Overall survival was defined as the time from randomization to the date of death from any cause. Participants were censored at the date they were last known to be alive and at the date of randomization if they were randomized but had no follow-up. Here "99999" signifies NA Tumor Mutational Burden (TMB) refers to the number of nonsynonymous somatic mutations that exist within a tumor’s genome as measured by the Foundation One CDx panel at Foundation Medicine. The analysis was done on subjects with baseline tumor mutation burden by a cutoff of 7 mutations/megabase (mut/Mb) and 10 mut/Mb

End point type

Secondary

End point timeframe

From randomization to death. Approximately 63 Months

Notes
[23] - 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: Endpoints are specific for subgroups not baseline period

End point values	Treatment A - Platinum Eligible Subgroup	Treatment B - Platinum Eligible Subgroup
Number of subjects analysed	123	61
Units: Months
median (confidence interval 95%)
TMB: <7	7.56 (4.83 to 12.25)	18.27 (4.04 to 33.74)
TMB: ≥ 7	16.30 (9.43 to 36.30)	13.08 (8.28 to 38.11)
TMB: < 10	9.99 (6.41 to 12.62)	15.01 (7.62 to 27.47)
TMB: ≥10	16.72 (4.47 to 99999)	14.77 (2.83 to 99999)
Not Reported	8.00 (3.84 to 26.12)	9.71 (2.56 to 18.79)

No statistical analyses for this end point

Secondary: Progression Free Survival (PFS) - Platinum Eligible subgroup Based on Tumor Mutation Burden (TMB) Status

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End point title

Progression Free Survival (PFS) - Platinum Eligible subgroup Based on Tumor Mutation Burden (TMB) Status ^[24]

End point description

End point type

Secondary

End point timeframe

From randomization to disease progression or death. Approximately 63 Months

Notes
[24] - 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: Endpoints are specific for subgroups not baseline period

End point values	Treatment A - Platinum Eligible Subgroup	Treatment B - Platinum Eligible Subgroup
Number of subjects analysed	123	61
Units: Months
median (confidence interval 95%)
TMB: < 7	2.63 (1.45 to 3.06)	2.92 (1.38 to 9.59)
TMB: ≥ 7	5.82 (1.45 to 12.42)	2.83 (1.41 to 13.01)
TMB: < 10	2.63 (1.45 to 3.06)	2.99 (1.41 to 13.01)
TMB: ≥ 10	6.97 (1.41 to 99999)	2.76 (0.72 to 27.60)
TMB: Not Reported	2.71 (1.45 to 8.48)	3.10 (1.38 to 9.82)

No statistical analyses for this end point

Secondary: Progression Free Survival (PFS) - Platinum Eligible subgroup based on HPV p-16 Status

Top of page

End point title

Progression Free Survival (PFS) - Platinum Eligible subgroup based on HPV p-16 Status ^[25]

End point description

End point type

Secondary

End point timeframe

From randomization to disease progression or death. Approximately 63 Months

Notes
[25] - 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: Endpoints are specific for subgroups not baseline period

End point values	Treatment A - Platinum Eligible Subgroup	Treatment B - Platinum Eligible Subgroup
Number of subjects analysed	123	61
Units: Months
median (confidence interval 95%)
Postive	2.92 (1.41 to 6.60)	6.83 (1.38 to 49.84)
Negative	2.66 (1.51 to 4.14)	2.83 (1.51 to 4.24)

No statistical analyses for this end point

Secondary: Duration of Response (DOR) - Platinum Eligible subgroup based on HPV p-16 Status

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End point title

Duration of Response (DOR) - Platinum Eligible subgroup based on HPV p-16 Status ^[26]

End point description

The time between the date of first confirmed response to the date of the first documented tumor progression, or death due to any cause, whichever occurs first. Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression). Here "99999" signifies NA

End point type

Secondary

End point timeframe

From randomization to disease progression or death. Approximately 63 Months

Notes
[26] - 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: Endpoints are specific for subgroups not baseline period

End point values	Treatment A - Platinum Eligible Subgroup	Treatment B - Platinum Eligible Subgroup
Number of subjects analysed	25	18
Units: Months
median (confidence interval 95%)
Positive	33.84 (4.14 to 99999)	48.49 (5.49 to 99999)
Negative	27.04 (10.97 to 99999)	19.32 (4.11 to 99999)

No statistical analyses for this end point

Secondary: Duration of Response (DOR) - Platinum Eligible subgroup based on Tumor Mutation Burden (TMB) Status

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End point title

Duration of Response (DOR) - Platinum Eligible subgroup based on Tumor Mutation Burden (TMB) Status ^[27]

End point description

The time between the date of first confirmed response to the date of the first documented tumor progression, or death due to any cause, whichever occurs first. Tumor Mutational Burden (TMB) refers to the number of nonsynonymous somatic mutations that exist within a tumor’s genome as measured by the Foundation One CDx panel at Foundation Medicine. The analysis was done on subjects with baseline tumor mutation burden by a cutoff of 7 mutations/megabase (mut/Mb) and 10 mut/Mb. Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression). Here "99999" signifies NA

End point type

Secondary

End point timeframe

From randomization to disease progression or death. Approximately 63 Months

Notes
[27] - 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: Endpoints are specific for subgroups not baseline period

End point values	Treatment A - Platinum Eligible Subgroup	Treatment B - Platinum Eligible Subgroup
Number of subjects analysed	25	18
Units: Months
median (confidence interval 95%)
TMB: <7	10.97 (4.14 to 35.55)	99999 (5.52 to 99999)
TMB ≥ 7	24.11 (10.97 to 99999)	19.32 (5.49 to 24.61)
TMB: <10	13.67 (8.28 to 35.55)	99999 (5.52 to 99999)
TMB: ≥ 10	99999 (5.78 to 99999)	19.32 (5.49 to 24.61)
TMB: Not Reported	99999 (27.04 to 99999)	48.49 (4.11 to 99999)

No statistical analyses for this end point

Secondary: Duration of Response (DOR) - Platinum Refractory subgroup based on PD-L1 Status

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End point title

Duration of Response (DOR) - Platinum Refractory subgroup based on PD-L1 Status ^[28]

End point description

The time between the date of first confirmed response to the date of the first documented tumor progression, or death due to any cause, whichever occurs first. Tumor PD-L1 expression was defined as the percent of tumor cell membrane staining in a minimum of 100 evaluable tumor cells per validated Dako PD-L1 IHC assay. Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression). Here "99999 and -99999" signifies NA Here "9999" signifies not calculated

End point type

Secondary

End point timeframe

From randomization to disease progression or death. Approximately 63 Months

Notes
[28] - 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: Endpoints are specific for subgroups not baseline period

End point values	Treatment A - Platinum Refractory Subgroup	Treatment B - Platinum Refractory Subgroup
Number of subjects analysed	21	15
Units: Months
median (confidence interval 95%)
PD-L1: ≥ 1%	39.43 (11.01 to 99999)	8.34 (2.79 to 99999)
PD-L1: < 25%	39.43 (6.87 to 99999)	11.10 (4.17 to 38.51)
PD-L1: ≥ 25%	9999 (6.93 to 99999)	8.34 (2.79 to 99999)
PD-L1: <50%	9999 (26.71 to 99999)	11.14 (4.17 to 38.51)
PD-L1: > 50%	9999 (6.93 to 99999)	6.24 (4.14 to 8.34)
PD-L1: 1 - < 25%	39.43 (3.06 to 39.43)	9999 (4.17 to 99999)
PD-L1: Unquantifiable	38.67 (-99999 to 99999)	9999 (-99999 to 99999)

No statistical analyses for this end point

Secondary: ORR - Platinum Refractory Subgroup based on PD-L1 Expression

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End point title

ORR - Platinum Refractory Subgroup based on PD-L1 Expression ^[29]

End point description

ORR is defined as percentage of participants with a complete response (CR) or partial response (PR) Tumor PD-L1 expression was defined as the percent of tumor cell membrane staining in a minimum of 100 evaluable tumor cells per validated Dako PD-L1 IHC assay Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes(whether target or non-target) must have reduction in short axis to < 10 mm. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Here "9999" signifies not calculated

End point type

Secondary

End point timeframe

From randomization to end of study. Approximately 63 Months

Notes
[29] - 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: Endpoints are specific for subgroups not baseline period

End point values	Treatment A - Platinum Refractory Subgroup	Treatment B - Platinum Refractory Subgroup
Number of subjects analysed	159	82
Units: Percentage of Participants
number (confidence interval 95%)
<1%	7.7 (2.1 to 18.5)	25.8 (11.9 to 44.6)
PD-L1: ≥ 1%	19.6 (12.0 to 29.1)	19.6 (9.4 to 33.9)
PD-L1: < 25%	11.1 (6.1 to 18.3)	21.1 (11.4 to 33.9)
PD-L1: ≥ 25%	33.3 (16.5 to 54.0)	25.0 (8.7 to 49.1)
PD-L1: <50%	13.2 (7.9 to 20.3)	22.7 (13.3 to 34.7)
PD-L1: > 50%	33.3 (11.8 to 61.6)	18.2 (2.3 to 51.8)
PD-L1: 1 - < 25%	13.8 (6.5 to 24.7)	15.4 (4.4 to 34.9)
without quantifiable PD-L1 expression at baseline	9999 (-9999 to 99999)	9999 (-99999 to 99999)

No statistical analyses for this end point

Secondary: Overall Survival (OS) - Platinum Refractory Subgroup based on PD-L1 status

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End point title

Overall Survival (OS) - Platinum Refractory Subgroup based on PD-L1 status ^[30]

End point description

Overall survival was defined as the time from randomization to the date of death from any cause. Participants were censored at the date they were last known to be alive and at the date of randomization if they were randomized but had no follow-up. Tumor PD-L1 expression was defined as the percent of tumor cell membrane staining in a minimum of 100 evaluable tumor cells per validated Dako PD-L1 IHC assay

