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Clinical Trial Results:
Open-Label, Randomized Trial of Nivolumab (BMS-936558) plus Pemetrexed/Platinum or Nivolumab plus Ipilimumab (BMS-734016) vs Pemetrexed plus Platinum in Stage IV or Recurrent Non-Small Cell Lung Cancer (NSCLC) Subjects with Epidermal Growth Factor Receptor (EGFR) Mutation Who Failed 1L or 2L EGFR Tyrosine Kinase Inhibitor Therapy: CheckMate 722: CHECKpoint pathway and nivoluMAb clinical Trial Evaluation 722.

Summary
EudraCT number	2017-002672-38
Trial protocol	ES
Global end of trial date	17 Oct 2022

Results information
Results version number	v1(current)
This version publication date	22 Sep 2023
First version publication date	22 Sep 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

CA209-722

ISRCTN number

US NCT number

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.com

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

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

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

Analysis stage

Final

Date of interim/final analysis

06 Dec 2022

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

17 Oct 2022

Was the trial ended prematurely?

Main objective of the trial

To compare the PFS by BICR of nivolumab plus pemetrexed/platinum to pemetrexed plus platinum in EGFR mutation positive (ie, G719X, L861Q, Del 19, and L858R), metastatic or recurrent NSCLC that has progressed on 1L or 2L EGFR TKI.

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 participants were followed.

Background therapy

Evidence for comparator

Actual start date of recruitment

17 Mar 2017

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

China: 54

Country: Number of subjects enrolled

France: 17

Country: Number of subjects enrolled

Hong Kong: 8

Country: Number of subjects enrolled

Japan: 100

Country: Number of subjects enrolled

Korea, Democratic People's Republic of: 91

Country: Number of subjects enrolled

Singapore: 13

Country: Number of subjects enrolled

Spain: 7

Country: Number of subjects enrolled

Taiwan: 74

Country: Number of subjects enrolled

United States: 3

Worldwide total number of subjects

367

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

211

From 65 to 84 years

155

85 years and over

Subject disposition

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Recruitment details

Screening details

367 participants were randomized; 355 participants were treated.

Period 1 title

Pre-Treatment

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Arm A: Nivolumab plus Platinum-doublet Chemotherapy

Arm description

Nivolumab was administered IV every 3 weeks with platinum-doublet chemotherapy (investigator’s choice of cisplatin or carboplatin) IV for a maximum of 4 cycles. Treatment administered was either Nivolumab 360 mg IV, followed by pemetrexed (500 mg/m2) with cisplatin (75 mg/m2) administered on Day 1 of each cycle OR Nivolumab 360 mg IV, followed by pemetrexed (500 mg/m2) with carboplatin (AUC 5 or 6) administered on Day 1 of each cycle. Following completion of the fourth cycle of nivolumab/chemotherapy, all participants who did not experience disease progression should have continued nivolumab 360 mg IV and pemetrexed (500 mg/m2) every 3 weeks until the progression of disease, discontinuation due to toxicity, withdrawal of consent, or study closure, whichever comes first. Nivolumab should only be administered for a maximum of 24 months (96 weeks) from the first study treatment.

Arm type

Experimental

Investigational medicinal product name

Nivolumab

Investigational medicinal product code

Other name

BMS-936558-01

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

360 mg IV every 3 weeks for a maximum of 4 cycles

Investigational medicinal product name

Pemetrexed

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for concentrate, Concentrate and solvent for solution for injection

Routes of administration

Intravenous use

Dosage and administration details

500 mg/m2 on Day 1 of each Cycle

Investigational medicinal product name

Cisplatin

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

75 mg/m2 administered on Day 1 of each cycle

Investigational medicinal product name

Carboplatin

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

AUC 5 or 6 administered on Day 1 of each cycle

Arm B: Nivolumab plus Ipilimumab

Arm description

Nivolumab 3 mg/kg IV was administered every 2 weeks and ipilimumab 1 mg/kg IV was administered every 6 weeks until the progression of disease, discontinuation due to toxicity, withdrawal of consent, a maximum of 24 months (96 weeks) from the first study treatment, or study closure.

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

1 mg/kg IV every 6 weeks for a maximum of 24 months

Investigational medicinal product name

Nivolumab

Investigational medicinal product code

Other name

BMS-936558-01

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

360 mg IV every 3 weeks for a maximum of 4 cycles

Arm C: Platinum Doublet Chemotherapy

Arm description

Platinum-doublet chemotherapy (investigator’s choice of cisplatin or carboplatin) was administered IV in 3-week cycles for up to a maximum of 4 cycles. Participants received either Pemetrexed (500 mg/m2) with cisplatin (75 mg/m2) administered on Day 1 of each cycle OR Pemetrexed (500 mg/m2) with carboplatin (AUC 5 or 6) administered on Day 1 of each cycle. Platinum-doublet chemotherapy continued until disease progression, unacceptable toxicity, or completion of the 4 cycles, whichever came first. Participants who had stable disease or response after 4 cycles of pemetrexed with cisplatin or carboplatin should have continued pemetrexed alone as maintenance therapy until disease progression, or unacceptable toxicity.

Arm type

Active comparator

Investigational medicinal product name

Pemetrexed

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for concentrate, Concentrate and solvent for solution for injection

Routes of administration

Intravenous use

Dosage and administration details

500 mg/m2 on Day 1 of each Cycle

Investigational medicinal product name

Carboplatin

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

AUC 5 or 6 administered on Day 1 of each cycle

Investigational medicinal product name

Cisplatin

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

75 mg/m2 administered on Day 1 of each cycle

Number of subjects in period 1	Arm A: Nivolumab plus Platinum-doublet Chemotherapy	Arm B: Nivolumab plus Ipilimumab	Arm C: Platinum Doublet Chemotherapy
Started	144	73	150
Completed	141	71	143
Not completed	3	2	7
Withdrawal by Participant	-	-	4
Other Reasons	-	1	1
Adverse Event Unrelated to Study drug	1	-	-
Participant no Longer Meets Study Criteria	2	1	2

