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Clinical Trial Results:
An Exploratory Study of the Biologic Effects and Biomarkers of Nivolumab in combination with Ipilimumab in Subjects with Treatment-Naive Stage IV or recurrent Non-Small Cell Lung Cancer (NSCLC) (CheckMate 592: CHECKpoint pathway and nivoluMAb clinical Trial Evaluation 592)

Summary
EudraCT number	2018-000462-11
Trial protocol	DE BE NL ES IT RO
Global end of trial date	24 Apr 2023

Results information
Results version number	v1(current)
This version publication date	08 May 2024
First version publication date	08 May 2024
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

CA209-592

ISRCTN number

US NCT number

WHO universal trial number (UTN)

Sponsor organisation name

Bristol-Myers Squibb

Sponsor organisation address

Chaussée 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

31 May 2023

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

24 Apr 2023

Was the trial ended prematurely?

Main objective of the trial

Investigate the biologic effects and biomarkers of nivolumab in combination ipilimumab in subjects, with no prior systemic anticancer therapy given as primary therapy for advanced or metastatic non-small cell lung cancer (NSCLC).

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

29 Mar 2017

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Belgium: 18

Country: Number of subjects enrolled

France: 13

Country: Number of subjects enrolled

Germany: 30

Country: Number of subjects enrolled

Italy: 11

Country: Number of subjects enrolled

Netherlands: 18

Country: Number of subjects enrolled

Romania: 34

Country: Number of subjects enrolled

Spain: 19

Country: Number of subjects enrolled

United States: 87

Worldwide total number of subjects

230

EEA total number of subjects

143

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)

101

From 65 to 84 years

126

85 years and over

Subject disposition

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Recruitment details

Screening details

In Part 1, upon determination of PD-L1 status (cut-off of 1%), 2 cohorts were defined: PD-L1 positive and negative. In Part 2, a separate group of participants were treated regardless of their PD-L1 status.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Non-randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

PART 1: PD-L1+ Status

Arm description

Nivolumab + ipilimumab at a flat dose of nivolumab 240 mg as a 30-minute intravenous (IV) infusion every two weeks + ipilimumab 1 mg/kg as a 30-minute IV infusion every 6 weeks. Treatment would continue until disease progression, unacceptable toxicity, withdrawal of consent, the study ending, or a maximum treatment duration of 2 years, whichever occurred first.

Arm type

Experimental

Investigational medicinal product name

Ipilimumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

1 mg/kg 30-minute IV infusion every 6 weeks.

Investigational medicinal product name

Nivolumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

240 mg 30-minute infusion every two weeks.

PART 1: PD-L1- Status

Arm description

Arm type

Experimental

Investigational medicinal product name

Ipilimumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

1 mg/kg 30-minute IV infusion every 6 weeks.

Investigational medicinal product name

Nivolumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

240 mg 30-minute infusion every two weeks.

PART 1: Not Evaluable/Indeterminate PD-L1 Status

Arm description

Arm type

Experimental

Investigational medicinal product name

Ipilimumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

1 mg/kg 30-minute IV infusion every 6 weeks.

Investigational medicinal product name

Nivolumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

240 mg 30-minute infusion every two weeks.

PART 2: PD-L1 Status Independent

Arm description

Arm type

Experimental

Investigational medicinal product name

Ipilimumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

1 mg/kg 30-minute IV infusion every 6 weeks.

Investigational medicinal product name

Nivolumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

240 mg 30-minute infusion every two weeks.

Number of subjects in period 1	PART 1: PD-L1+ Status	PART 1: PD-L1- Status	PART 1: Not Evaluable/Indeterminate PD-L1 Status	PART 2: PD-L1 Status Independent
Started	31	28	1	170
Completed	0	0	0	0
Not completed	31	28	1	170
Adverse event, serious fatal	1	-	-	3
Disease progression	16	14	1	90
Participant requested to d/c study treatment	-	-	-	2
Participant withdrew consent	-	1	-	5
Not reported	-	-	-	6
Maximum clinical benefit	2	3	-	10
AE unrelated to study drug	3	3	-	11
Other reasons	1	2	-	5
Study Drug Toxicity	8	5	-	37
Administrative reason by sponsor	-	-	-	1

Baseline characteristics

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Reporting group title

PART 1: PD-L1+ Status

Reporting group description

Reporting group title

PART 1: PD-L1- Status

Reporting group description

Reporting group title

PART 1: Not Evaluable/Indeterminate PD-L1 Status

Reporting group description

Reporting group title

PART 2: PD-L1 Status Independent

Reporting group description

Reporting group values	PART 1: PD-L1+ Status	PART 1: PD-L1- Status	PART 1: Not Evaluable/Indeterminate PD-L1 Status	PART 2: PD-L1 Status Independent	Total
Number of subjects	31	28	1	170	230
Age Categorical
Units: Participants
<=18 years	0	0	0	0	0
Between 18 and 65 years	10	15	0	76	101
>=65 years	21	13	1	94	129
Sex: Female, Male
Units: Participants
Female	15	11	0	54	80
Male	16	17	1	116	150
Ethnicity (NIH/OMB)
Units: Subjects
Hispanic or Latino	1	1	0	4	6
Not Hispanic or Latino	24	25	1	98	148
Unknown or Not Reported	6	2	0	68	76
Race/Ethnicity, Customized
Race
Units: Subjects
White	27	25	1	164	217
Black or African American	3	3	0	5	11
Other	1	0	0	1	2