End point type

Secondary

End point timeframe

From randomization to death. Approximately 63 Months

Notes
[30] - 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: Endpoints are specific for subgroups not baseline period

End point values	Treatment A - Platinum Refractory Subgroup	Treatment B - Platinum Refractory Subgroup
Number of subjects analysed	159	82
Units: Months
median (confidence interval 95%)
<1%	9.53 (6.31 to 12.62)	12.29 (6.08 to 20.27)
PD-L1: ≥ 1%	10.22 (5.95 to 14.52)	9.02 (6.74 to 13.34)
PD-L1: < 25%	9.95 (7.26 to 11.37)	8.77 (6.28 to 14.78)
PD-L1: ≥ 25%	5.78 (2.43 to 48.69)	10.23 (7.03 to 16.66)
PD-L1: <50%	9.76 (6.51 to 11.37)	10.61 (6.74 to 14.26)
PD-L1: > 50%	26.02 (2.43 to 48.69)	7.33 (1.51 to 16.66)
PD-L1: 1 - < 25%	10.32 (5.98 to 14.32)	7.56 (4.86 to 17.51)
Without quantifiable PD-L1 expression at baseline	6.93 (1.71 to 14.16)	28.09 (7.56 to 44.88)

No statistical analyses for this end point

Secondary: Progression Free Survival (PFS) - Platinum Refractory subgroup based on PD-L1 Status

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End point title

Progression Free Survival (PFS) - Platinum Refractory subgroup based on PD-L1 Status ^[31]

End point description

The time from randomization to the date of first documented disease progression, or death due to any cause, whichever occurs first. Tumor PD-L1 expression was defined as the percent of tumor cell membrane staining in a minimum of 100 evaluable tumor cells per validated Dako PD-L1 IHC assay. Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression). Here "99999" signifies NA

End point type

Secondary

End point timeframe

From randomization to disease progression or death. Approximately 63 Months

Notes
[31] - 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: Endpoints are specific for subgroups not baseline period

End point values	Treatment A - Platinum Refractory Subgroup	Treatment B - Platinum Refractory Subgroup
Number of subjects analysed	159	82
Units: Months
median (confidence interval 95%)
<1%	2.60 (1.41 to 2.86)	2.96 (1.38 to 5.32)
PD-L1: ≥ 1%	2.60 (1.45 to 2.83)	2.60 (1.41 to 4.11)
PD-L1: < 25%	2.60 (1.45 to 2.83)	2.79 (1.41 to 4.01)
PD-L1: ≥ 25%	2.12 (1.38 to 13.77)	1.54 (1.25 to 7.03)
PD-L1: <50%	2.60 (1.45 to 2.79)	2.79 (1.54 to 4.07)
PD-L1: > 50%	2.79 (0.59 to 13.77)	1.54 (0.66 to 7.03)
PD-L1: 1 - < 25%	2.66 (1.45 to 2.83)	2.60 (1.38 to 4.07)
Without Quantifiable PD-L1 expression at Baseline	2.17 (1.08 to 2.66)	1.71 (1.22 to 99999)

No statistical analyses for this end point

Secondary: Duration of Response (DOR) - Platinum Eligible subgroup based on PD-L1 Status

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End point title

Duration of Response (DOR) - Platinum Eligible subgroup based on PD-L1 Status ^[32]

End point description

The time between the date of first confirmed response to the date of the first documented tumor progression, or death due to any cause, whichever occurs first. Tumor PD-L1 expression was defined as the percent of tumor cell membrane staining in a minimum of 100 evaluable tumor cells per validated Dako PD-L1 IHC assay Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression). Here "99999" signifies NA

End point type

Secondary

End point timeframe

From randomization to disease progression or death. Approximately 63 Months

Notes
[32] - 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: Endpoints are specific for subgroups not baseline period

End point values	Treatment A - Platinum Eligible Subgroup	Treatment B - Platinum Eligible Subgroup
Number of subjects analysed	25	18
Units: Months
median (confidence interval 95%)
PD-L1: ≥ 1%	33.84 (8.28 to 99999)	24.61 (4.11 to 99999)
PD-L1: < 25%	13.17 (4.17 to 35.55)	12.42 (4.11 to 99999)
PD-L1: ≥ 25%	99999 (8.28 to 99999)	99999 (24.61 to 99999)
PD-L1: <50%	13.67 (5.78 to 35.55)	15.87 (4.11 to 99999)
PD-L1: > 50%	99999 (33.84 to 99999)	99999 (24.61 to 99999)
PD-L1: 1 - < 25%	13.13 (4.14 to 99999)	6.21 (4.11 to 12.42)
PD-L1: Unquantifiable	99999 (27.04 to 99999)	28.99 (9.49 to 48.49)

No statistical analyses for this end point

Secondary: ORR - Platinum Eligible Subgroup based on PD-L1 Expression

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End point title

ORR - Platinum Eligible Subgroup based on PD-L1 Expression ^[33]

End point description

End point type

Secondary

End point timeframe

From randomization to end of study. Approximately 63 Months

Notes
[33] - 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: Endpoints are specific for subgroups not baseline period

End point values	Treatment A - Platinum Eligible Subgroup	Treatment B - Platinum Eligible Subgroup
Number of subjects analysed	123	61
Units: percentage of participants
number (confidence interval 95%)
<1%	15.7 (7.0 to 28.6)	21.7 (7.5 to 43.7)
PD-L1: ≥ 1%	21.5 (12.3 to 33.5)	30.3 (15.6 to 48.7)
PD-L1: < 25%	14.9 (8.2 to 24.2)	24.3 (11.8 to 41.2)
PD-L1: ≥ 25%	31.0 (15.3 to 50.8)	31.6 (12.6 to 56.6)
PD-L1: <50%	16.7 (9.8 to 25.6)	24.4 (12.4 to 40.3)
PD-L1: > 50%	30.0 (11.9 to 54.3)	33.3 (11.8 to 61.6)
PD-L1: 1 - < 25%	13.9 (4.7 to 29.5)	28.6 (8.4 to 58.1)
Without quantifiable PD-L1 expression at baseline	99999 (99999 to 99999)	99999 (99999 to 99999)

No statistical analyses for this end point

Secondary: Overall Survival (OS) - Platinum Eligible Subgroup based on PD-L1 status

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End point title

Overall Survival (OS) - Platinum Eligible Subgroup based on PD-L1 status ^[34]

End point description

Overall survival was defined as the time from randomization to the date of death from any cause. Participants were censored at the date they were last known to be alive and at the date of randomization if they were randomized but had no follow-up. Tumor PD-L1 expression was defined as the percent of tumor cell membrane staining in a minimum of 100 evaluable tumor cells per validated Dako PD-L1 IHC assay Here "99999" signifies NA

End point type

Secondary

End point timeframe

From randomization to death. Approximately 63 Months

Notes
[34] - 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: Endpoints are specific for subgroups not baseline period

End point values	Treatment A - Platinum Eligible Subgroup	Treatment B - Platinum Eligible Subgroup
Number of subjects analysed	123	61
Units: months
median (confidence interval 95%)
<1%	12.52 (8.21 to 17.68)	11.17 (3.42 to 21.52)
PD-L1: ≥ 1%	7.56 (5.06 to 11.24)	14.00 (7.62 to 23.66)
PD-L1: < 25%	8.72 (5.91 to 12.25)	11.17 (5.32 to 21.52)
PD-L1: ≥ 25%	12.39 (5.06 to 36.30)	14.00 (6.34 to 38.74)
PD-L1: <50%	9.10 (6.57 to 12.62)	9.92 (4.04 to 18.79)
PD-L1: > 50%	9.40 (4.11 to 36.30)	15.01 (7.62 to 99999)
PD-L1: 1 - < 25%	6.16 (4.57 to 8.11)	8.48 (2.83 to 22.41)
Without quantifiable PD-L1 expression at baseline	26.12 (1.64 to 99999)	33.74 (5.72 to 99999)

No statistical analyses for this end point

Secondary: Progression Free Survival (PFS) - Platinum Eligible subgroup based on PD-L1 Status

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End point title

Progression Free Survival (PFS) - Platinum Eligible subgroup based on PD-L1 Status ^[35]

End point description

The time from randomization to the date of first documented disease progression, or death due to any cause, whichever occurs first. Tumor PD-L1 expression was defined as the percent of tumor cell membrane staining in a minimum of 100 evaluable tumor cells per validated Dako PD-L1 IHC assay Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression). Here "99999" signifies NA

End point type

Secondary

End point timeframe

From randomization to disease progression or death. Approximately 63 Months

Notes
[35] - 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: Endpoints are specific for subgroups not baseline period

End point values	Treatment A - Platinum Eligible Subgroup	Treatment B - Platinum Eligible Subgroup
Number of subjects analysed	123	61
Units: Months
median (confidence interval 95%)
<1%	2.61 (1.38 to 5.78)	2.73 (1.41 to 9.82)
PD-L1: ≥ 1%	2.89 (1.51 to 4.21)	2.99 (1.38 to 5.65)
PD-L1: < 25%	2.37 (1.41 to 2.76)	2.76 (1.41 to 5.65)
PD-L1: ≥ 25%	5.75 (3.71 to 16.59)	2.99 (1.38 to 99999)
PD-L1: <50%	2.55 (1.45 to 2.89)	2.76 (1.41 to 5.65)
PD-L1: > 50%	4.21 (2.79 to 99999)	2.99 (1.38 to 99999)
PD-L1: 1 - < 25%	1.51 (1.41 to 2.86)	3.10 (1.28 to 8.28)
Without quantifiable PD-L1 expression at baseline	6.47 (1.51 to 99999)	13.73 (1.28 to 49.84)

No statistical analyses for this end point

Post-hoc: Objective Response Rate (ORR) as determined by Blinded Independent Central Review (BIRC) - Platinum refractory subgroup - Post Hoc Analysis