Period 2 title

Treatment

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Arm A: Nivolumab plus Platinum-doublet Chemotherapy

Arm description

Arm type

Experimental

Investigational medicinal product name

Nivolumab

Investigational medicinal product code

Other name

BMS-936558-01

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

360 mg IV every 3 weeks for a maximum of 4 cycles

Investigational medicinal product name

Carboplatin

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

AUC 5 or 6 administered on Day 1 of each cycle

Investigational medicinal product name

Cisplatin

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

75 mg/m2 administered on Day 1 of each cycle

Investigational medicinal product name

Pemetrexed

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for concentrate, Concentrate and solvent for solution for injection

Routes of administration

Intravenous use

Dosage and administration details

500 mg/m2 on Day 1 of each Cycle

Arm B: Nivolumab plus Ipilimumab

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

1 mg/kg IV every 6 weeks for a maximum of 24 months

Investigational medicinal product name

Nivolumab

Investigational medicinal product code

Other name

BMS-936558-01

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

360 mg IV every 3 weeks for a maximum of 4 cycles

Arm C: Platinum Doublet Chemotherapy

Arm description

Arm type

Experimental

Investigational medicinal product name

Pemetrexed

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for concentrate, Concentrate and solvent for solution for injection

Routes of administration

Intravenous use

Dosage and administration details

500 mg/m2 on Day 1 of each Cycle

Investigational medicinal product name

Carboplatin

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

AUC 5 or 6 administered on Day 1 of each cycle

Investigational medicinal product name

Cisplatin

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

75 mg/m2 administered on Day 1 of each cycle

Number of subjects in period 2	Arm A: Nivolumab plus Platinum-doublet Chemotherapy	Arm B: Nivolumab plus Ipilimumab	Arm C: Platinum Doublet Chemotherapy
Started	141	71	143
Completed	3	5	0
Not completed	138	66	143
Adverse event, serious fatal	-	2	3
Withdrawal by Participant	8	5	13
Other Reasons	1	1	4
Participant Req to Discontinue Study Treatment	8	-	5
Maximum Clinical Benefit	1	-	1
Study Drug Toxicity	9	4	10
Adverse Event Unrelated to Study drug	1	1	6
Participant no Longer Meets Study Criteria	-	1	-
Disease Progression	109	52	101
Administrative Reason by Sponsor	1	-	-

Baseline characteristics

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Reporting group title

Arm A: Nivolumab plus Platinum-doublet Chemotherapy

Reporting group description

Reporting group title

Arm B: Nivolumab plus Ipilimumab

Reporting group description

Reporting group title

Arm C: Platinum Doublet Chemotherapy

Reporting group description

Reporting group values	Arm A: Nivolumab plus Platinum-doublet Chemotherapy	Arm B: Nivolumab plus Ipilimumab	Arm C: Platinum Doublet Chemotherapy	Total
Number of subjects	144	73	150	367
Age categorical
Units: Subjects
In utero	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0
Newborns (0-27 days)	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0
Children (2-11 years)	0	0	0	0
Adolescents (12-17 years)	0	0	0	0
Adults (18-64 years)	75	44	92	211
From 65-84 years	69	29	57	155
85 years and over	0	0	1	1
Age Continuous
Units: Years
arithmetic mean (standard deviation)	62.3 ( 10.6 )	61.9 ( 10.6 )	60.7 ( 10.1 )	-
Sex: Female, Male
Units: Participants
Female	83	37	94	214
Male	61	36	56	153
Race (NIH/OMB)
Units: Subjects
American Indian or Alaska Native	0	0	0	0
Asian	136	68	139	343
Native Hawaiian or Other Pacific Islander	0	0	0	0
Black or African American	0	0	0	0
White	7	3	11	21
More than one race	0	0	0	0
Unknown or Not Reported	1	2	0	3
Ethnicity (NIH/OMB)
Units: Subjects
Hispanic or Latino	0	0	0	0
Not Hispanic or Latino	59	39	73	171
Unknown or Not Reported	85	34	77	196

End points

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Reporting group title

Arm A: Nivolumab plus Platinum-doublet Chemotherapy

Reporting group description

Reporting group title

Arm B: Nivolumab plus Ipilimumab

Reporting group description

Reporting group title

Arm C: Platinum Doublet Chemotherapy

Reporting group description

Reporting group title

Arm A: Nivolumab plus Platinum-doublet Chemotherapy

Reporting group description

Reporting group title

Arm B: Nivolumab plus Ipilimumab

Reporting group description

Reporting group title

Arm C: Platinum Doublet Chemotherapy

Reporting group description

Primary: Progression Free Survival (PFS) by Blinded Independent Centralized Review (BICR)

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End point title

Progression Free Survival (PFS) by Blinded Independent Centralized Review (BICR)

End point description

PFS is defined as the time between the date of randomization and the date of first documented tumor progression, as determined by BICR (per RECIST v1.1 criteria), or death due to any cause, whichever occurs first. Participants who died without reported progression will be considered to have progressed on the date of their death. Subsequent therapy was accounted for by censoring at the last evaluable tumor assessment on or prior to the date of subsequent therapy. Progression is the appearance of one or more new lesions. RECIST - "response evaluation criteria in solid tumors" is a standard system to measure tumor response to treatment. Based on Kaplan-Meier estimates

End point type

Primary

End point timeframe

From randomization to the date of first documented tumor progression or death (approximately 58 months)

End point values	Arm A: Nivolumab plus Platinum-doublet Chemotherapy	Arm B: Nivolumab plus Ipilimumab	Arm C: Platinum Doublet Chemotherapy
Number of subjects analysed	144	73	150
Units: Months
median (confidence interval 95%)	5.59 (4.47 to 6.80)	1.54 (1.41 to 2.63)	5.45 (4.40 to 5.65)

Hazard Ratio

Comparison groups

Arm B: Nivolumab plus Ipilimumab v Arm C: Platinum Doublet Chemotherapy

Number of subjects included in analysis

223

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Hazard ratio (HR)

Point estimate

2.07

Confidence interval

level

95%

sides

2-sided

lower limit

1.43

upper limit

2.99

Hazard Ratio

Comparison groups

Arm A: Nivolumab plus Platinum-doublet Chemotherapy v Arm C: Platinum Doublet Chemotherapy

Number of subjects included in analysis

294

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0528 ^[1]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.75

Confidence interval

level

95%

sides

2-sided

lower limit

0.56

upper limit

Notes
[1] - Log-rank test stratified by PD-L1 expression (>= 1% vs <1%/indeterminate/not evaluable), brain metastases (presence vs absence), smoking history (current/former vs never smoker), and prior osimertinib use (yes vs no) from IRT.