End points

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Reporting group title

PART 1: PD-L1+ Status

Reporting group description

Reporting group title

PART 1: PD-L1- Status

Reporting group description

Reporting group title

PART 1: Not Evaluable/Indeterminate PD-L1 Status

Reporting group description

Reporting group title

PART 2: PD-L1 Status Independent

Reporting group description

Subject analysis set title

PART 1: PD-L1 + Status

Subject analysis set type

Per protocol

Subject analysis set description

Subject analysis set title

PART 2: PD-L1- Status

Subject analysis set type

Per protocol

Subject analysis set description

Subject analysis set title

PART 2: PD-L1 + Status

Subject analysis set type

Per protocol

Subject analysis set description

Subject analysis set title

PART 2: PD-L1 + Status

Subject analysis set type

Per protocol

Subject analysis set description

Subject analysis set title

PART 2: PD-L1- Status

Subject analysis set type

Per protocol

Subject analysis set description

Subject analysis set title

PART 1

Subject analysis set type

Per protocol

Subject analysis set description

Subject analysis set title

PART 2

Subject analysis set type

Per protocol

Subject analysis set description

Subject analysis set title

PART 1

Subject analysis set type

Per protocol

Subject analysis set description

Subject analysis set title

PART 2

Subject analysis set type

Per protocol

Subject analysis set description

Primary: Objective Response Rate (ORR) per Investigator by Blood TMB (bTMB) within PD-L1 Subgroup (TMB Cut-point = 16 mutations/MB)

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End point title

Objective Response Rate (ORR) per Investigator by Blood TMB (bTMB) within PD-L1 Subgroup (TMB Cut-point = 16 mutations/MB) ^[1] ^[2]

End point description

Objective response rate (ORR) is defined as the percent of treated participants with a best overall response of a complete response (CR) or partial response (PR) assessed by investigator per Response Evaluation Criteria In Solid Tumors (RECIST 1.1). PR is at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. CR is disappearance of all target lesions and a reduction in pathological lymph node (whether target or non-target) short axis to <10 mm. Blood tumor mutational burden (bTMB) is the total number of nonsynonymous somatic mutations produced by a tumor that are detected in serum. CR+PR, confidence interval based on the Clopper and Pearson method.

End point type

Primary

End point timeframe

From first dose up to the date of objectively documented progression, or the date of initiation of palliative local therapy or the date of initiation of subsequent anticancer therapy (up to approximately 58 months)

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

End point values	PART 1: PD-L1- Status	PART 1: Not Evaluable/Indeterminate PD-L1 Status	PART 1: PD-L1 + Status	PART 2: PD-L1- Status	PART 2: PD-L1 + Status
Number of subjects analysed	16	0 ^[3]	19	62	39
Units: Percent of Participants
number (confidence interval 95%)
bTMB High (Cut-point = 16-mutations)	50 (18.7 to 81.3)	( to )	30 (6.7 to 65.2)	30.3 (15.6 to 48.7)	58.8 (32.9 to 81.6)
bTMB Low (Cut-point = 16-mutations)	33.3 (4.3 to 77.7)	( to )	33.3 (7.5 to 70.1)	24.1 (10.3 to 43.5)	31.8 (13.9 to 54.9)

Notes
[3] - 0 participants analyzed

No statistical analyses for this end point

Primary: Objective Response Rate (ORR) per Investigator by Blood TMB (bTMB) within PD-L1 Subgroup (Blood TMB Cut-point = 21-mutations/MB)

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End point title

Objective Response Rate (ORR) per Investigator by Blood TMB (bTMB) within PD-L1 Subgroup (Blood TMB Cut-point = 21-mutations/MB) ^[4] ^[5]

End point description

End point type

Primary

End point timeframe

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: Only summary analysis planned for this endpoint.
[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: Only summary analysis planned for pre-specified arms.

End point values	PART 1: PD-L1+ Status	PART 1: PD-L1- Status	PART 1: Not Evaluable/Indeterminate PD-L1 Status	PART 2: PD-L1- Status	PART 2: PD-L1 + Status
Number of subjects analysed	19	16	0 ^[6]	62	39
Units: Percent of Participants
number (confidence interval 95%)
bTMB High (Cut-point = 21-mutations)	33.3 (4.3 to 77.7)	66.7 (22.3 to 95.7)	( to )	40.9 (20.7 to 63.6)	64.3 (35.1 to 87.2)
bTMB Low (Cut-point = 21-mutations)	30.8 (9.1 to 61.4)	30.0 (6.7 to 65.2)	( to )	20.0 (9.1 to 35.6)	32.0 (14.9 to 53.5)

Notes
[6] - 0 participants analyzed

No statistical analyses for this end point

Primary: Objective Response Rate (ORR) per Investigator by Tissue TMB within PD-L1 Subgroup (Tissue TMB Cut-point = 10-mutations/MB)

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End point title

Objective Response Rate (ORR) per Investigator by Tissue TMB within PD-L1 Subgroup (Tissue TMB Cut-point = 10-mutations/MB) ^[7] ^[8]

End point description

Objective response rate (ORR) is defined as the percent of treated participants with a best overall response of a complete response (CR) or partial response (PR) assessed by investigator per Response Evaluation Criteria In Solid Tumors (RECIST 1.1). PR is at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. CR is disappearance of all target lesions and a reduction in pathological lymph node (whether target or non-target) short axis to <10 mm. Tissue tumor mutational burden (tTMB) is the total number of nonsynonymous somatic mutations produced by a tumor that are detected in tumor tissue samples. CR+PR, confidence interval based on the Clopper and Pearson method.

End point type

Primary

End point timeframe

Notes
[7] - 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: Only summary analysis planned for this endpoint.
[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: Only summary analysis planned for pre-specified arms.