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End point title

Objective Response Rate (ORR) as determined by Blinded Independent Central Review (BIRC) - Platinum refractory subgroup - Post Hoc Analysis ^[36]

End point description

End point type

Post-hoc

End point timeframe

From randomization to end of study. Approximately 63 Months

Notes
[36] - 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: Endpoints are specific for subgroups not baseline period

End point values	Treatment A - Platinum Refractory Subgroup	Treatment B - Platinum Refractory Subgroup
Number of subjects analysed	159	82
Units: percentage of participants
number (confidence interval 95%)	14.5 (9.4 to 20.9)	20.7 (12.6 to 31.1)

Statistical Analysis

Statistical analysis description

Treatment A over Treatment B

Comparison groups

Treatment A - Platinum Refractory Subgroup v Treatment B - Platinum Refractory Subgroup

Number of subjects included in analysis

241

Analysis specification

Post-hoc

Analysis type

Method

Mantel-Haenszel

Parameter type

Odds ratio (OR)

Point estimate

0.64

Confidence interval

level

95%

sides

2-sided

lower limit

0.32

upper limit

1.29

Post-hoc: Duration of Response (DOR) as determined by Blinded Independent Central Review (BIRC) - Platinum refractory subgroup - Post Hoc Analysis

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End point title

Duration of Response (DOR) as determined by Blinded Independent Central Review (BIRC) - Platinum refractory subgroup - Post Hoc Analysis ^[37]

End point description

End point type

Post-hoc

End point timeframe

From randomization to disease progression or death. Approximately 63 Months

Notes
[37] - 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: Endpoints are specific for subgroups not baseline period

End point values	Treatment A - Platinum Refractory Subgroup	Treatment B - Platinum Refractory Subgroup
Number of subjects analysed	23	17
Units: Months
median (confidence interval 95%)	39.43 (26.71 to 99999)	11.07 (4.17 to 38.51)

No statistical analyses for this end point

Post-hoc: Time to Response (TTR) as determined by Blinded Independent Central Review (BIRC) - Platinum refractory subgroup - Post Hoc Analysis

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End point title

Time to Response (TTR) as determined by Blinded Independent Central Review (BIRC) - Platinum refractory subgroup - Post Hoc Analysis ^[38]

End point description

End point type

Post-hoc

End point timeframe

From randomization to a confirmed response. Approximately 35 Months

Notes
[38] - 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: Endpoints are specific for subgroups not baseline period

End point values	Treatment A - Platinum Refractory Subgroup	Treatment B - Platinum Refractory Subgroup
Number of subjects analysed	23	17
Units: Months
median (full range (min-max))	2.63 (1.1 to 34.3)	1.71 (1.2 to 7.7)

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Adverse Events and Serious Adverse Events: Approximately 32 months All-Cause mortality: Approximately 65 months

Adverse event reporting additional description

Adverse Event and Serious Adverse Events are measured from first dose to last dose + 100 days. All-Cause mortality will be measured from the time of randomization to the end of study.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