Secondary: Overall Survival (OS)

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End point title

Overall Survival (OS)

End point description

Overall Survival (OS) is defined as the time between the date of randomization and the date of death due to any cause. OS will be censored on the last date a participant was known to be alive. Median based on Kaplan-Meier Estimates

End point type

Secondary

End point timeframe

From randomization to the date of death due to any cause (up to approximately 67 months)

End point values	Arm A: Nivolumab plus Platinum-doublet Chemotherapy	Arm B: Nivolumab plus Ipilimumab	Arm C: Platinum Doublet Chemotherapy
Number of subjects analysed	144	73	150
Units: Months
median (confidence interval 95%)	19.35 (16.13 to 20.99)	17.12 (13.67 to 23.59)	15.90 (14.00 to 18.79)

Hazard Ratio

Comparison groups

Arm B: Nivolumab plus Ipilimumab v Arm C: Platinum Doublet Chemotherapy

Number of subjects included in analysis

223

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Hazard ratio (HR)

Point estimate

1.06

Confidence interval

level

95%

sides

2-sided

lower limit

0.75

upper limit

1.52

Hazard Ratio

Comparison groups

Arm A: Nivolumab plus Platinum-doublet Chemotherapy v Arm C: Platinum Doublet Chemotherapy

Number of subjects included in analysis

294

Analysis specification

Pre-specified

Analysis type

P-value

= 0.218

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.83

Confidence interval

level

95%

sides

2-sided

lower limit

0.62

upper limit

1.12

Secondary: Objective Response Rate (ORR) by Blinded Independent Centralized Review (BICR)

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End point title

Objective Response Rate (ORR) by Blinded Independent Centralized Review (BICR)

End point description

ORR is number of randomized participants who have confirmed best overall response (BOR) of complete response (CR) or partial response (PR) using RECIST v1.1 criteria by BICR assessment. BOR is the best response designation, between randomization and objectively documented progression per RECIST v1.1 criteria by BICR or the date of subsequent anti-cancer therapy, whichever occurs first. PR is at least a 30% decrease in the sum of diameters of target lesions, using the baseline sum diameters as reference. CR is disappearance of all target lesions and a reduction in the short axis of pathological lymph nodes to <10 mm (whether target or non-target). Radiographic tumor response assessments from Week 7 (± 7 days), then every 6 weeks (± 7 days) until Week 49 and every 12 weeks (± 7 days) thereafter, until disease progression, treatment discontinued, or the start of subsequent anti-cancer therapy. CR+PR, confidence interval based on the Clopper and Pearson method.

End point type

Secondary

End point timeframe

From randomization to the date of objectively documented progression, date of death, or the date of subsequent therapy (up to approximately 67 months)

End point values	Arm A: Nivolumab plus Platinum-doublet Chemotherapy	Arm B: Nivolumab plus Ipilimumab	Arm C: Platinum Doublet Chemotherapy
Number of subjects analysed	144	73	150
Units: Percent of Participants
number (confidence interval 95%)	30.6 (23.2 to 38.8)	13.7 (6.8 to 23.8)	26.7 (19.8 to 34.5)

Hazard Ratio

Comparison groups

Arm A: Nivolumab plus Platinum-doublet Chemotherapy v Arm C: Platinum Doublet Chemotherapy

Number of subjects included in analysis

294

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Odds ratio (OR)

Point estimate

1.27

Confidence interval

level

95%

sides

2-sided

lower limit

0.75

upper limit

2.16

Secondary: 12 Month Progression Free Survival Rates (PFSR) by Blinded Independent Centralized Review (BICR)

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End point title

12 Month Progression Free Survival Rates (PFSR) by Blinded Independent Centralized Review (BICR)

End point description

The PFSR at 12 months is defined as the percent of treated participants remaining progression free and surviving at 12 months since the first dosing date. Progression is the appearance of one or more new lesions. Point estimates are derived from Kaplan-Meier analyses.

End point type

Secondary

End point timeframe

12 Months after first treatment dose

End point values	Arm A: Nivolumab plus Platinum-doublet Chemotherapy	Arm B: Nivolumab plus Ipilimumab	Arm C: Platinum Doublet Chemotherapy
Number of subjects analysed	144	73	150
Units: Percent of Participants
number (confidence interval 95%)	21.2 (14.3 to 29.1)	12.2 (5.5 to 21.7)	15.9 (9.3 to 24.0)

No statistical analyses for this end point

Secondary: Duration of Response (DOR) by Blinded Independent Centralized Review (BICR)

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End point title

Duration of Response (DOR) by Blinded Independent Centralized Review (BICR)

End point description

DOR is the time between first response (CR or PR) and first documented disease progression as determined by Response Evaluation Criteria In Solid Tumors (RECIST 1.1) or death due to any cause (death occurring after re-treatment or randomization to new combination treatment not included), whichever occurred first. PR is at least a 30% decrease in the sum of diameters of target lesions, using baseline sum diameters as reference. CR is disappearance of all target lesions and a reduction in the short axis of pathological lymph nodes to <10 mm (target or non-target). Radiographic tumor response assessments from Week 7 (± 7 days), then every 6 weeks (± 7 days) until Week 49 and every 12 weeks (± 7 days) thereafter, until disease progression, treatment discontinued, or the start of subsequent anti-cancer therapy. Participants who neither progress nor die were censored on the date of their last assessment. 99999 = Not Available/ Not Applicable Median computed using Kaplan-Meier method

End point type

Secondary

End point timeframe

From randomization to the date of first documented disease progression or death due to any cause (approximately 67 months)