End point values	PART 1: PD-L1+ Status	PART 1: PD-L1- Status	PART 1: Not Evaluable/Indeterminate PD-L1 Status	PART 2: PD-L1 + Status	PART 2: PD-L1- Status
Number of subjects analysed	19	16	0 ^[9]	31	57
Units: Percent of Participants
number (confidence interval 95%)
tTMB High (Cut-point = 10-mutations)	25.0 (3.2 to 65.1)	71.4 (29.0 to 96.3)	( to )	60.0 (32.3 to 83.7)	46.7 (21.3 to 73.4)
tTMB Low (Cut-point = 10-mutations	27.3 (6.0 to 61.0)	22.2 (2.8 to 60.0)	( to )	25.0 (7.3 to 52.4)	21.4 (10.3 to 36.8)

Notes
[9] - 0 participants analyzed

No statistical analyses for this end point

Secondary: Objective Response Rate (ORR) for All Treated Participants by Investigator per RECIST 1.1

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End point title

Objective Response Rate (ORR) for All Treated Participants by Investigator per RECIST 1.1

End point description

Objective response rate (ORR) is defined as the percent of treated participants with a best overall response of a complete response (CR) or partial response (PR) assessed by investigator per Response Evaluation Criteria In Solid Tumors (RECIST 1.1). Partial Response (PR) is at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Complete Response (CR) is disappearance of all target lesions and a reduction in pathological lymph node (whether target or non-target) short axis to <10 mm. CR+PR, confidence interval based on the Clopper and Pearson method.

End point type

Secondary

End point timeframe

From first dose until the date of objectively documented progression, or the date of initiation of palliative local therapy or the date of initiation of subsequent anticancer therapy, whichever occurs first (Up to approximately 67 months)

End point values	PART 1: PD-L1+ Status	PART 1: PD-L1- Status	PART 1: Not Evaluable/Indeterminate PD-L1 Status	PART 2: PD-L1 Status Independent
Number of subjects analysed	31	28	1	170
Units: Percent of Participants
number (confidence interval 95%)	29.0 (14.2 to 48.0)	39.3 (21.5 to 59.4)	0 (0.0 to 97.5)	29.4 (22.7 to 36.9)

No statistical analyses for this end point

Secondary: Disease Control Rate (DCR) for Part 1

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End point title

Disease Control Rate (DCR) for Part 1 ^[10]

End point description

Disease control rate (DCR) is the percent of treated participants with a best overall response of a complete response (CR), partial response (PR), or stable disease (SD), assessed by investigator per Response Evaluation Criteria In Solid Tumors (RECIST 1.1). 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 short axis to <10 mm of any pathological lymph nodes (target or non-target). SD is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking smallest sum diameters as reference. PD is at least a 20% increase in the sum of diameters of target lesions, taking the smallest sum as reference. The sum must also demonstrate an absolute increase of at least 5 mm. (one or more new lesions is also considered progression). CR+PR, confidence interval based on the Clopper and Pearson method.

End point type

Secondary

End point timeframe

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: Only summary analysis planned for pre-specified arms.

End point values	PART 1: PD-L1+ Status	PART 1: PD-L1- Status	PART 1: Not Evaluable/Indeterminate PD-L1 Status
Number of subjects analysed	31	28	1
Units: Percent of Participants
number (confidence interval 95%)	58.1 (39.1 to 75.5)	64.3 (44.1 to 81.4)	100.0 (2.5 to 100.0)

No statistical analyses for this end point

Secondary: Duration of Response (DOR) for Part 1

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End point title

Duration of Response (DOR) for Part 1 ^[11]

End point description

DOR is the time between first confirmed response (Complete/Partial Response) and first documented tumor progression (per RECIST 1.1) or death due to any cause. Participants who don't progress or die are censored on the date of their last evaluable tumor assessment. Participants who started subsequent anti-cancer therapy without prior reported progression were censored at the last evaluable tumor assessment prior to or on the date of subsequent anti-cancer therapy. PR is at least 30% decrease in the sum of diameters of target lesions, using baseline sum diameters as reference. CR is disappearance of all target lesions and reduction in short axis to <10 mm of any pathological lymph nodes (target or non-target). Progressive Disease (PD) is at least 20% increase in the sum of diameters of target lesions, taking the smallest sum as reference. The sum must also show an overall increase of > 5 mm. (one or more new lesions is also progression). Median computed using Kaplan-Meier method.

End point type

Secondary

End point timeframe

From first dose to the date of the first documented tumor progression or death due to any cause (Up to approximately 67 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: Only summary analysis planned for pre-specified arms.

End point values	PART 1: PD-L1+ Status	PART 1: PD-L1- Status	PART 1: Not Evaluable/Indeterminate PD-L1 Status
Number of subjects analysed	9	11	0 ^[12]
Units: Months
median (full range (min-max))	24.56 (1.9 to 61.7)	29.57 (2.8 to 48.9)	( to )

Notes
[12] - 0 participants analyzed

No statistical analyses for this end point

Secondary: Time to Response (TTR) for Part 1

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End point title

Time to Response (TTR) for Part 1 ^[13]

End point description

TTR is the time taken from first dosing date to the time the criteria for Complete Response (CR)/Partial Response (PR) are first met. Partial Response (PR) is at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Complete Response (CR) is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm.

End point type

Secondary

End point timeframe

From first dose to the time the criteria for Complete Response/Partial Response are first met (Up to approximately 67 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: Only summary analysis planned for pre-specified arms.