24.1

Reporting group title

Treatment A - Platinum Refractory Subgroup

Reporting group description

Reporting group title

Treatment B - Platinum Eligible Subgroup

Reporting group description

Reporting group title

Treatment A - Platinum Eligible Subgroup

Reporting group description

Reporting group title

Treatment B - Platinum Refractory Subgroup

Reporting group description

Serious adverse events	Treatment A - Platinum Refractory Subgroup	Treatment B - Platinum Eligible Subgroup	Treatment A - Platinum Eligible Subgroup	Treatment B - Platinum Refractory Subgroup
Total subjects affected by serious adverse events
subjects affected / exposed	103 / 159 (64.78%)	35 / 61 (57.38%)	89 / 123 (72.36%)	52 / 82 (63.41%)
number of deaths (all causes)	131	49	102	71
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cancer pain
subjects affected / exposed ^[1]	1 / 158 (0.63%)	0 / 61 (0.00%)	1 / 122 (0.82%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Basal cell carcinoma
subjects affected / exposed ^[2]	1 / 158 (0.63%)	0 / 61 (0.00%)	1 / 122 (0.82%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatocellular carcinoma
subjects affected / exposed ^[3]	0 / 158 (0.00%)	0 / 61 (0.00%)	1 / 122 (0.82%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Malignant neoplasm progression
subjects affected / exposed ^[4]	61 / 158 (38.61%)	16 / 61 (26.23%)	47 / 122 (38.52%)	25 / 82 (30.49%)
occurrences causally related to treatment / all	0 / 63	0 / 16	0 / 48	0 / 25
deaths causally related to treatment / all	0 / 58	0 / 16	0 / 45	0 / 25
Malignant pleural effusion
subjects affected / exposed ^[5]	0 / 158 (0.00%)	0 / 61 (0.00%)	1 / 122 (0.82%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Metastases to bone
subjects affected / exposed ^[6]	1 / 158 (0.63%)	0 / 61 (0.00%)	0 / 122 (0.00%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Second primary malignancy
subjects affected / exposed ^[7]	0 / 158 (0.00%)	1 / 61 (1.64%)	0 / 122 (0.00%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Tumour associated fever
subjects affected / exposed ^[8]	0 / 158 (0.00%)	0 / 61 (0.00%)	1 / 122 (0.82%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Tumour haemorrhage
subjects affected / exposed ^[9]	2 / 158 (1.27%)	0 / 61 (0.00%)	1 / 122 (0.82%)	1 / 82 (1.22%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Tumour pain
subjects affected / exposed ^[10]	0 / 158 (0.00%)	0 / 61 (0.00%)	0 / 122 (0.00%)	1 / 82 (1.22%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Hypovolaemic shock
subjects affected / exposed ^[11]	0 / 158 (0.00%)	0 / 61 (0.00%)	0 / 122 (0.00%)	1 / 82 (1.22%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Haemorrhage
subjects affected / exposed ^[12]	1 / 158 (0.63%)	0 / 61 (0.00%)	2 / 122 (1.64%)	1 / 82 (1.22%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0
Embolism
subjects affected / exposed ^[13]	0 / 158 (0.00%)	0 / 61 (0.00%)	0 / 122 (0.00%)	1 / 82 (1.22%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lymphoedema
subjects affected / exposed ^[14]	1 / 158 (0.63%)	0 / 61 (0.00%)	0 / 122 (0.00%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Peripheral venous disease
subjects affected / exposed ^[15]	0 / 158 (0.00%)	0 / 61 (0.00%)	2 / 122 (1.64%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Superior vena cava syndrome
subjects affected / exposed ^[16]	1 / 158 (0.63%)	0 / 61 (0.00%)	0 / 122 (0.00%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Hyperthermia
subjects affected / exposed ^[17]	1 / 158 (0.63%)	0 / 61 (0.00%)	0 / 122 (0.00%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Generalised oedema
subjects affected / exposed ^[18]	1 / 158 (0.63%)	0 / 61 (0.00%)	0 / 122 (0.00%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
General physical health deterioration
subjects affected / exposed ^[19]	0 / 158 (0.00%)	0 / 61 (0.00%)	3 / 122 (2.46%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Fatigue
subjects affected / exposed ^[20]	0 / 158 (0.00%)	0 / 61 (0.00%)	1 / 122 (0.82%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Face oedema
subjects affected / exposed ^[21]	1 / 158 (0.63%)	0 / 61 (0.00%)	0 / 122 (0.00%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Drug intolerance
subjects affected / exposed ^[22]	1 / 158 (0.63%)	0 / 61 (0.00%)	0 / 122 (0.00%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Death
subjects affected / exposed ^[23]	0 / 158 (0.00%)	1 / 61 (1.64%)	0 / 122 (0.00%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Chest pain
subjects affected / exposed ^[24]	0 / 158 (0.00%)	0 / 61 (0.00%)	0 / 122 (0.00%)	1 / 82 (1.22%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Swelling
subjects affected / exposed ^[25]	1 / 158 (0.63%)	0 / 61 (0.00%)	0 / 122 (0.00%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Sudden death
subjects affected / exposed ^[26]	0 / 158 (0.00%)	0 / 61 (0.00%)	3 / 122 (2.46%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 3	0 / 0
Pyrexia
subjects affected / exposed ^[27]	1 / 158 (0.63%)	0 / 61 (0.00%)	1 / 122 (0.82%)	1 / 82 (1.22%)
occurrences causally related to treatment / all	0 / 1	0 / 0	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Impaired healing
subjects affected / exposed ^[28]	0 / 158 (0.00%)	0 / 61 (0.00%)	1 / 122 (0.82%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Mucosal inflammation
subjects affected / exposed ^[29]	1 / 158 (0.63%)	0 / 61 (0.00%)	2 / 122 (1.64%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Malaise
subjects affected / exposed ^[30]	0 / 158 (0.00%)	1 / 61 (1.64%)	1 / 122 (0.82%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Inflammation
subjects affected / exposed ^[31]	0 / 158 (0.00%)	0 / 61 (0.00%)	1 / 122 (0.82%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pain
subjects affected / exposed ^[32]	0 / 158 (0.00%)	0 / 61 (0.00%)	1 / 122 (0.82%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Immune system disorders
Drug hypersensitivity
subjects affected / exposed ^[33]	0 / 158 (0.00%)	0 / 61 (0.00%)	1 / 122 (0.82%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Autoimmune lung disease
subjects affected / exposed ^[34]	1 / 158 (0.63%)	0 / 61 (0.00%)	0 / 122 (0.00%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Chronic obstructive pulmonary disease
subjects affected / exposed ^[35]	0 / 158 (0.00%)	0 / 61 (0.00%)	1 / 122 (0.82%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed ^[36]	4 / 158 (2.53%)	1 / 61 (1.64%)	4 / 122 (3.28%)	3 / 82 (3.66%)
occurrences causally related to treatment / all	0 / 4	0 / 1	0 / 4	1 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Haemoptysis
subjects affected / exposed ^[37]	0 / 158 (0.00%)	0 / 61 (0.00%)	3 / 122 (2.46%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypoxia
subjects affected / exposed ^[38]	0 / 158 (0.00%)	0 / 61 (0.00%)	0 / 122 (0.00%)	1 / 82 (1.22%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Laryngeal dyspnoea
subjects affected / exposed ^[39]	0 / 158 (0.00%)	0 / 61 (0.00%)	0 / 122 (0.00%)	1 / 82 (1.22%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lung disorder
subjects affected / exposed ^[40]	0 / 158 (0.00%)	0 / 61 (0.00%)	1 / 122 (0.82%)	1 / 82 (1.22%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Laryngeal oedema
subjects affected / exposed ^[41]	0 / 158 (0.00%)	0 / 61 (0.00%)	1 / 122 (0.82%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Laryngeal obstruction
subjects affected / exposed ^[42]	1 / 158 (0.63%)	0 / 61 (0.00%)	0 / 122 (0.00%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Laryngeal haemorrhage
subjects affected / exposed ^[43]	0 / 158 (0.00%)	1 / 61 (1.64%)	1 / 122 (0.82%)	1 / 82 (1.22%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Nasal obstruction
subjects affected / exposed ^[44]	0 / 158 (0.00%)	1 / 61 (1.64%)	0 / 122 (0.00%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Obstructive airways disorder
subjects affected / exposed ^[45]	0 / 158 (0.00%)	0 / 61 (0.00%)	1 / 122 (0.82%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pharyngeal oedema
subjects affected / exposed ^[46]	0 / 158 (0.00%)	0 / 61 (0.00%)	1 / 122 (0.82%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed ^[47]	3 / 158 (1.90%)	0 / 61 (0.00%)	0 / 122 (0.00%)	1 / 82 (1.22%)
occurrences causally related to treatment / all	1 / 3	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonitis
subjects affected / exposed ^[48]	1 / 158 (0.63%)	1 / 61 (1.64%)	2 / 122 (1.64%)	2 / 82 (2.44%)
occurrences causally related to treatment / all	1 / 1	0 / 1	2 / 2	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumothorax
subjects affected / exposed ^[49]	0 / 158 (0.00%)	0 / 61 (0.00%)	2 / 122 (1.64%)	1 / 82 (1.22%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed ^[50]	1 / 158 (0.63%)	1 / 61 (1.64%)	0 / 122 (0.00%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory distress
subjects affected / exposed ^[51]	1 / 158 (0.63%)	0 / 61 (0.00%)	0 / 122 (0.00%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Respiratory failure
subjects affected / exposed ^[52]	3 / 158 (1.90%)	1 / 61 (1.64%)	2 / 122 (1.64%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Insomnia
subjects affected / exposed ^[53]	0 / 158 (0.00%)	0 / 61 (0.00%)	1 / 122 (0.82%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Product issues
Device leakage
subjects affected / exposed ^[54]	2 / 158 (1.27%)	0 / 61 (0.00%)	2 / 122 (1.64%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Device dislocation
subjects affected / exposed ^[55]	0 / 158 (0.00%)	2 / 61 (3.28%)	0 / 122 (0.00%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
Weight decreased
subjects affected / exposed ^[56]	1 / 158 (0.63%)	0 / 61 (0.00%)	0 / 122 (0.00%)	1 / 82 (1.22%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Platelet count decreased
subjects affected / exposed ^[57]	0 / 158 (0.00%)	0 / 61 (0.00%)	0 / 122 (0.00%)	1 / 82 (1.22%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Creatinine renal clearance decreased
subjects affected / exposed ^[58]	0 / 158 (0.00%)	0 / 61 (0.00%)	1 / 122 (0.82%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Head injury
subjects affected / exposed ^[59]	0 / 158 (0.00%)	0 / 61 (0.00%)	1 / 122 (0.82%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
Hand fracture
subjects affected / exposed ^[60]	0 / 158 (0.00%)	0 / 61 (0.00%)	0 / 122 (0.00%)	1 / 82 (1.22%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Foot fracture
subjects affected / exposed ^[61]	0 / 158 (0.00%)	0 / 61 (0.00%)	0 / 122 (0.00%)	1 / 82 (1.22%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Femur fracture
subjects affected / exposed ^[62]	0 / 158 (0.00%)	0 / 61 (0.00%)	1 / 122 (0.82%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Accidental overdose
subjects affected / exposed ^[63]	0 / 158 (0.00%)	0 / 61 (0.00%)	1 / 122 (0.82%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infusion related reaction
subjects affected / exposed ^[64]	0 / 158 (0.00%)	0 / 61 (0.00%)	1 / 122 (0.82%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Spinal compression fracture
subjects affected / exposed ^[65]	1 / 158 (0.63%)	0 / 61 (0.00%)	0 / 122 (0.00%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Post procedural haemorrhage
subjects affected / exposed ^[66]	0 / 158 (0.00%)	0 / 61 (0.00%)	1 / 122 (0.82%)	1 / 82 (1.22%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Overdose
subjects affected / exposed ^[67]	1 / 158 (0.63%)	0 / 61 (0.00%)	0 / 122 (0.00%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Toxicity to various agents
subjects affected / exposed ^[68]	1 / 158 (0.63%)	0 / 61 (0.00%)	0 / 122 (0.00%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Tracheal haemorrhage
subjects affected / exposed ^[69]	0 / 158 (0.00%)	0 / 61 (0.00%)	2 / 122 (1.64%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Upper limb fracture
subjects affected / exposed ^[70]	0 / 158 (0.00%)	1 / 61 (1.64%)	1 / 122 (0.82%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vasoplegia syndrome
subjects affected / exposed ^[71]	0 / 158 (0.00%)	0 / 61 (0.00%)	1 / 122 (0.82%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Cardiac failure congestive
subjects affected / exposed ^[72]	0 / 158 (0.00%)	0 / 61 (0.00%)	1 / 122 (0.82%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Arrhythmia
subjects affected / exposed ^[73]	0 / 158 (0.00%)	0 / 61 (0.00%)	0 / 122 (0.00%)	1 / 82 (1.22%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Cardiac arrest
subjects affected / exposed ^[74]	1 / 158 (0.63%)	0 / 61 (0.00%)	0 / 122 (0.00%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Cardiac failure
subjects affected / exposed ^[75]	0 / 158 (0.00%)	0 / 61 (0.00%)	1 / 122 (0.82%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Acute myocardial infarction
subjects affected / exposed ^[76]	0 / 158 (0.00%)	0 / 61 (0.00%)	0 / 122 (0.00%)	1 / 82 (1.22%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pericardial effusion
subjects affected / exposed ^[77]	2 / 158 (1.27%)	0 / 61 (0.00%)	1 / 122 (0.82%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Myocardial infarction
subjects affected / exposed ^[78]	1 / 158 (0.63%)	0 / 61 (0.00%)	0 / 122 (0.00%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Carotid aneurysm rupture
subjects affected / exposed ^[79]	0 / 158 (0.00%)	0 / 61 (0.00%)	0 / 122 (0.00%)	1 / 82 (1.22%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ischaemic stroke
subjects affected / exposed ^[80]	0 / 158 (0.00%)	0 / 61 (0.00%)	0 / 122 (0.00%)	1 / 82 (1.22%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cerebrovascular accident
subjects affected / exposed ^[81]	0 / 158 (0.00%)	0 / 61 (0.00%)	1 / 122 (0.82%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cerebral ischaemia
subjects affected / exposed ^[82]	0 / 158 (0.00%)	0 / 61 (0.00%)	0 / 122 (0.00%)	1 / 82 (1.22%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorder
subjects affected / exposed ^[83]	0 / 158 (0.00%)	0 / 61 (0.00%)	1 / 122 (0.82%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Syncope
subjects affected / exposed ^[84]	1 / 158 (0.63%)	0 / 61 (0.00%)	1 / 122 (0.82%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Neuropathy peripheral
subjects affected / exposed ^[85]	0 / 158 (0.00%)	0 / 61 (0.00%)	1 / 122 (0.82%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed ^[86]	1 / 158 (0.63%)	0 / 61 (0.00%)	1 / 122 (0.82%)	1 / 82 (1.22%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lymph node pain
subjects affected / exposed ^[87]	1 / 158 (0.63%)	0 / 61 (0.00%)	0 / 122 (0.00%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Neutropenia
subjects affected / exposed ^[88]	0 / 158 (0.00%)	0 / 61 (0.00%)	1 / 122 (0.82%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Febrile bone marrow aplasia
subjects affected / exposed ^[89]	2 / 158 (1.27%)	0 / 61 (0.00%)	0 / 122 (0.00%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Ear and labyrinth disorders