End point values	Arm A: Nivolumab plus Platinum-doublet Chemotherapy	Arm B: Nivolumab plus Ipilimumab	Arm C: Platinum Doublet Chemotherapy
Number of subjects analysed	44	10	40
Units: Months
median (confidence interval 95%)	6.67 (4.17 to 12.45)	50.04 (2.86 to 99999)	5.55 (4.07 to 9.92)

No statistical analyses for this end point

Secondary: 9 Month Progression Free Survival Rates (PFSR) by Blinded Independent Centralized Review (BICR)

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End point title

9 Month Progression Free Survival Rates (PFSR) by Blinded Independent Centralized Review (BICR)

End point description

The PFSR at 9 months is defined as the percent of treated participants remaining progression free and surviving at 9 months since the first dosing date. Progression is the appearance of one or more new lesions. Point estimates are derived from Kaplan-Meier analyses.

End point type

Secondary

End point timeframe

9 months after first treatment dose

End point values	Arm A: Nivolumab plus Platinum-doublet Chemotherapy	Arm B: Nivolumab plus Ipilimumab	Arm C: Platinum Doublet Chemotherapy
Number of subjects analysed	144	73	150
Units: Percent of Participants
number (confidence interval 95%)	25.9 (18.4 to 34.0)	12.2 (5.5 to 21.7)	19.8 (12.6 to 28.1)

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Serious Adverse Events (SAEs) and Non-Serious Adverse Events (NSAEs) was assessed from first dose to 100 days post the last dose of study therapy (up to approximately an average of 11 months and a maximum of 51 months).

Adverse event reporting additional description

The number at risk for SAEs and NSAEs represents all participants that received at least 1 dose of study therapy or similar.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