End point values	PART 1: PD-L1+ Status	PART 1: PD-L1- Status	PART 1: Not Evaluable/Indeterminate PD-L1 Status
Number of subjects analysed	9	11	0 ^[14]
Units: Months
median (full range (min-max))	1.84 (1.6 to 3.7)	5.26 (1.7 to 18.5)	( to )

Notes
[14] - 0 participants analyzed

No statistical analyses for this end point

Secondary: Progression Free Survival (PFS)

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End point title

Progression Free Survival (PFS)

End point description

PFS is defined as the time from first dosing date to the date of the first documented tumor progression (per RECIST 1.1) or death due to any cause. Participants who neither progress nor die will be censored on the date of their last evaluable tumor assessment. Participants who started any subsequent anti-cancer therapy without a prior reported progression will be censored at the last evaluable tumor assessment prior to or on the date of initiation of subsequent anti-cancer therapy. Progressive Disease (PD) is at least a 20% increase in the sum of diameters of target lesions, taking the smallest sum on study as reference. The sum must also show an overall increase of > 5 mm. (one or more new lesions is also progression). Median calculated using Kaplan-Meier estimates. +/-99999=NA

End point type

Secondary

End point timeframe

From first dose to the date of the first documented tumor progression or death due to any causes (Assessed up to approximately 67 months)

End point values	PART 1: PD-L1+ Status	PART 1: PD-L1- Status	PART 1: Not Evaluable/Indeterminate PD-L1 Status	PART 2: PD-L1 Status Independent
Number of subjects analysed	31	28	1	170
Units: Months
median (confidence interval 95%)	3.71 (1.97 to 8.90)	4.30 (1.84 to 13.60)	3.61 (-99999 to 99999)	6.28 (5.09 to 7.56)

No statistical analyses for this end point

Secondary: Number of Participants with Select Adverse Events (AEs) for Study Part 2

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End point title

Number of Participants with Select Adverse Events (AEs) for Study Part 2 ^[15]

End point description

An Adverse Event (AE) is any new untoward medical occurrence or worsening preexisting medical condition in a treated participant and that does not necessarily have a causal relationship with treatment. An AE can be any unfavorable, unintended sign, symptom, or disease temporally associated with the use of treatment, whether or not related to the treatment.

End point type

Secondary

End point timeframe

From first dose to 30 days after last dosing date (up to approximately 27 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: Only summary analysis planned for pre-specified arms.

End point values	PART 2: PD-L1 Status Independent
Number of subjects analysed	170
Units: Participants
Gastrointestinal Adverse Events	68
Hepatic Adverse Events	49
Pulmonary Adverse Events	17
Renal Adverse Events	28
Skin Adverse Events	73
Hypersensitivity/Infusion Reaction	12

No statistical analyses for this end point

Secondary: Number of Participants with Serious Adverse Events (SAEs) for Study Part 2

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End point title

Number of Participants with Serious Adverse Events (SAEs) for Study Part 2 ^[16]

End point description

A Serious Adverse Event (SAE) results in death, is life-threatening (defined as an event in which the participant was at risk of death at the time of the event; it does not refer to an event which hypothetically might have caused death if it were more severe), or requires inpatient hospitalization or causes prolongation of existing hospitalization.

End point type

Secondary

End point timeframe

From first dose to 30 days after last dosing date (assessed up to approximately 27 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: Only summary analysis planned for pre-specified arms.

End point values	PART 2: PD-L1 Status Independent
Number of subjects analysed	170
Units: Participants	102

No statistical analyses for this end point

Secondary: Number of Participants with Adverse Events (AEs) for Study Part 2

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End point title

Number of Participants with Adverse Events (AEs) for Study Part 2 ^[17]

End point description

End point type

Secondary

End point timeframe

From first dose to 30 days after last dosing date (assessed up to approximately 27 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: Only summary analysis planned for pre-specified arms.

End point values	PART 2: PD-L1 Status Independent
Number of subjects analysed	170
Units: Participants	169

No statistical analyses for this end point

Secondary: Overall Survival (OS)

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End point title

Overall Survival (OS)

End point description

OS is defined as the time from first dosing date to the date of death. If a participant didn’t die, OS will be censored on the last date the participant was known to be alive. Median based on Kaplan-Meier estimates. +/-99999=NA

End point type

Secondary

End point timeframe

From first dose to the date of death (Assessed up to approximately 67 months)

End point values	PART 1: PD-L1+ Status	PART 1: PD-L1- Status	PART 1: Not Evaluable/Indeterminate PD-L1 Status	PART 2: PD-L1 Status Independent
Number of subjects analysed	31	28	1	170
Units: Months
median (confidence interval 95%)	9.63 (4.47 to 20.57)	22.29 (11.56 to 25.23)	9.23 (-99999 to 99999)	14.78 (11.99 to 20.60)

No statistical analyses for this end point

Post-hoc: Extended Collection of Objective Response Rate (ORR) per Investigator by Blood TMB (bTMB) (TMB Cut-point = 16 mutations/MB)

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End point title

Extended Collection of Objective Response Rate (ORR) per Investigator by Blood TMB (bTMB) (TMB Cut-point = 16 mutations/MB) ^[18]

End point description

End point type

Post-hoc

End point timeframe

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: Only summary analysis planned for pre-specified arms.

End point values	PART 1: Not Evaluable/Indeterminate PD-L1 Status	PART 1	PART 2
Number of subjects analysed	0 ^[19]	36	131
Units: Percent of Participants
number (confidence interval 95%)
bTMB High (Cut-point = 16-mutations)	( to )	40.0 (19.1 to 63.9)	34.3 (22.9 to 47.3)
bTMB Low (Cut-point = 16-mutations)	( to )	25.0 (7.3 to 52.4)	26.9 (16.8 to 39.1)

Notes
[19] - 0 participants analyzed

No statistical analyses for this end point

Post-hoc: Extended Collection of Objective Response Rate (ORR) per Investigator by Blood TMB (bTMB) (Blood TMB Cut-point = 21-mutations/MB)

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End point title

Extended Collection of Objective Response Rate (ORR) per Investigator by Blood TMB (bTMB) (Blood TMB Cut-point = 21-mutations/MB) ^[20]

End point description

End point type

Post-hoc

End point timeframe

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: Only summary analysis planned for pre-specified arms.