Vestibular disorder
subjects affected / exposed ^[90]	1 / 158 (0.63%)	0 / 61 (0.00%)	0 / 122 (0.00%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Ascites
subjects affected / exposed ^[91]	1 / 158 (0.63%)	0 / 61 (0.00%)	0 / 122 (0.00%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal distension
subjects affected / exposed ^[92]	0 / 158 (0.00%)	0 / 61 (0.00%)	1 / 122 (0.82%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal pain upper
subjects affected / exposed ^[93]	0 / 158 (0.00%)	1 / 61 (1.64%)	0 / 122 (0.00%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed ^[94]	3 / 158 (1.90%)	0 / 61 (0.00%)	4 / 122 (3.28%)	1 / 82 (1.22%)
occurrences causally related to treatment / all	3 / 3	0 / 0	2 / 4	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Constipation
subjects affected / exposed ^[95]	0 / 158 (0.00%)	0 / 61 (0.00%)	0 / 122 (0.00%)	1 / 82 (1.22%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Colitis
subjects affected / exposed ^[96]	1 / 158 (0.63%)	1 / 61 (1.64%)	0 / 122 (0.00%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	1 / 1	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Autoimmune colitis
subjects affected / exposed ^[97]	2 / 158 (1.27%)	0 / 61 (0.00%)	0 / 122 (0.00%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	3 / 3	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Duodenitis
subjects affected / exposed ^[98]	0 / 158 (0.00%)	0 / 61 (0.00%)	1 / 122 (0.82%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Haematemesis
subjects affected / exposed ^[99]	0 / 158 (0.00%)	0 / 61 (0.00%)	1 / 122 (0.82%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal haemorrhage
subjects affected / exposed ^[100]	1 / 158 (0.63%)	0 / 61 (0.00%)	0 / 122 (0.00%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Gastric ulcer
subjects affected / exposed ^[101]	1 / 158 (0.63%)	0 / 61 (0.00%)	0 / 122 (0.00%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dysphagia
subjects affected / exposed ^[102]	3 / 158 (1.90%)	0 / 61 (0.00%)	5 / 122 (4.10%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 5	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hernial eventration
subjects affected / exposed ^[103]	0 / 158 (0.00%)	0 / 61 (0.00%)	0 / 122 (0.00%)	1 / 82 (1.22%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Immune-mediated enterocolitis
subjects affected / exposed ^[104]	3 / 158 (1.90%)	1 / 61 (1.64%)	2 / 122 (1.64%)	1 / 82 (1.22%)
occurrences causally related to treatment / all	3 / 3	1 / 1	3 / 3	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Impaired gastric emptying
subjects affected / exposed ^[105]	0 / 158 (0.00%)	0 / 61 (0.00%)	0 / 122 (0.00%)	1 / 82 (1.22%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Mouth haemorrhage
subjects affected / exposed ^[106]	2 / 158 (1.27%)	1 / 61 (1.64%)	1 / 122 (0.82%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Small intestinal perforation
subjects affected / exposed ^[107]	0 / 158 (0.00%)	0 / 61 (0.00%)	1 / 122 (0.82%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatitis
subjects affected / exposed ^[108]	0 / 158 (0.00%)	1 / 61 (1.64%)	1 / 122 (0.82%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
Palatal disorder
subjects affected / exposed ^[109]	1 / 158 (0.63%)	0 / 61 (0.00%)	0 / 122 (0.00%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Oesophageal fistula
subjects affected / exposed ^[110]	0 / 158 (0.00%)	0 / 61 (0.00%)	0 / 122 (0.00%)	1 / 82 (1.22%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nausea
subjects affected / exposed ^[111]	0 / 158 (0.00%)	0 / 61 (0.00%)	0 / 122 (0.00%)	2 / 82 (2.44%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Mouth ulceration
subjects affected / exposed ^[112]	0 / 158 (0.00%)	0 / 61 (0.00%)	0 / 122 (0.00%)	1 / 82 (1.22%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Stomatitis
subjects affected / exposed ^[113]	0 / 158 (0.00%)	0 / 61 (0.00%)	0 / 122 (0.00%)	1 / 82 (1.22%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed ^[114]	6 / 158 (3.80%)	0 / 61 (0.00%)	2 / 122 (1.64%)	3 / 82 (3.66%)
occurrences causally related to treatment / all	2 / 6	0 / 0	0 / 2	2 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Hepatobiliary disorders
Autoimmune hepatitis
subjects affected / exposed ^[115]	0 / 158 (0.00%)	1 / 61 (1.64%)	1 / 122 (0.82%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cholecystitis
subjects affected / exposed ^[116]	0 / 158 (0.00%)	0 / 61 (0.00%)	1 / 122 (0.82%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatitis
subjects affected / exposed ^[117]	0 / 158 (0.00%)	1 / 61 (1.64%)	0 / 122 (0.00%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatotoxicity
subjects affected / exposed ^[118]	0 / 158 (0.00%)	0 / 61 (0.00%)	0 / 122 (0.00%)	1 / 82 (1.22%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Immune-mediated hepatitis
subjects affected / exposed ^[119]	0 / 158 (0.00%)	0 / 61 (0.00%)	1 / 122 (0.82%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Pruritus
subjects affected / exposed ^[120]	1 / 158 (0.63%)	0 / 61 (0.00%)	0 / 122 (0.00%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Rash
subjects affected / exposed ^[121]	2 / 158 (1.27%)	0 / 61 (0.00%)	1 / 122 (0.82%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
Rash maculo-papular
subjects affected / exposed ^[122]	1 / 158 (0.63%)	0 / 61 (0.00%)	0 / 122 (0.00%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed ^[123]	2 / 158 (1.27%)	1 / 61 (1.64%)	0 / 122 (0.00%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	1 / 2	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal failure
subjects affected / exposed ^[124]	1 / 158 (0.63%)	0 / 61 (0.00%)	2 / 122 (1.64%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Endocrine disorders
Adrenal insufficiency
subjects affected / exposed ^[125]	0 / 158 (0.00%)	0 / 61 (0.00%)	2 / 122 (1.64%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypophysitis
subjects affected / exposed ^[126]	0 / 158 (0.00%)	0 / 61 (0.00%)	2 / 122 (1.64%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Adrenocortical insufficiency acute
subjects affected / exposed ^[127]	0 / 158 (0.00%)	1 / 61 (1.64%)	0 / 122 (0.00%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed ^[128]	1 / 158 (0.63%)	0 / 61 (0.00%)	0 / 122 (0.00%)	1 / 82 (1.22%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Neck pain
subjects affected / exposed ^[129]	1 / 158 (0.63%)	0 / 61 (0.00%)	0 / 122 (0.00%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Spinal pain
subjects affected / exposed ^[130]	0 / 158 (0.00%)	0 / 61 (0.00%)	1 / 122 (0.82%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pathological fracture
subjects affected / exposed ^[131]	1 / 158 (0.63%)	0 / 61 (0.00%)	1 / 122 (0.82%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Osteonecrosis
subjects affected / exposed ^[132]	0 / 158 (0.00%)	0 / 61 (0.00%)	1 / 122 (0.82%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Abscess neck
subjects affected / exposed ^[133]	1 / 158 (0.63%)	0 / 61 (0.00%)	0 / 122 (0.00%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bacteraemia
subjects affected / exposed ^[134]	1 / 158 (0.63%)	0 / 61 (0.00%)	0 / 122 (0.00%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cellulitis
subjects affected / exposed ^[135]	2 / 158 (1.27%)	0 / 61 (0.00%)	0 / 122 (0.00%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Encephalitis
subjects affected / exposed ^[136]	0 / 158 (0.00%)	0 / 61 (0.00%)	0 / 122 (0.00%)	1 / 82 (1.22%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Empyema
subjects affected / exposed ^[137]	0 / 158 (0.00%)	1 / 61 (1.64%)	0 / 122 (0.00%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Influenza
subjects affected / exposed ^[138]	0 / 158 (0.00%)	0 / 61 (0.00%)	1 / 122 (0.82%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lower respiratory tract infection
subjects affected / exposed ^[139]	1 / 158 (0.63%)	0 / 61 (0.00%)	0 / 122 (0.00%)	1 / 82 (1.22%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ludwig angina
subjects affected / exposed ^[140]	0 / 158 (0.00%)	0 / 61 (0.00%)	1 / 122 (0.82%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Endocarditis
subjects affected / exposed ^[141]	0 / 158 (0.00%)	0 / 61 (0.00%)	0 / 122 (0.00%)	1 / 82 (1.22%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Epiglottitis
subjects affected / exposed ^[142]	0 / 158 (0.00%)	0 / 61 (0.00%)	1 / 122 (0.82%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Focal peritonitis
subjects affected / exposed ^[143]	0 / 158 (0.00%)	0 / 61 (0.00%)	1 / 122 (0.82%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed ^[144]	0 / 158 (0.00%)	0 / 61 (0.00%)	1 / 122 (0.82%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatic infection bacterial
subjects affected / exposed ^[145]	0 / 158 (0.00%)	0 / 61 (0.00%)	1 / 122 (0.82%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Herpes zoster
subjects affected / exposed ^[146]	1 / 158 (0.63%)	0 / 61 (0.00%)	0 / 122 (0.00%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infective myositis
subjects affected / exposed ^[147]	0 / 158 (0.00%)	1 / 61 (1.64%)	0 / 122 (0.00%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lymph node abscess
subjects affected / exposed ^[148]	0 / 158 (0.00%)	1 / 61 (1.64%)	0 / 122 (0.00%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Neutropenic sepsis
subjects affected / exposed ^[149]	0 / 158 (0.00%)	0 / 61 (0.00%)	0 / 122 (0.00%)	1 / 82 (1.22%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Oral infection
subjects affected / exposed ^[150]	0 / 158 (0.00%)	1 / 61 (1.64%)	0 / 122 (0.00%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumococcal sepsis
subjects affected / exposed ^[151]	0 / 158 (0.00%)	0 / 61 (0.00%)	0 / 122 (0.00%)	1 / 82 (1.22%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Sepsis syndrome
subjects affected / exposed ^[152]	1 / 158 (0.63%)	0 / 61 (0.00%)	0 / 122 (0.00%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia aspiration
subjects affected / exposed ^[153]	2 / 158 (1.27%)	1 / 61 (1.64%)	3 / 122 (2.46%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
Pneumonia pseudomonal
subjects affected / exposed ^[154]	0 / 158 (0.00%)	0 / 61 (0.00%)	1 / 122 (0.82%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed ^[155]	1 / 158 (0.63%)	1 / 61 (1.64%)	0 / 122 (0.00%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed ^[156]	18 / 158 (11.39%)	4 / 61 (6.56%)	10 / 122 (8.20%)	5 / 82 (6.10%)
occurrences causally related to treatment / all	0 / 19	0 / 5	0 / 13	0 / 6
deaths causally related to treatment / all	0 / 6	0 / 1	0 / 0	0 / 1
Septic shock
subjects affected / exposed ^[157]	0 / 158 (0.00%)	1 / 61 (1.64%)	0 / 122 (0.00%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Sinusitis
subjects affected / exposed ^[158]	0 / 158 (0.00%)	0 / 61 (0.00%)	0 / 122 (0.00%)	1 / 82 (1.22%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Skin infection
subjects affected / exposed ^[159]	0 / 158 (0.00%)	1 / 61 (1.64%)	1 / 122 (0.82%)	1 / 82 (1.22%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Staphylococcal bacteraemia
subjects affected / exposed ^[160]	0 / 158 (0.00%)	0 / 61 (0.00%)	0 / 122 (0.00%)	2 / 82 (2.44%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Staphylococcal scalded skin syndrome
subjects affected / exposed ^[161]	0 / 158 (0.00%)	0 / 61 (0.00%)	1 / 122 (0.82%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Subcutaneous abscess
subjects affected / exposed ^[162]	0 / 158 (0.00%)	0 / 61 (0.00%)	0 / 122 (0.00%)	1 / 82 (1.22%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Tracheitis
subjects affected / exposed ^[163]	2 / 158 (1.27%)	0 / 61 (0.00%)	0 / 122 (0.00%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Tracheobronchitis
subjects affected / exposed ^[164]	1 / 158 (0.63%)	0 / 61 (0.00%)	0 / 122 (0.00%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Viral myocarditis
subjects affected / exposed ^[165]	0 / 158 (0.00%)	0 / 61 (0.00%)	0 / 122 (0.00%)	1 / 82 (1.22%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Vascular access site infection
subjects affected / exposed ^[166]	1 / 158 (0.63%)	0 / 61 (0.00%)	0 / 122 (0.00%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed ^[167]	1 / 158 (0.63%)	1 / 61 (1.64%)	2 / 122 (1.64%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
Tracheostomy infection
subjects affected / exposed ^[168]	0 / 158 (0.00%)	1 / 61 (1.64%)	1 / 122 (0.82%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Upper respiratory tract infection
subjects affected / exposed ^[169]	0 / 158 (0.00%)	0 / 61 (0.00%)	1 / 122 (0.82%)	2 / 82 (2.44%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Viral upper respiratory tract infection
subjects affected / exposed ^[170]	1 / 158 (0.63%)	0 / 61 (0.00%)	0 / 122 (0.00%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Diabetes mellitus
subjects affected / exposed ^[171]	0 / 158 (0.00%)	0 / 61 (0.00%)	2 / 122 (1.64%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dehydration
subjects affected / exposed ^[172]	4 / 158 (2.53%)	0 / 61 (0.00%)	2 / 122 (1.64%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Failure to thrive
subjects affected / exposed ^[173]	0 / 158 (0.00%)	0 / 61 (0.00%)	1 / 122 (0.82%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Electrolyte imbalance
subjects affected / exposed ^[174]	0 / 158 (0.00%)	0 / 61 (0.00%)	1 / 122 (0.82%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Feeding disorder
subjects affected / exposed ^[175]	1 / 158 (0.63%)	0 / 61 (0.00%)	0 / 122 (0.00%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hyperkalaemia
subjects affected / exposed ^[176]	0 / 158 (0.00%)	0 / 61 (0.00%)	0 / 122 (0.00%)	1 / 82 (1.22%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hyperglycaemia
subjects affected / exposed ^[177]	0 / 158 (0.00%)	0 / 61 (0.00%)	1 / 122 (0.82%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypercalcaemia
subjects affected / exposed ^[178]	6 / 158 (3.80%)	1 / 61 (1.64%)	1 / 122 (0.82%)	2 / 82 (2.44%)
occurrences causally related to treatment / all	0 / 6	0 / 1	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
Malnutrition
subjects affected / exposed ^[179]	1 / 158 (0.63%)	0 / 61 (0.00%)	0 / 122 (0.00%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hyponatraemia
subjects affected / exposed ^[180]	2 / 158 (1.27%)	1 / 61 (1.64%)	0 / 122 (0.00%)	2 / 82 (2.44%)
occurrences causally related to treatment / all	0 / 2	1 / 1	0 / 0	2 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypokalaemia
subjects affected / exposed ^[181]	1 / 158 (0.63%)	0 / 61 (0.00%)	0 / 122 (0.00%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypernatraemia
subjects affected / exposed ^[182]	0 / 158 (0.00%)	0 / 61 (0.00%)	1 / 122 (0.82%)	0 / 82 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0