25.1

Reporting group title

Arm A: Nivolumab plus Platinum-doublet Chemotherapy

Reporting group description

Reporting group title

Arm C: Platinum Doublet Chemotherapy

Reporting group description

Reporting group title

Arm B: Nivolumab plus Ipilimumab

Reporting group description

Serious adverse events	Arm A: Nivolumab plus Platinum-doublet Chemotherapy	Arm C: Platinum Doublet Chemotherapy	Arm B: Nivolumab plus Ipilimumab
Total subjects affected by serious adverse events
subjects affected / exposed	77 / 141 (54.61%)	55 / 143 (38.46%)	46 / 71 (64.79%)
number of deaths (all causes)	91	104	55
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Lymphangiosis carcinomatosa
subjects affected / exposed	0 / 141 (0.00%)	0 / 143 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lung neoplasm malignant
subjects affected / exposed	0 / 141 (0.00%)	1 / 143 (0.70%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Cancer pain
subjects affected / exposed	2 / 141 (1.42%)	0 / 143 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 1
Brain cancer metastatic
subjects affected / exposed	0 / 141 (0.00%)	1 / 143 (0.70%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Plasma cell myeloma
subjects affected / exposed	1 / 141 (0.71%)	0 / 143 (0.00%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Non-small cell lung cancer
subjects affected / exposed	1 / 141 (0.71%)	0 / 143 (0.00%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Neoplasm progression
subjects affected / exposed	1 / 141 (0.71%)	1 / 143 (0.70%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Metastases to peritoneum
subjects affected / exposed	1 / 141 (0.71%)	0 / 143 (0.00%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Metastases to meninges
subjects affected / exposed	0 / 141 (0.00%)	2 / 143 (1.40%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal cancer
subjects affected / exposed	1 / 141 (0.71%)	0 / 143 (0.00%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Metastases to bone
subjects affected / exposed	0 / 141 (0.00%)	2 / 143 (1.40%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Malignant pleural effusion
subjects affected / exposed	1 / 141 (0.71%)	0 / 143 (0.00%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Malignant neoplasm progression
subjects affected / exposed	25 / 141 (17.73%)	22 / 143 (15.38%)	20 / 71 (28.17%)
occurrences causally related to treatment / all	0 / 27	0 / 29	0 / 22
deaths causally related to treatment / all	0 / 12	0 / 12	0 / 10
Malignant ascites
subjects affected / exposed	0 / 141 (0.00%)	1 / 143 (0.70%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Metastases to central nervous system
subjects affected / exposed	1 / 141 (0.71%)	0 / 143 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Tumour pain
subjects affected / exposed	2 / 141 (1.42%)	0 / 143 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Tumour associated fever
subjects affected / exposed	1 / 141 (0.71%)	0 / 143 (0.00%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Transitional cell carcinoma
subjects affected / exposed	0 / 141 (0.00%)	1 / 143 (0.70%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Vascular disorders
Deep vein thrombosis
subjects affected / exposed	3 / 141 (2.13%)	1 / 143 (0.70%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	1 / 3	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 1	0 / 0
Peripheral venous disease
subjects affected / exposed	0 / 141 (0.00%)	1 / 143 (0.70%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
General disorders and administration site conditions
Catheter site oedema
subjects affected / exposed	0 / 141 (0.00%)	1 / 143 (0.70%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Asthenia
subjects affected / exposed	0 / 141 (0.00%)	1 / 143 (0.70%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Fatigue
subjects affected / exposed	1 / 141 (0.71%)	0 / 143 (0.00%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Non-cardiac chest pain
subjects affected / exposed	0 / 141 (0.00%)	1 / 143 (0.70%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pain
subjects affected / exposed	0 / 141 (0.00%)	1 / 143 (0.70%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	3 / 141 (2.13%)	1 / 143 (0.70%)	2 / 71 (2.82%)
occurrences causally related to treatment / all	1 / 3	0 / 1	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Sudden death
subjects affected / exposed	1 / 141 (0.71%)	0 / 143 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 1
Swelling
subjects affected / exposed	0 / 141 (0.00%)	1 / 143 (0.70%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Reproductive system and breast disorders
Benign prostatic hyperplasia
subjects affected / exposed	0 / 141 (0.00%)	1 / 143 (0.70%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Postmenopausal haemorrhage
subjects affected / exposed	0 / 141 (0.00%)	1 / 143 (0.70%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Pulmonary haemorrhage
subjects affected / exposed	1 / 141 (0.71%)	1 / 143 (0.70%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Respiratory failure
subjects affected / exposed	0 / 141 (0.00%)	1 / 143 (0.70%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 1
Dyspnoea
subjects affected / exposed	0 / 141 (0.00%)	2 / 143 (1.40%)	5 / 71 (7.04%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 2
Interstitial lung disease
subjects affected / exposed	1 / 141 (0.71%)	1 / 143 (0.70%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	1 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	1 / 1	1 / 1	0 / 0
Pleural effusion
subjects affected / exposed	1 / 141 (0.71%)	3 / 143 (2.10%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonitis
subjects affected / exposed	5 / 141 (3.55%)	1 / 143 (0.70%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	6 / 6	1 / 1	1 / 1
deaths causally related to treatment / all	1 / 1	0 / 0	0 / 0
Pneumothorax
subjects affected / exposed	1 / 141 (0.71%)	1 / 143 (0.70%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Pulmonary embolism
subjects affected / exposed	1 / 141 (0.71%)	0 / 143 (0.00%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Psychiatric disorders
Insomnia
subjects affected / exposed	1 / 141 (0.71%)	0 / 143 (0.00%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Depression
subjects affected / exposed	0 / 141 (0.00%)	1 / 143 (0.70%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Delirium
subjects affected / exposed	0 / 141 (0.00%)	0 / 143 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Investigations
Alanine aminotransferase increased
subjects affected / exposed	0 / 141 (0.00%)	0 / 143 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Aspartate aminotransferase increased
subjects affected / exposed	0 / 141 (0.00%)	0 / 143 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Blood alkaline phosphatase increased
subjects affected / exposed	0 / 141 (0.00%)	1 / 143 (0.70%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Blood bilirubin increased
subjects affected / exposed	0 / 141 (0.00%)	0 / 143 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Blood creatine increased
subjects affected / exposed	1 / 141 (0.71%)	0 / 143 (0.00%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Blood creatinine increased