End point values	PART 1: Not Evaluable/Indeterminate PD-L1 Status	PART 1	PART 2
Number of subjects analysed	0 ^[21]	36	131
Units: Percent of Participants
number (confidence interval 95%)
bTMB High (Cut-point = 21-mutations)	( to )	50.0 (21.1 to 78.9)	44.4 (29.6 to 60.0)
bTMB Low (Cut-point = 21-mutations)	( to )	25.0 (9.8 to 46.7)	23.3 (14.8 to 33.6)

Notes
[21] - 0 participants analyzed

No statistical analyses for this end point

Post-hoc: Extended Collection of Objective Response Rate (ORR) per Investigator by Tissue TMB (Tissue TMB Cut-point = 10-mutations/MB)

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End point title

Extended Collection of Objective Response Rate (ORR) per Investigator by Tissue TMB (Tissue TMB Cut-point = 10-mutations/MB) ^[22]

End point description

Objective response rate (ORR) is defined as the percent of treated participants with a best overall response of a complete response (CR) or partial response (PR) assessed by investigator per Response Evaluation Criteria In Solid Tumors (RECIST 1.1). PR is at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. CR is disappearance of all target lesions and a reduction in pathological lymph node (whether target or non-target) short axis to <10 mm. Tissue tumor mutational burden (tTMB) is the total number of nonsynonymous somatic mutations produced by a tumor that are detected in tumor tissue samples. CR+PR, confidence interval based on the Clopper and Pearson method.

End point type

Post-hoc

End point timeframe

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: Only summary analysis planned for pre-specified arms.

End point values	PART 1: Not Evaluable/Indeterminate PD-L1 Status	PART 1	PART 2
Number of subjects analysed	0 ^[23]	35	101
Units: Percent of Participants
number (confidence interval 95%)
tTMB High (Cut-point = 10-mutations)	( to )	46.7 (21.3 to 73.4)	50.0 (32.4 to 67.6)
tTMB Low (Cut-point = 10-mutations	( to )	20.0 (5.7 to 43.7)	19.4 (10.8 to 30.9)

Notes
[23] - 0 participants analyzed

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Subjects assessed for Deaths (all-causes) from their first dose to their study completion (up to 67 months.) SAEs and NSAEs were assessed from first dose to 100 days post last dose (up to an avg. of 8 months and a max. of 29 months).