Notes
[1] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[2] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[3] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[4] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[5] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[6] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[7] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[8] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[9] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[10] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[11] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[12] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[13] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[14] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[15] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[16] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[17] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[18] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[19] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[20] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[21] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[22] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[23] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[24] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[25] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[26] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[27] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[28] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[29] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[30] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[31] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[32] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[33] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[34] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[35] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[36] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[37] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[38] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[39] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[40] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[41] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[42] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[43] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[44] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[45] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[46] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[47] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[48] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[49] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[50] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[51] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[52] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[53] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[54] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[55] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[56] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[57] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[58] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[59] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[60] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[61] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[62] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[63] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[64] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[65] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[66] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[67] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[68] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[69] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[70] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[71] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[72] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[73] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[74] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[75] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[76] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[77] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[78] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[79] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[80] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[81] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[82] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[83] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[84] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[85] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[86] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[87] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[88] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[89] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[90] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[91] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[92] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[93] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[94] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[95] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[96] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[97] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[98] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[99] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[100] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[101] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[102] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[103] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[104] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[105] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[106] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[107] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[108] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[109] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[110] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[111] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[112] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[113] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[114] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[115] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[116] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[117] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[118] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[119] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[120] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[121] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[122] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[123] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[124] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[125] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[126] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[127] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[128] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[129] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[130] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[131] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[132] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[133] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[134] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[135] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[136] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[137] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[138] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[139] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[140] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[141] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[142] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[143] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[144] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[145] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[146] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[147] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[148] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[149] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[150] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[151] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[152] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[153] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[154] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[155] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[156] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[157] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[158] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[159] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[160] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[161] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[162] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[163] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[164] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[165] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[166] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[167] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[168] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[169] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[170] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[171] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[172] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[173] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[174] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[175] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[176] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[177] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[178] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[179] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[180] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[181] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[182] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants

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

Non-serious adverse events	Treatment A - Platinum Refractory Subgroup	Treatment B - Platinum Eligible Subgroup	Treatment A - Platinum Eligible Subgroup	Treatment B - Platinum Refractory Subgroup
Total subjects affected by non serious adverse events
subjects affected / exposed	139 / 159 (87.42%)	54 / 61 (88.52%)	118 / 123 (95.93%)	76 / 82 (92.68%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cancer pain
subjects affected / exposed ^[183]	3 / 158 (1.90%)	4 / 61 (6.56%)	2 / 122 (1.64%)	1 / 82 (1.22%)
occurrences all number	3	4	2	1
Vascular disorders
Hypotension
subjects affected / exposed ^[184]	6 / 158 (3.80%)	6 / 61 (9.84%)	5 / 122 (4.10%)	2 / 82 (2.44%)
occurrences all number	7	6	7	2
Hypertension
subjects affected / exposed ^[185]	2 / 158 (1.27%)	4 / 61 (6.56%)	5 / 122 (4.10%)	3 / 82 (3.66%)
occurrences all number	2	4	5	4
General disorders and administration site conditions
Asthenia
subjects affected / exposed ^[186]	27 / 158 (17.09%)	7 / 61 (11.48%)	13 / 122 (10.66%)	14 / 82 (17.07%)
occurrences all number	42	13	18	16
Chills
subjects affected / exposed ^[187]	2 / 158 (1.27%)	0 / 61 (0.00%)	7 / 122 (5.74%)	0 / 82 (0.00%)
occurrences all number	3	0	7	0
Face oedema
subjects affected / exposed ^[188]	9 / 158 (5.70%)	2 / 61 (3.28%)	7 / 122 (5.74%)	3 / 82 (3.66%)
occurrences all number	9	3	7	3
Fatigue
subjects affected / exposed ^[189]	29 / 158 (18.35%)	22 / 61 (36.07%)	46 / 122 (37.70%)	21 / 82 (25.61%)
occurrences all number	31	22	55	22
Mucosal inflammation
subjects affected / exposed ^[190]	9 / 158 (5.70%)	2 / 61 (3.28%)	8 / 122 (6.56%)	4 / 82 (4.88%)
occurrences all number	9	2	9	5
Pyrexia
subjects affected / exposed ^[191]	15 / 158 (9.49%)	5 / 61 (8.20%)	15 / 122 (12.30%)	9 / 82 (10.98%)
occurrences all number	16	8	20	12
Oedema peripheral
subjects affected / exposed ^[192]	7 / 158 (4.43%)	1 / 61 (1.64%)	10 / 122 (8.20%)	6 / 82 (7.32%)
occurrences all number	7	1	10	6
Respiratory, thoracic and mediastinal disorders
Productive cough
subjects affected / exposed ^[193]	9 / 158 (5.70%)	7 / 61 (11.48%)	6 / 122 (4.92%)	2 / 82 (2.44%)
occurrences all number	12	8	6	2
Dyspnoea
subjects affected / exposed ^[194]	17 / 158 (10.76%)	9 / 61 (14.75%)	20 / 122 (16.39%)	11 / 82 (13.41%)
occurrences all number	17	12	22	12
Cough
subjects affected / exposed ^[195]	20 / 158 (12.66%)	9 / 61 (14.75%)	20 / 122 (16.39%)	8 / 82 (9.76%)
occurrences all number	22	13	21	13
Psychiatric disorders
Insomnia
subjects affected / exposed ^[196]	13 / 158 (8.23%)	5 / 61 (8.20%)	5 / 122 (4.10%)	7 / 82 (8.54%)
occurrences all number	14	5	7	9
Anxiety
subjects affected / exposed ^[197]	9 / 158 (5.70%)	4 / 61 (6.56%)	2 / 122 (1.64%)	4 / 82 (4.88%)
occurrences all number	9	4	2	4
Investigations
Aspartate aminotransferase increased
subjects affected / exposed ^[198]	9 / 158 (5.70%)	5 / 61 (8.20%)	11 / 122 (9.02%)	4 / 82 (4.88%)
occurrences all number	15	8	27	5
Amylase increased
subjects affected / exposed ^[199]	4 / 158 (2.53%)	3 / 61 (4.92%)	10 / 122 (8.20%)	5 / 82 (6.10%)
occurrences all number	7	6	19	13
Alanine aminotransferase increased
subjects affected / exposed ^[200]	8 / 158 (5.06%)	6 / 61 (9.84%)	7 / 122 (5.74%)	4 / 82 (4.88%)
occurrences all number	9	9	17	5
Blood alkaline phosphatase increased
subjects affected / exposed ^[201]	7 / 158 (4.43%)	3 / 61 (4.92%)	9 / 122 (7.38%)	9 / 82 (10.98%)
occurrences all number	17	4	16	13
Weight decreased
subjects affected / exposed ^[202]	20 / 158 (12.66%)	5 / 61 (8.20%)	25 / 122 (20.49%)	9 / 82 (10.98%)
occurrences all number	22	5	25	10
Lipase increased
subjects affected / exposed ^[203]	13 / 158 (8.23%)	5 / 61 (8.20%)	11 / 122 (9.02%)	4 / 82 (4.88%)
occurrences all number	18	10	17	4
Blood thyroid stimulating hormone increased
subjects affected / exposed ^[204]	4 / 158 (2.53%)	4 / 61 (6.56%)	5 / 122 (4.10%)	1 / 82 (1.22%)
occurrences all number	6	6	8	2
Blood creatinine increased
subjects affected / exposed ^[205]	11 / 158 (6.96%)	5 / 61 (8.20%)	7 / 122 (5.74%)	10 / 82 (12.20%)
occurrences all number	20	6	17	20
Injury, poisoning and procedural complications
Fall
subjects affected / exposed ^[206]	1 / 158 (0.63%)	4 / 61 (6.56%)	2 / 122 (1.64%)	1 / 82 (1.22%)
occurrences all number	1	5	3	1
Nervous system disorders
Headache
subjects affected / exposed ^[207]	14 / 158 (8.86%)	6 / 61 (9.84%)	11 / 122 (9.02%)	5 / 82 (6.10%)
occurrences all number	16	6	16	7
Dizziness
subjects affected / exposed ^[208]	8 / 158 (5.06%)	4 / 61 (6.56%)	5 / 122 (4.10%)	2 / 82 (2.44%)
occurrences all number	8	4	6	2
Blood and lymphatic system disorders
Lymphopenia
subjects affected / exposed ^[209]	12 / 158 (7.59%)	2 / 61 (3.28%)	0 / 122 (0.00%)	3 / 82 (3.66%)
occurrences all number	16	2	0	6
Anaemia
subjects affected / exposed ^[210]	41 / 158 (25.95%)	15 / 61 (24.59%)	30 / 122 (24.59%)	33 / 82 (40.24%)
occurrences all number	50	18	39	45
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed ^[211]	8 / 158 (5.06%)	4 / 61 (6.56%)	10 / 122 (8.20%)	5 / 82 (6.10%)
occurrences all number	14	4	15	8
Dysphagia
subjects affected / exposed ^[212]	16 / 158 (10.13%)	7 / 61 (11.48%)	18 / 122 (14.75%)	10 / 82 (12.20%)
occurrences all number	17	7	19	16
Nausea
subjects affected / exposed ^[213]	31 / 158 (19.62%)	13 / 61 (21.31%)	28 / 122 (22.95%)	18 / 82 (21.95%)
occurrences all number	41	18	38	34
Stomatitis
subjects affected / exposed ^[214]	2 / 158 (1.27%)	1 / 61 (1.64%)	6 / 122 (4.92%)	5 / 82 (6.10%)
occurrences all number	2	1	7	5
Vomiting
subjects affected / exposed ^[215]	18 / 158 (11.39%)	5 / 61 (8.20%)	14 / 122 (11.48%)	9 / 82 (10.98%)
occurrences all number	23	12	25	18
Dyspepsia
subjects affected / exposed ^[216]	6 / 158 (3.80%)	3 / 61 (4.92%)	7 / 122 (5.74%)	0 / 82 (0.00%)
occurrences all number	7	4	7	0
Abdominal pain upper
subjects affected / exposed ^[217]	7 / 158 (4.43%)	5 / 61 (8.20%)	4 / 122 (3.28%)	0 / 82 (0.00%)
occurrences all number	8	6	4	0
Constipation
subjects affected / exposed ^[218]	24 / 158 (15.19%)	9 / 61 (14.75%)	26 / 122 (21.31%)	14 / 82 (17.07%)
occurrences all number	32	10	28	16
Dry mouth
subjects affected / exposed ^[219]	11 / 158 (6.96%)	3 / 61 (4.92%)	9 / 122 (7.38%)	4 / 82 (4.88%)
occurrences all number	12	3	9	5
Diarrhoea
subjects affected / exposed ^[220]	33 / 158 (20.89%)	15 / 61 (24.59%)	27 / 122 (22.13%)	17 / 82 (20.73%)
occurrences all number	52	20	39	30
Skin and subcutaneous tissue disorders
Dry skin
subjects affected / exposed ^[221]	10 / 158 (6.33%)	1 / 61 (1.64%)	6 / 122 (4.92%)	5 / 82 (6.10%)
occurrences all number	10	1	6	11
Pruritus
subjects affected / exposed ^[222]	33 / 158 (20.89%)	10 / 61 (16.39%)	24 / 122 (19.67%)	6 / 82 (7.32%)
occurrences all number	46	13	29	9
Rash
subjects affected / exposed ^[223]	32 / 158 (20.25%)	6 / 61 (9.84%)	19 / 122 (15.57%)	9 / 82 (10.98%)
occurrences all number	49	7	25	14
Erythema
subjects affected / exposed ^[224]	3 / 158 (1.90%)	1 / 61 (1.64%)	8 / 122 (6.56%)	3 / 82 (3.66%)
occurrences all number	3	2	9	4
Endocrine disorders
Hyperthyroidism
subjects affected / exposed ^[225]	12 / 158 (7.59%)	1 / 61 (1.64%)	11 / 122 (9.02%)	4 / 82 (4.88%)
occurrences all number	13	1	11	4
Hypothyroidism
subjects affected / exposed ^[226]	28 / 158 (17.72%)	12 / 61 (19.67%)	23 / 122 (18.85%)	10 / 82 (12.20%)
occurrences all number	29	15	23	11
Musculoskeletal and connective tissue disorders
Neck pain
subjects affected / exposed ^[227]	18 / 158 (11.39%)	9 / 61 (14.75%)	7 / 122 (5.74%)	11 / 82 (13.41%)
occurrences all number	23	12	7	12
Myalgia
subjects affected / exposed ^[228]	5 / 158 (3.16%)	3 / 61 (4.92%)	8 / 122 (6.56%)	3 / 82 (3.66%)
occurrences all number	5	4	8	3
Back pain
subjects affected / exposed ^[229]	10 / 158 (6.33%)	5 / 61 (8.20%)	12 / 122 (9.84%)	11 / 82 (13.41%)
occurrences all number	10	5	13	12
Arthralgia
subjects affected / exposed ^[230]	20 / 158 (12.66%)	10 / 61 (16.39%)	18 / 122 (14.75%)	9 / 82 (10.98%)
occurrences all number	21	10	21	11
Infections and infestations
Pneumonia
subjects affected / exposed ^[231]	10 / 158 (6.33%)	2 / 61 (3.28%)	8 / 122 (6.56%)	5 / 82 (6.10%)
occurrences all number	13	3	9	6
Oral candidiasis
subjects affected / exposed ^[232]	9 / 158 (5.70%)	2 / 61 (3.28%)	1 / 122 (0.82%)	2 / 82 (2.44%)
occurrences all number	9	2	1	2
Nasopharyngitis
subjects affected / exposed ^[233]	2 / 158 (1.27%)	4 / 61 (6.56%)	6 / 122 (4.92%)	1 / 82 (1.22%)
occurrences all number	2	6	8	3
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed ^[234]	21 / 158 (13.29%)	8 / 61 (13.11%)	25 / 122 (20.49%)	17 / 82 (20.73%)
occurrences all number	22	8	29	18
Hypercalcaemia
subjects affected / exposed ^[235]	18 / 158 (11.39%)	4 / 61 (6.56%)	11 / 122 (9.02%)	10 / 82 (12.20%)
occurrences all number	21	5	12	13
Hyperglycaemia
subjects affected / exposed ^[236]	5 / 158 (3.16%)	4 / 61 (6.56%)	5 / 122 (4.10%)	4 / 82 (4.88%)
occurrences all number	6	5	7	4
Hyperkalaemia
subjects affected / exposed ^[237]	7 / 158 (4.43%)	1 / 61 (1.64%)	0 / 122 (0.00%)	8 / 82 (9.76%)
occurrences all number	7	2	0	11
Hypokalaemia
subjects affected / exposed ^[238]	5 / 158 (3.16%)	3 / 61 (4.92%)	12 / 122 (9.84%)	2 / 82 (2.44%)
occurrences all number	5	3	16	2
Hypomagnesaemia
subjects affected / exposed ^[239]	8 / 158 (5.06%)	6 / 61 (9.84%)	9 / 122 (7.38%)	6 / 82 (7.32%)
occurrences all number	8	10	13	6
Hyponatraemia
subjects affected / exposed ^[240]	11 / 158 (6.96%)	5 / 61 (8.20%)	14 / 122 (11.48%)	11 / 82 (13.41%)
occurrences all number	21	7	18	14