subjects affected / exposed	1 / 141 (0.71%)	0 / 143 (0.00%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gamma-glutamyltransferase increased
subjects affected / exposed	0 / 141 (0.00%)	1 / 143 (0.70%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Liver function test increased
subjects affected / exposed	1 / 141 (0.71%)	0 / 143 (0.00%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Neutrophil count decreased
subjects affected / exposed	0 / 141 (0.00%)	2 / 143 (1.40%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 0	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Platelet count decreased
subjects affected / exposed	1 / 141 (0.71%)	0 / 143 (0.00%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Subdural haemorrhage
subjects affected / exposed	1 / 141 (0.71%)	0 / 143 (0.00%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Femoral neck fracture
subjects affected / exposed	1 / 141 (0.71%)	0 / 143 (0.00%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hip fracture
subjects affected / exposed	1 / 141 (0.71%)	0 / 143 (0.00%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Post procedural discharge
subjects affected / exposed	0 / 141 (0.00%)	0 / 143 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Spinal compression fracture
subjects affected / exposed	1 / 141 (0.71%)	0 / 143 (0.00%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Spinal fracture
subjects affected / exposed	0 / 141 (0.00%)	1 / 143 (0.70%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Fall
subjects affected / exposed	0 / 141 (0.00%)	0 / 143 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Wrist fracture
subjects affected / exposed	1 / 141 (0.71%)	0 / 143 (0.00%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac disorders
Acute myocardial infarction
subjects affected / exposed	0 / 141 (0.00%)	1 / 143 (0.70%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Atrial fibrillation
subjects affected / exposed	1 / 141 (0.71%)	1 / 143 (0.70%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac tamponade
subjects affected / exposed	0 / 141 (0.00%)	0 / 143 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardio-respiratory arrest
subjects affected / exposed	0 / 141 (0.00%)	1 / 143 (0.70%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Pericardial effusion
subjects affected / exposed	0 / 141 (0.00%)	0 / 143 (0.00%)	2 / 71 (2.82%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Pericarditis
subjects affected / exposed	0 / 141 (0.00%)	0 / 143 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Prinzmetal angina
subjects affected / exposed	0 / 141 (0.00%)	0 / 143 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	1 / 1
Sinus bradycardia
subjects affected / exposed	1 / 141 (0.71%)	0 / 143 (0.00%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Immune-mediated myocarditis
subjects affected / exposed	0 / 141 (0.00%)	0 / 143 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nervous system disorders
Cerebral infarction
subjects affected / exposed	1 / 141 (0.71%)	0 / 143 (0.00%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Cervical cord compression
subjects affected / exposed	1 / 141 (0.71%)	0 / 143 (0.00%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Optic neuritis
subjects affected / exposed	1 / 141 (0.71%)	0 / 143 (0.00%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ischaemic stroke
subjects affected / exposed	1 / 141 (0.71%)	0 / 143 (0.00%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Intracranial pressure increased
subjects affected / exposed	0 / 141 (0.00%)	1 / 143 (0.70%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Hydrocephalus
subjects affected / exposed	1 / 141 (0.71%)	1 / 143 (0.70%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 1	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	1 / 141 (0.71%)	3 / 143 (2.10%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	1 / 1	3 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	1 / 1	0 / 1
Febrile neutropenia
subjects affected / exposed	1 / 141 (0.71%)	1 / 143 (0.70%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	0 / 1	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Neutropenia
subjects affected / exposed	1 / 141 (0.71%)	0 / 143 (0.00%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Myelosuppression
subjects affected / exposed	1 / 141 (0.71%)	1 / 143 (0.70%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	1 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Leukocytosis
subjects affected / exposed	1 / 141 (0.71%)	0 / 143 (0.00%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Pancytopenia
subjects affected / exposed	2 / 141 (1.42%)	0 / 143 (0.00%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Eye disorders
Cataract
subjects affected / exposed	1 / 141 (0.71%)	0 / 143 (0.00%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Ascites
subjects affected / exposed	0 / 141 (0.00%)	0 / 143 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Colitis
subjects affected / exposed	1 / 141 (0.71%)	0 / 143 (0.00%)	2 / 71 (2.82%)
occurrences causally related to treatment / all	1 / 1	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	1 / 1
Diarrhoea
subjects affected / exposed	0 / 141 (0.00%)	0 / 143 (0.00%)	2 / 71 (2.82%)
occurrences causally related to treatment / all	0 / 0	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Enteritis
subjects affected / exposed	1 / 141 (0.71%)	0 / 143 (0.00%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Inguinal hernia
subjects affected / exposed	1 / 141 (0.71%)	0 / 143 (0.00%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nausea
subjects affected / exposed	3 / 141 (2.13%)	0 / 143 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	2 / 3	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pancreatitis acute
subjects affected / exposed	1 / 141 (0.71%)	0 / 143 (0.00%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	4 / 141 (2.84%)	1 / 143 (0.70%)	2 / 71 (2.82%)
occurrences causally related to treatment / all	4 / 5	1 / 1	1 / 2
deaths causally related to treatment / all	1 / 1	0 / 0	0 / 1
Immune-mediated enterocolitis
subjects affected / exposed	0 / 141 (0.00%)	0 / 143 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	0 / 0	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Hepatic function abnormal
subjects affected / exposed	3 / 141 (2.13%)	0 / 143 (0.00%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	2 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Immune-mediated hepatitis
subjects affected / exposed	0 / 141 (0.00%)	0 / 143 (0.00%)	2 / 71 (2.82%)
occurrences causally related to treatment / all	0 / 0	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Drug eruption
subjects affected / exposed	1 / 141 (0.71%)	0 / 143 (0.00%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Rash
subjects affected / exposed	2 / 141 (1.42%)	0 / 143 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	1 / 2	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Rash maculo-papular
subjects affected / exposed	0 / 141 (0.00%)	0 / 143 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Stevens-Johnson syndrome