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

26.0

Reporting group title

PART 1: PD-L1+ Status

Reporting group description

Reporting group title

PART 2: PD-L1 Status Independent

Reporting group description

Reporting group title

PART 1: Not Evaluable/Indeterminate PD-L1 Status

Reporting group description

Reporting group title

PART 1: PD-L1- Status

Reporting group description

Serious adverse events	PART 1: PD-L1+ Status	PART 2: PD-L1 Status Independent	PART 1: Not Evaluable/Indeterminate PD-L1 Status	PART 1: PD-L1- Status
Total subjects affected by serious adverse events
subjects affected / exposed	24 / 31 (77.42%)	113 / 170 (66.47%)	0 / 1 (0.00%)	14 / 28 (50.00%)
number of deaths (all causes)	27	134	1	22
number of deaths resulting from adverse events	15	49	0	5
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Malignant neoplasm progression
subjects affected / exposed	10 / 31 (32.26%)	38 / 170 (22.35%)	0 / 1 (0.00%)	5 / 28 (17.86%)
occurrences causally related to treatment / all	0 / 10	0 / 40	0 / 0	0 / 5
deaths causally related to treatment / all	0 / 10	0 / 36	0 / 0	0 / 5
Cancer pain
subjects affected / exposed	0 / 31 (0.00%)	2 / 170 (1.18%)	0 / 1 (0.00%)	0 / 28 (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
Malignant pleural effusion
subjects affected / exposed	0 / 31 (0.00%)	1 / 170 (0.59%)	0 / 1 (0.00%)	0 / 28 (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
Phaeochromocytoma
subjects affected / exposed	0 / 31 (0.00%)	1 / 170 (0.59%)	0 / 1 (0.00%)	0 / 28 (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
Non-small cell lung cancer
subjects affected / exposed	0 / 31 (0.00%)	1 / 170 (0.59%)	0 / 1 (0.00%)	0 / 28 (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
Neoplasm progression
subjects affected / exposed	0 / 31 (0.00%)	1 / 170 (0.59%)	0 / 1 (0.00%)	0 / 28 (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
Metastases to central nervous system
subjects affected / exposed	0 / 31 (0.00%)	1 / 170 (0.59%)	0 / 1 (0.00%)	0 / 28 (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	0 / 31 (0.00%)	1 / 170 (0.59%)	0 / 1 (0.00%)	0 / 28 (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 ulceration
subjects affected / exposed	0 / 31 (0.00%)	0 / 170 (0.00%)	0 / 1 (0.00%)	1 / 28 (3.57%)
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
Tumour necrosis
subjects affected / exposed	0 / 31 (0.00%)	1 / 170 (0.59%)	0 / 1 (0.00%)	0 / 28 (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
Vascular disorders
Hypotension
subjects affected / exposed	0 / 31 (0.00%)	3 / 170 (1.76%)	0 / 1 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Embolism
subjects affected / exposed	0 / 31 (0.00%)	1 / 170 (0.59%)	0 / 1 (0.00%)	1 / 28 (3.57%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Fatigue
subjects affected / exposed	0 / 31 (0.00%)	1 / 170 (0.59%)	0 / 1 (0.00%)	0 / 28 (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
Asthenia
subjects affected / exposed	1 / 31 (3.23%)	0 / 170 (0.00%)	0 / 1 (0.00%)	0 / 28 (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
Chest pain
subjects affected / exposed	0 / 31 (0.00%)	2 / 170 (1.18%)	0 / 1 (0.00%)	0 / 28 (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
Death
subjects affected / exposed	1 / 31 (3.23%)	0 / 170 (0.00%)	0 / 1 (0.00%)	0 / 28 (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
Adverse drug reaction
subjects affected / exposed	0 / 31 (0.00%)	1 / 170 (0.59%)	0 / 1 (0.00%)	0 / 28 (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
General physical health deterioration
subjects affected / exposed	0 / 31 (0.00%)	4 / 170 (2.35%)	0 / 1 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 4	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Inflammation
subjects affected / exposed	0 / 31 (0.00%)	2 / 170 (1.18%)	0 / 1 (0.00%)	0 / 28 (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
Non-cardiac chest pain
subjects affected / exposed	0 / 31 (0.00%)	1 / 170 (0.59%)	0 / 1 (0.00%)	0 / 28 (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
Systemic inflammatory response syndrome
subjects affected / exposed	0 / 31 (0.00%)	1 / 170 (0.59%)	0 / 1 (0.00%)	0 / 28 (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
Performance status decreased
subjects affected / exposed	0 / 31 (0.00%)	1 / 170 (0.59%)	0 / 1 (0.00%)	0 / 28 (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
Pyrexia
subjects affected / exposed	0 / 31 (0.00%)	5 / 170 (2.94%)	0 / 1 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	3 / 6	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
Sudden death
subjects affected / exposed	0 / 31 (0.00%)	3 / 170 (1.76%)	0 / 1 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 3	0 / 0	0 / 0
Pain
subjects affected / exposed	0 / 31 (0.00%)	3 / 170 (1.76%)	0 / 1 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Immune system disorders
Hypersensitivity
subjects affected / exposed	0 / 31 (0.00%)	1 / 170 (0.59%)	0 / 1 (0.00%)	0 / 28 (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
Reproductive system and breast disorders
Adnexa uteri mass
subjects affected / exposed	0 / 31 (0.00%)	0 / 170 (0.00%)	0 / 1 (0.00%)	1 / 28 (3.57%)
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
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure
subjects affected / exposed	2 / 31 (6.45%)	1 / 170 (0.59%)	0 / 1 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Chronic obstructive pulmonary disease
subjects affected / exposed	1 / 31 (3.23%)	3 / 170 (1.76%)	0 / 1 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 1	1 / 4	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	0 / 31 (0.00%)	10 / 170 (5.88%)	0 / 1 (0.00%)	3 / 28 (10.71%)
occurrences causally related to treatment / all	0 / 0	0 / 10	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Epistaxis
subjects affected / exposed	0 / 31 (0.00%)	1 / 170 (0.59%)	0 / 1 (0.00%)	0 / 28 (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
Pulmonary embolism
subjects affected / exposed	1 / 31 (3.23%)	3 / 170 (1.76%)	0 / 1 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 1	1 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Hypoxia
subjects affected / exposed	0 / 31 (0.00%)	2 / 170 (1.18%)	0 / 1 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
Immune-mediated lung disease
subjects affected / exposed	0 / 31 (0.00%)	1 / 170 (0.59%)	0 / 1 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	0 / 31 (0.00%)	6 / 170 (3.53%)	0 / 1 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 6	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Pneumonitis