Notes
[183] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[184] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[185] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[186] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[187] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[188] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[189] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[190] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[191] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[192] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[193] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[194] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[195] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[196] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[197] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[198] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[199] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[200] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[201] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[202] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[203] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[204] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[205] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[206] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[207] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[208] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[209] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[210] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[211] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[212] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[213] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[214] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[215] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[216] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[217] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[218] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[219] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[220] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[221] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[222] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[223] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[224] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[225] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[226] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[227] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participantsNumber exposed is reflecting all randomized participants
[228] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[229] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[230] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[231] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[232] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[233] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[234] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[235] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[236] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[237] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[238] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[239] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants
[240] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: Number exposed is reflecting all randomized participants

More information

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Were there any global substantial amendments to the protocol? Yes

19 Jul 2016

PK and IMG Follow up visit samples no longer required to be collected; Updated Biomarker sample collection schedule; Updated Contraceptive language; Updated Algorithms for Renal, Hepatic, Pulmonary and Skin to match with updated Nivolumab IB v15 (includes Nivo IB 15 erratum update). Other minor edits, clarifications, corrections

27 Jun 2017

1. Increase in the size of the platinum eligible population in order to provide greater statistical precision 2. Alignment of protocol with responses to regulatory authorities 3. Minor changes to eligibility criteria and study processes 4. Clarification of outstanding issues and correction of typographical errors

14 Nov 2017

To clarify additional detail about existing endpoints To provide clarity on the planned interim descriptive analyses for the platinum eligible cohort. Necessary window shortened in light of evolving data on radiotherapy plus immuno-oncology agents. Clarification of applicability to palliative and curative settings. To provide clarity, eliminate redundancy, and to align with the nivolumab program standards.

25 May 2018

Tumor mutational burden has been shown to be a predictive biomarker of efficacy for checkpoint inhibitors in several tumors. Therefore, it is important to elevate this endpoint To establish the methods which will be used to analyze the primary and secondary objective of the study. Provide clarification to sites regarding time permitted for treatment beyond progression, to align with recent evidence (CA209153) indicating limited activity of retreatment. Myocarditis is a potential serious adverse event for immunooncology agents. This guidance was included to reduce the risk of serious outcomes for subjects. To provide clarity that the sponsor will remain blinded to both cohorts until the time of the interim analysis.

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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Baseline characteristics

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Primary: Objective Response Rate (ORR) as determined by Blinded Independent Central Review (BIRC) - Platinum refractory subgroup

Primary: Objective Response Rate (ORR) as determined by Blinded Independent Central Review (BIRC) - Platinum refractory subgroup

Primary: Duration of Response (DOR) as determined by Blinded Independent Central Review (BIRC) - Platinum refractory subgroup

Primary: Duration of Response (DOR) as determined by Blinded Independent Central Review (BIRC) - Platinum refractory subgroup

Primary: Time to Response (TTR) as determined by Blinded Independent Central Review (BIRC) - Platinum refractory subgroup

Primary: Time to Response (TTR) as determined by Blinded Independent Central Review (BIRC) - Platinum refractory subgroup

Secondary: Objective Response Rate (ORR) as determined by Blinded Independent Central Review (BIRC) - Platinum Eligible subgroup

Secondary: Objective Response Rate (ORR) as determined by Blinded Independent Central Review (BIRC) - Platinum Eligible subgroup

Secondary: Duration of Response (DOR) as determined by Blinded Independent Central Review (BIRC) - Platinum Eligible subgroup

Secondary: Duration of Response (DOR) as determined by Blinded Independent Central Review (BIRC) - Platinum Eligible subgroup

Secondary: Progression Free Survival (PFS) as determined by Blinded Independent Central Review (BIRC) - Platinum Refractory subgroup

Secondary: Progression Free Survival (PFS) as determined by Blinded Independent Central Review (BIRC) - Platinum Refractory subgroup

Secondary: Progression Free Survival (PFS) as determined by Blinded Independent Central Review (BIRC) - Platinum Eligible subgroup

Secondary: Progression Free Survival (PFS) as determined by Blinded Independent Central Review (BIRC) - Platinum Eligible subgroup

Secondary: Overall Survival (OS)

Secondary: Overall Survival (OS)

Secondary: Overall Survival (OS) - Platinum Refractory Subgroup

Secondary: Overall Survival (OS) - Platinum Refractory Subgroup

Secondary: Overall Survival (OS) - Platinum Eligible Subgroup

Secondary: Overall Survival (OS) - Platinum Eligible Subgroup

Secondary: ORR - Platinum Eligible Subgroup based on HPV p-16 status

Secondary: ORR - Platinum Eligible Subgroup based on HPV p-16 status

Secondary: ORR - Platinum Eligible Subgroup based on Tumor Mutation Burden (TMB) Biomarker

Secondary: ORR - Platinum Eligible Subgroup based on Tumor Mutation Burden (TMB) Biomarker

Secondary: ORR - Platinum Refractory Subgroup based on HPV p-16 Status

Secondary: ORR - Platinum Refractory Subgroup based on HPV p-16 Status

Secondary: ORR - Platinum Refractory Subgroup based on Tumor Mutation Burden (TMB) Biomarker

Secondary: ORR - Platinum Refractory Subgroup based on Tumor Mutation Burden (TMB) Biomarker

Secondary: Duration of Response (DOR) - Platinum Refractory subgroup based on HPV p-16 Status

Secondary: Duration of Response (DOR) - Platinum Refractory subgroup based on HPV p-16 Status

Secondary: Duration of Response (DOR) - Platinum Refractory subgroup based on Tumor Mutation Burden (TMB) Status

Secondary: Duration of Response (DOR) - Platinum Refractory subgroup based on Tumor Mutation Burden (TMB) Status

Secondary: Progression Free Survival (PFS) - Platinum Refractory subgroup based on HPV p-16 Status

Secondary: Progression Free Survival (PFS) - Platinum Refractory subgroup based on HPV p-16 Status

Secondary: Progression Free Survival (PFS) - Platinum Refractory subgroup Based on Tumor Mutation Burden (TMB) Status

Secondary: Progression Free Survival (PFS) - Platinum Refractory subgroup Based on Tumor Mutation Burden (TMB) Status

Secondary: Overall Survival (OS) - Platinum Refractory Subgroup based on HPV p-16 status

Secondary: Overall Survival (OS) - Platinum Refractory Subgroup based on HPV p-16 status

Secondary: Overall Survival (OS) - Platinum Refractory Subgroup based on Tumor Mutation Burden (TMB) status

Secondary: Overall Survival (OS) - Platinum Refractory Subgroup based on Tumor Mutation Burden (TMB) status

Secondary: Overall Survival (OS) - Platinum Eligible Subgroup based on HPV p-16 status

Secondary: Overall Survival (OS) - Platinum Eligible Subgroup based on HPV p-16 status

Secondary: Overall Survival (OS) - Platinum Eligible Subgroup based on Tumor Mutation Burden (TMB) status

Secondary: Overall Survival (OS) - Platinum Eligible Subgroup based on Tumor Mutation Burden (TMB) status

Secondary: Progression Free Survival (PFS) - Platinum Eligible subgroup Based on Tumor Mutation Burden (TMB) Status

Secondary: Progression Free Survival (PFS) - Platinum Eligible subgroup Based on Tumor Mutation Burden (TMB) Status

Secondary: Progression Free Survival (PFS) - Platinum Eligible subgroup based on HPV p-16 Status

Secondary: Progression Free Survival (PFS) - Platinum Eligible subgroup based on HPV p-16 Status

Secondary: Duration of Response (DOR) - Platinum Eligible subgroup based on HPV p-16 Status

Secondary: Duration of Response (DOR) - Platinum Eligible subgroup based on HPV p-16 Status

Secondary: Duration of Response (DOR) - Platinum Eligible subgroup based on Tumor Mutation Burden (TMB) Status

Secondary: Duration of Response (DOR) - Platinum Eligible subgroup based on Tumor Mutation Burden (TMB) Status

Secondary: Duration of Response (DOR) - Platinum Refractory subgroup based on PD-L1 Status

Secondary: Duration of Response (DOR) - Platinum Refractory subgroup based on PD-L1 Status

Secondary: ORR - Platinum Refractory Subgroup based on PD-L1 Expression

Secondary: ORR - Platinum Refractory Subgroup based on PD-L1 Expression

Secondary: Overall Survival (OS) - Platinum Refractory Subgroup based on PD-L1 status

Secondary: Overall Survival (OS) - Platinum Refractory Subgroup based on PD-L1 status

Secondary: Progression Free Survival (PFS) - Platinum Refractory subgroup based on PD-L1 Status

Secondary: Progression Free Survival (PFS) - Platinum Refractory subgroup based on PD-L1 Status

Secondary: Duration of Response (DOR) - Platinum Eligible subgroup based on PD-L1 Status

Secondary: Duration of Response (DOR) - Platinum Eligible subgroup based on PD-L1 Status

Secondary: ORR - Platinum Eligible Subgroup based on PD-L1 Expression

Secondary: ORR - Platinum Eligible Subgroup based on PD-L1 Expression

Secondary: Overall Survival (OS) - Platinum Eligible Subgroup based on PD-L1 status

Secondary: Overall Survival (OS) - Platinum Eligible Subgroup based on PD-L1 status

Secondary: Progression Free Survival (PFS) - Platinum Eligible subgroup based on PD-L1 Status

Secondary: Progression Free Survival (PFS) - Platinum Eligible subgroup based on PD-L1 Status

Post-hoc: Objective Response Rate (ORR) as determined by Blinded Independent Central Review (BIRC) - Platinum refractory subgroup - Post Hoc Analysis

Post-hoc: Objective Response Rate (ORR) as determined by Blinded Independent Central Review (BIRC) - Platinum refractory subgroup - Post Hoc Analysis

Post-hoc: Duration of Response (DOR) as determined by Blinded Independent Central Review (BIRC) - Platinum refractory subgroup - Post Hoc Analysis