subjects affected / exposed	2 / 141 (1.42%)	0 / 143 (0.00%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Urticarial vasculitis
subjects affected / exposed	0 / 141 (0.00%)	1 / 143 (0.70%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	2 / 141 (1.42%)	1 / 143 (0.70%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 2	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nephrolithiasis
subjects affected / exposed	1 / 141 (0.71%)	0 / 143 (0.00%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pyelocaliectasis
subjects affected / exposed	0 / 141 (0.00%)	0 / 143 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Endocrine disorders
Inappropriate antidiuretic hormone secretion
subjects affected / exposed	1 / 141 (0.71%)	0 / 143 (0.00%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Hypopituitarism
subjects affected / exposed	0 / 141 (0.00%)	0 / 143 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Thyroiditis subacute
subjects affected / exposed	0 / 141 (0.00%)	0 / 143 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Arthritis
subjects affected / exposed	0 / 141 (0.00%)	1 / 143 (0.70%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Tenosynovitis stenosans
subjects affected / exposed	1 / 141 (0.71%)	0 / 143 (0.00%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Myositis
subjects affected / exposed	0 / 141 (0.00%)	0 / 143 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Immune-mediated myositis
subjects affected / exposed	0 / 141 (0.00%)	0 / 143 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Flank pain
subjects affected / exposed	1 / 141 (0.71%)	0 / 143 (0.00%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infections and infestations
Carbuncle
subjects affected / exposed	1 / 141 (0.71%)	0 / 143 (0.00%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Atypical pneumonia
subjects affected / exposed	0 / 141 (0.00%)	1 / 143 (0.70%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Breast cellulitis
subjects affected / exposed	0 / 141 (0.00%)	1 / 143 (0.70%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Cellulitis
subjects affected / exposed	3 / 141 (2.13%)	0 / 143 (0.00%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 5	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Clostridium difficile colitis
subjects affected / exposed	0 / 141 (0.00%)	0 / 143 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Device related infection
subjects affected / exposed	0 / 141 (0.00%)	0 / 143 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastroenteritis viral
subjects affected / exposed	1 / 141 (0.71%)	0 / 143 (0.00%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Herpes zoster
subjects affected / exposed	1 / 141 (0.71%)	0 / 143 (0.00%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonia influenzal
subjects affected / exposed	0 / 141 (0.00%)	1 / 143 (0.70%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Influenza
subjects affected / exposed	0 / 141 (0.00%)	0 / 143 (0.00%)	2 / 71 (2.82%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Meningitis
subjects affected / exposed	1 / 141 (0.71%)	0 / 143 (0.00%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0	0 / 0
Pneumocystis jirovecii pneumonia
subjects affected / exposed	0 / 141 (0.00%)	1 / 143 (0.70%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	10 / 141 (7.09%)	7 / 143 (4.90%)	4 / 71 (5.63%)
occurrences causally related to treatment / all	3 / 10	1 / 7	1 / 4
deaths causally related to treatment / all	1 / 4	1 / 3	0 / 1
Pneumonia aspiration
subjects affected / exposed	2 / 141 (1.42%)	0 / 143 (0.00%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 2	0 / 0	0 / 0
Infection
subjects affected / exposed	1 / 141 (0.71%)	0 / 143 (0.00%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Pneumonia klebsiella
subjects affected / exposed	1 / 141 (0.71%)	0 / 143 (0.00%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Post procedural infection
subjects affected / exposed	0 / 141 (0.00%)	0 / 143 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Staphylococcal sepsis
subjects affected / exposed	1 / 141 (0.71%)	0 / 143 (0.00%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Tuberculosis
subjects affected / exposed	0 / 141 (0.00%)	1 / 143 (0.70%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	1 / 141 (0.71%)	0 / 143 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vestibular neuronitis
subjects affected / exposed	1 / 141 (0.71%)	0 / 143 (0.00%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Metabolism and nutrition disorders
Hyperkalaemia
subjects affected / exposed	1 / 141 (0.71%)	0 / 143 (0.00%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Decreased appetite
subjects affected / exposed	4 / 141 (2.84%)	0 / 143 (0.00%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	3 / 4	0 / 0	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0	0 / 0
Diabetes mellitus
subjects affected / exposed	0 / 141 (0.00%)	0 / 143 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Arm A: Nivolumab plus Platinum-doublet Chemotherapy	Arm C: Platinum Doublet Chemotherapy	Arm B: Nivolumab plus Ipilimumab
Total subjects affected by non serious adverse events
subjects affected / exposed	136 / 141 (96.45%)	140 / 143 (97.90%)	62 / 71 (87.32%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumour pain
subjects affected / exposed	4 / 141 (2.84%)	3 / 143 (2.10%)	7 / 71 (9.86%)
occurrences all number	4	3	7
Malignant neoplasm progression
subjects affected / exposed	1 / 141 (0.71%)	1 / 143 (0.70%)	4 / 71 (5.63%)
occurrences all number	2	1	4
Cancer pain
subjects affected / exposed	9 / 141 (6.38%)	9 / 143 (6.29%)	5 / 71 (7.04%)
occurrences all number	9	9	5
Vascular disorders
Hypertension
subjects affected / exposed	9 / 141 (6.38%)	4 / 143 (2.80%)	5 / 71 (7.04%)
occurrences all number	13	4	5
General disorders and administration site conditions
Face oedema
subjects affected / exposed	8 / 141 (5.67%)	9 / 143 (6.29%)	0 / 71 (0.00%)
occurrences all number	10	9	0
Malaise
subjects affected / exposed	18 / 141 (12.77%)	21 / 143 (14.69%)	5 / 71 (7.04%)
occurrences all number	24	25	6
Fatigue
subjects affected / exposed	30 / 141 (21.28%)	19 / 143 (13.29%)	15 / 71 (21.13%)
occurrences all number	69	26	17
Asthenia
subjects affected / exposed	12 / 141 (8.51%)	10 / 143 (6.99%)	3 / 71 (4.23%)
occurrences all number	20	11	3
Pyrexia
subjects affected / exposed	29 / 141 (20.57%)	17 / 143 (11.89%)	14 / 71 (19.72%)
occurrences all number	38	18	19
Oedema peripheral
subjects affected / exposed	26 / 141 (18.44%)	18 / 143 (12.59%)	8 / 71 (11.27%)
occurrences all number	30	20	8
Non-cardiac chest pain
subjects affected / exposed	10 / 141 (7.09%)	8 / 143 (5.59%)	7 / 71 (9.86%)
occurrences all number	10	8	8
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	16 / 141 (11.35%)	18 / 143 (12.59%)	16 / 71 (22.54%)
occurrences all number	17	18	17
Productive cough
subjects affected / exposed	9 / 141 (6.38%)	11 / 143 (7.69%)	8 / 71 (11.27%)
occurrences all number	15	12	8
Hiccups
subjects affected / exposed	12 / 141 (8.51%)	8 / 143 (5.59%)	2 / 71 (2.82%)
occurrences all number	16	13	3
Haemoptysis