subjects affected / exposed	3 / 31 (9.68%)	7 / 170 (4.12%)	0 / 1 (0.00%)	2 / 28 (7.14%)
occurrences causally related to treatment / all	3 / 3	9 / 9	0 / 0	3 / 3
deaths causally related to treatment / all	1 / 1	1 / 1	0 / 0	0 / 0
Pulmonary haemorrhage
subjects affected / exposed	1 / 31 (3.23%)	0 / 170 (0.00%)	0 / 1 (0.00%)	0 / 28 (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
Pulmonary oedema
subjects affected / exposed	0 / 31 (0.00%)	1 / 170 (0.59%)	0 / 1 (0.00%)	0 / 28 (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
Respiratory distress
subjects affected / exposed	0 / 31 (0.00%)	1 / 170 (0.59%)	0 / 1 (0.00%)	0 / 28 (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
Respiratory failure
subjects affected / exposed	1 / 31 (3.23%)	2 / 170 (1.18%)	0 / 1 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Psychiatric disorders
Confusional state
subjects affected / exposed	0 / 31 (0.00%)	2 / 170 (1.18%)	0 / 1 (0.00%)	0 / 28 (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
Alanine aminotransferase increased
subjects affected / exposed	2 / 31 (6.45%)	2 / 170 (1.18%)	0 / 1 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	2 / 2	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Amylase increased
subjects affected / exposed	3 / 31 (9.68%)	0 / 170 (0.00%)	0 / 1 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	2 / 3	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Aspartate aminotransferase increased
subjects affected / exposed	1 / 31 (3.23%)	1 / 170 (0.59%)	0 / 1 (0.00%)	0 / 28 (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
Blood bilirubin increased
subjects affected / exposed	0 / 31 (0.00%)	1 / 170 (0.59%)	0 / 1 (0.00%)	0 / 28 (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
General physical condition abnormal
subjects affected / exposed	0 / 31 (0.00%)	1 / 170 (0.59%)	0 / 1 (0.00%)	0 / 28 (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
Lipase increased
subjects affected / exposed	2 / 31 (6.45%)	1 / 170 (0.59%)	0 / 1 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	2 / 2	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Troponin I increased
subjects affected / exposed	0 / 31 (0.00%)	0 / 170 (0.00%)	0 / 1 (0.00%)	1 / 28 (3.57%)
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
Blood creatinine increased
subjects affected / exposed	1 / 31 (3.23%)	2 / 170 (1.18%)	0 / 1 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	1 / 1	1 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Compression fracture
subjects affected / exposed	0 / 31 (0.00%)	1 / 170 (0.59%)	0 / 1 (0.00%)	0 / 28 (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
Brachial plexus injury
subjects affected / exposed	1 / 31 (3.23%)	0 / 170 (0.00%)	0 / 1 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Depressed fracture
subjects affected / exposed	0 / 31 (0.00%)	1 / 170 (0.59%)	0 / 1 (0.00%)	0 / 28 (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
Fall
subjects affected / exposed	1 / 31 (3.23%)	1 / 170 (0.59%)	0 / 1 (0.00%)	0 / 28 (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
Hip fracture
subjects affected / exposed	0 / 31 (0.00%)	0 / 170 (0.00%)	0 / 1 (0.00%)	1 / 28 (3.57%)
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
Infusion related reaction
subjects affected / exposed	0 / 31 (0.00%)	1 / 170 (0.59%)	0 / 1 (0.00%)	0 / 28 (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
Tendon rupture
subjects affected / exposed	0 / 31 (0.00%)	1 / 170 (0.59%)	0 / 1 (0.00%)	0 / 28 (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
Cardiac disorders
Atrial fibrillation
subjects affected / exposed	0 / 31 (0.00%)	1 / 170 (0.59%)	0 / 1 (0.00%)	0 / 28 (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
Atrial flutter
subjects affected / exposed	1 / 31 (3.23%)	0 / 170 (0.00%)	0 / 1 (0.00%)	0 / 28 (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 arrest
subjects affected / exposed	0 / 31 (0.00%)	1 / 170 (0.59%)	0 / 1 (0.00%)	0 / 28 (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
Cardiac tamponade
subjects affected / exposed	1 / 31 (3.23%)	1 / 170 (0.59%)	0 / 1 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Tachycardia
subjects affected / exposed	0 / 31 (0.00%)	1 / 170 (0.59%)	0 / 1 (0.00%)	0 / 28 (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
Nodal rhythm
subjects affected / exposed	0 / 31 (0.00%)	1 / 170 (0.59%)	0 / 1 (0.00%)	0 / 28 (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
Pericardial effusion
subjects affected / exposed	0 / 31 (0.00%)	5 / 170 (2.94%)	0 / 1 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 5	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Sinus tachycardia
subjects affected / exposed	0 / 31 (0.00%)	0 / 170 (0.00%)	0 / 1 (0.00%)	1 / 28 (3.57%)
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
Cardio-respiratory arrest
subjects affected / exposed	0 / 31 (0.00%)	1 / 170 (0.59%)	0 / 1 (0.00%)	0 / 28 (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
Nervous system disorders
Dizziness
subjects affected / exposed	0 / 31 (0.00%)	0 / 170 (0.00%)	0 / 1 (0.00%)	1 / 28 (3.57%)
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	1 / 31 (3.23%)	1 / 170 (0.59%)	0 / 1 (0.00%)	1 / 28 (3.57%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Hemiparesis
subjects affected / exposed	0 / 31 (0.00%)	1 / 170 (0.59%)	0 / 1 (0.00%)	0 / 28 (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
Headache
subjects affected / exposed	0 / 31 (0.00%)	1 / 170 (0.59%)	0 / 1 (0.00%)	0 / 28 (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
Encephalitis autoimmune
subjects affected / exposed	1 / 31 (3.23%)	0 / 170 (0.00%)	0 / 1 (0.00%)	0 / 28 (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
Ischaemic stroke
subjects affected / exposed	0 / 31 (0.00%)	1 / 170 (0.59%)	0 / 1 (0.00%)	0 / 28 (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
Radiculopathy
subjects affected / exposed	0 / 31 (0.00%)	1 / 170 (0.59%)	0 / 1 (0.00%)	0 / 28 (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
Metabolic encephalopathy
subjects affected / exposed	2 / 31 (6.45%)	0 / 170 (0.00%)	0 / 1 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Neuralgia
subjects affected / exposed	0 / 31 (0.00%)	1 / 170 (0.59%)	0 / 1 (0.00%)	0 / 28 (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
Polyneuropathy
subjects affected / exposed	0 / 31 (0.00%)	1 / 170 (0.59%)	0 / 1 (0.00%)	0 / 28 (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