subjects affected / exposed	9 / 141 (6.38%)	9 / 143 (6.29%)	4 / 71 (5.63%)
occurrences all number	9	10	4
Dyspnoea
subjects affected / exposed	15 / 141 (10.64%)	12 / 143 (8.39%)	14 / 71 (19.72%)
occurrences all number	18	13	16
Psychiatric disorders
Insomnia
subjects affected / exposed	17 / 141 (12.06%)	22 / 143 (15.38%)	6 / 71 (8.45%)
occurrences all number	18	25	6
Anxiety
subjects affected / exposed	6 / 141 (4.26%)	3 / 143 (2.10%)	4 / 71 (5.63%)
occurrences all number	7	3	4
Investigations
Neutrophil count decreased
subjects affected / exposed	42 / 141 (29.79%)	45 / 143 (31.47%)	4 / 71 (5.63%)
occurrences all number	118	117	6
Blood creatinine increased
subjects affected / exposed	19 / 141 (13.48%)	15 / 143 (10.49%)	1 / 71 (1.41%)
occurrences all number	27	23	2
Aspartate aminotransferase increased
subjects affected / exposed	35 / 141 (24.82%)	27 / 143 (18.88%)	11 / 71 (15.49%)
occurrences all number	87	39	12
Amylase increased
subjects affected / exposed	13 / 141 (9.22%)	9 / 143 (6.29%)	3 / 71 (4.23%)
occurrences all number	23	13	3
Alanine aminotransferase increased
subjects affected / exposed	35 / 141 (24.82%)	26 / 143 (18.18%)	12 / 71 (16.90%)
occurrences all number	83	41	16
Platelet count decreased
subjects affected / exposed	19 / 141 (13.48%)	28 / 143 (19.58%)	6 / 71 (8.45%)
occurrences all number	45	50	7
Weight decreased
subjects affected / exposed	9 / 141 (6.38%)	6 / 143 (4.20%)	7 / 71 (9.86%)
occurrences all number	10	6	7
White blood cell count decreased
subjects affected / exposed	38 / 141 (26.95%)	35 / 143 (24.48%)	3 / 71 (4.23%)
occurrences all number	129	95	6
Nervous system disorders
Headache
subjects affected / exposed	22 / 141 (15.60%)	19 / 143 (13.29%)	5 / 71 (7.04%)
occurrences all number	25	23	5
Dysgeusia
subjects affected / exposed	9 / 141 (6.38%)	10 / 143 (6.99%)	1 / 71 (1.41%)
occurrences all number	13	11	1
Dizziness
subjects affected / exposed	15 / 141 (10.64%)	14 / 143 (9.79%)	7 / 71 (9.86%)
occurrences all number	21	14	7
Blood and lymphatic system disorders
Thrombocytopenia
subjects affected / exposed	10 / 141 (7.09%)	6 / 143 (4.20%)	1 / 71 (1.41%)
occurrences all number	32	9	1
Neutropenia
subjects affected / exposed	22 / 141 (15.60%)	6 / 143 (4.20%)	3 / 71 (4.23%)
occurrences all number	110	7	5
Anaemia
subjects affected / exposed	66 / 141 (46.81%)	58 / 143 (40.56%)	7 / 71 (9.86%)
occurrences all number	115	77	8
Gastrointestinal disorders
Vomiting
subjects affected / exposed	35 / 141 (24.82%)	21 / 143 (14.69%)	7 / 71 (9.86%)
occurrences all number	51	35	10
Stomatitis
subjects affected / exposed	12 / 141 (8.51%)	10 / 143 (6.99%)	4 / 71 (5.63%)
occurrences all number	14	12	4
Nausea
subjects affected / exposed	63 / 141 (44.68%)	60 / 143 (41.96%)	12 / 71 (16.90%)
occurrences all number	104	98	15
Diarrhoea
subjects affected / exposed	18 / 141 (12.77%)	17 / 143 (11.89%)	17 / 71 (23.94%)
occurrences all number	23	19	25
Constipation
subjects affected / exposed	52 / 141 (36.88%)	57 / 143 (39.86%)	21 / 71 (29.58%)
occurrences all number	66	82	32
Abdominal pain upper
subjects affected / exposed	3 / 141 (2.13%)	4 / 143 (2.80%)	4 / 71 (5.63%)
occurrences all number	3	5	4
Abdominal pain
subjects affected / exposed	3 / 141 (2.13%)	11 / 143 (7.69%)	5 / 71 (7.04%)
occurrences all number	3	11	8
Skin and subcutaneous tissue disorders
Rash pruritic
subjects affected / exposed	12 / 141 (8.51%)	1 / 143 (0.70%)	9 / 71 (12.68%)
occurrences all number	12	2	15
Rash
subjects affected / exposed	2 / 141 (1.42%)	0 / 143 (0.00%)	9 / 71 (12.68%)
occurrences all number	3	0	10
Pruritus
subjects affected / exposed	17 / 141 (12.06%)	8 / 143 (5.59%)	18 / 71 (25.35%)
occurrences all number	22	9	25
Eczema
subjects affected / exposed	2 / 141 (1.42%)	1 / 143 (0.70%)	5 / 71 (7.04%)
occurrences all number	2	1	5
Alopecia
subjects affected / exposed	6 / 141 (4.26%)	8 / 143 (5.59%)	4 / 71 (5.63%)
occurrences all number	6	8	4
Rash maculo-papular
subjects affected / exposed	9 / 141 (6.38%)	4 / 143 (2.80%)	2 / 71 (2.82%)
occurrences all number	9	4	2
Endocrine disorders
Hypothyroidism
subjects affected / exposed	15 / 141 (10.64%)	0 / 143 (0.00%)	12 / 71 (16.90%)
occurrences all number	16	0	12
Hyperthyroidism
subjects affected / exposed	7 / 141 (4.96%)	0 / 143 (0.00%)	8 / 71 (11.27%)
occurrences all number	8	0	8
Musculoskeletal and connective tissue disorders
Pain in extremity
subjects affected / exposed	6 / 141 (4.26%)	3 / 143 (2.10%)	5 / 71 (7.04%)
occurrences all number	7	3	6
Arthralgia
subjects affected / exposed	15 / 141 (10.64%)	10 / 143 (6.99%)	9 / 71 (12.68%)
occurrences all number	17	10	11
Back pain
subjects affected / exposed	21 / 141 (14.89%)	12 / 143 (8.39%)	5 / 71 (7.04%)
occurrences all number	26	12	5
Muscular weakness
subjects affected / exposed	7 / 141 (4.96%)	3 / 143 (2.10%)	4 / 71 (5.63%)
occurrences all number	8	3	4
Myalgia
subjects affected / exposed	6 / 141 (4.26%)	4 / 143 (2.80%)	6 / 71 (8.45%)
occurrences all number	9	5	7
Infections and infestations
Urinary tract infection
subjects affected / exposed	5 / 141 (3.55%)	3 / 143 (2.10%)	4 / 71 (5.63%)
occurrences all number	5	5	4
Upper respiratory tract infection
subjects affected / exposed	9 / 141 (6.38%)	9 / 143 (6.29%)	6 / 71 (8.45%)
occurrences all number	11	10	8
Pneumonia
subjects affected / exposed	7 / 141 (4.96%)	7 / 143 (4.90%)	5 / 71 (7.04%)
occurrences all number	8	7	5
Paronychia
subjects affected / exposed	6 / 141 (4.26%)	1 / 143 (0.70%)	4 / 71 (5.63%)
occurrences all number	7	1	4
Nasopharyngitis
subjects affected / exposed	8 / 141 (5.67%)	1 / 143 (0.70%)	1 / 71 (1.41%)
occurrences all number	9	1	2
Conjunctivitis
subjects affected / exposed	10 / 141 (7.09%)	2 / 143 (1.40%)	2 / 71 (2.82%)
occurrences all number	10	2	6
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	42 / 141 (29.79%)	52 / 143 (36.36%)	16 / 71 (22.54%)
occurrences all number	83	68	23
Hypoalbuminaemia
subjects affected / exposed	9 / 141 (6.38%)	6 / 143 (4.20%)	2 / 71 (2.82%)
occurrences all number	18	6	4
Hypokalaemia
subjects affected / exposed	11 / 141 (7.80%)	6 / 143 (4.20%)	6 / 71 (8.45%)
occurrences all number	14	6	9

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Were there any global substantial amendments to the protocol? Yes

20 Nov 2018

Stopped enrollment to Arm B (nivolumab + ipilimumab)

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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Primary: Progression Free Survival (PFS) by Blinded Independent Centralized Review (BICR)

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Secondary: Objective Response Rate (ORR) by Blinded Independent Centralized Review (BICR)

Secondary: 12 Month Progression Free Survival Rates (PFSR) by Blinded Independent Centralized Review (BICR)

Secondary: 12 Month Progression Free Survival Rates (PFSR) by Blinded Independent Centralized Review (BICR)

Secondary: Duration of Response (DOR) by Blinded Independent Centralized Review (BICR)

Secondary: Duration of Response (DOR) by Blinded Independent Centralized Review (BICR)

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Secondary: 9 Month Progression Free Survival Rates (PFSR) by Blinded Independent Centralized Review (BICR)

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