Lethargy
subjects affected / exposed	1 / 31 (3.23%)	0 / 170 (0.00%)	0 / 1 (0.00%)	0 / 28 (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
Syncope
subjects affected / exposed	0 / 31 (0.00%)	1 / 170 (0.59%)	0 / 1 (0.00%)	0 / 28 (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
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 31 (0.00%)	1 / 170 (0.59%)	0 / 1 (0.00%)	1 / 28 (3.57%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Thrombocytopenia
subjects affected / exposed	0 / 31 (0.00%)	1 / 170 (0.59%)	0 / 1 (0.00%)	0 / 28 (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
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	0 / 31 (0.00%)	1 / 170 (0.59%)	0 / 1 (0.00%)	0 / 28 (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	0 / 31 (0.00%)	9 / 170 (5.29%)	0 / 1 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	6 / 9	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Ascites
subjects affected / exposed	0 / 31 (0.00%)	1 / 170 (0.59%)	0 / 1 (0.00%)	0 / 28 (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
Autoimmune pancreatitis
subjects affected / exposed	1 / 31 (3.23%)	0 / 170 (0.00%)	0 / 1 (0.00%)	0 / 28 (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
Constipation
subjects affected / exposed	0 / 31 (0.00%)	1 / 170 (0.59%)	0 / 1 (0.00%)	0 / 28 (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
Anal fissure
subjects affected / exposed	1 / 31 (3.23%)	0 / 170 (0.00%)	0 / 1 (0.00%)	0 / 28 (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	1 / 31 (3.23%)	0 / 170 (0.00%)	0 / 1 (0.00%)	0 / 28 (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
Enterocolitis
subjects affected / exposed	0 / 31 (0.00%)	0 / 170 (0.00%)	0 / 1 (0.00%)	1 / 28 (3.57%)
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
Gastric haemorrhage
subjects affected / exposed	0 / 31 (0.00%)	0 / 170 (0.00%)	0 / 1 (0.00%)	1 / 28 (3.57%)
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	0 / 31 (0.00%)	1 / 170 (0.59%)	0 / 1 (0.00%)	0 / 28 (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
Immune-mediated enterocolitis
subjects affected / exposed	0 / 31 (0.00%)	1 / 170 (0.59%)	0 / 1 (0.00%)	0 / 28 (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
Intestinal obstruction
subjects affected / exposed	0 / 31 (0.00%)	1 / 170 (0.59%)	0 / 1 (0.00%)	0 / 28 (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
Intestinal perforation
subjects affected / exposed	0 / 31 (0.00%)	1 / 170 (0.59%)	0 / 1 (0.00%)	0 / 28 (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
Gastritis
subjects affected / exposed	0 / 31 (0.00%)	2 / 170 (1.18%)	0 / 1 (0.00%)	1 / 28 (3.57%)
occurrences causally related to treatment / all	0 / 0	1 / 2	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatitis
subjects affected / exposed	0 / 31 (0.00%)	2 / 170 (1.18%)	0 / 1 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Rectal haemorrhage
subjects affected / exposed	0 / 31 (0.00%)	1 / 170 (0.59%)	0 / 1 (0.00%)	0 / 28 (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
Vomiting
subjects affected / exposed	1 / 31 (3.23%)	2 / 170 (1.18%)	0 / 1 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 1	2 / 5	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Autoimmune hepatitis
subjects affected / exposed	1 / 31 (3.23%)	0 / 170 (0.00%)	0 / 1 (0.00%)	0 / 28 (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
Cholecystitis
subjects affected / exposed	1 / 31 (3.23%)	0 / 170 (0.00%)	0 / 1 (0.00%)	0 / 28 (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-induced liver injury
subjects affected / exposed	0 / 31 (0.00%)	1 / 170 (0.59%)	0 / 1 (0.00%)	0 / 28 (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
Hepatitis
subjects affected / exposed	0 / 31 (0.00%)	2 / 170 (1.18%)	0 / 1 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatotoxicity
subjects affected / exposed	0 / 31 (0.00%)	1 / 170 (0.59%)	0 / 1 (0.00%)	0 / 28 (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
Hepatitis acute
subjects affected / exposed	0 / 31 (0.00%)	1 / 170 (0.59%)	0 / 1 (0.00%)	0 / 28 (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
Skin and subcutaneous tissue disorders
Drug eruption
subjects affected / exposed	0 / 31 (0.00%)	0 / 170 (0.00%)	0 / 1 (0.00%)	1 / 28 (3.57%)
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
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	1 / 31 (3.23%)	3 / 170 (1.76%)	0 / 1 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 2	2 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	1 / 1	0 / 0	0 / 0
Haematuria
subjects affected / exposed	0 / 31 (0.00%)	1 / 170 (0.59%)	0 / 1 (0.00%)	0 / 28 (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
Urinary retention
subjects affected / exposed	1 / 31 (3.23%)	0 / 170 (0.00%)	0 / 1 (0.00%)	0 / 28 (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
Renal failure
subjects affected / exposed	0 / 31 (0.00%)	1 / 170 (0.59%)	0 / 1 (0.00%)	0 / 28 (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
Endocrine disorders
Adrenal insufficiency
subjects affected / exposed	0 / 31 (0.00%)	3 / 170 (1.76%)	0 / 1 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	3 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypophysitis
subjects affected / exposed	0 / 31 (0.00%)	4 / 170 (2.35%)	0 / 1 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	5 / 5	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Thyroiditis
subjects affected / exposed	1 / 31 (3.23%)	0 / 170 (0.00%)	0 / 1 (0.00%)	0 / 28 (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
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	1 / 31 (3.23%)	2 / 170 (1.18%)	0 / 1 (0.00%)	1 / 28 (3.57%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Arthralgia
subjects affected / exposed	0 / 31 (0.00%)	2 / 170 (1.18%)	0 / 1 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Muscular weakness
subjects affected / exposed	0 / 31 (0.00%)	1 / 170 (0.59%)	0 / 1 (0.00%)	0 / 28 (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
Musculoskeletal pain
subjects affected / exposed	0 / 31 (0.00%)	1 / 170 (0.59%)	0 / 1 (0.00%)	0 / 28 (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
Myositis
subjects affected / exposed	0 / 31 (0.00%)	2 / 170 (1.18%)	0 / 1 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pain in extremity
subjects affected / exposed	0 / 31 (0.00%)	1 / 170 (0.59%)	0 / 1 (0.00%)	0 / 28 (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
Neck pain
subjects affected / exposed	0 / 31 (0.00%)	1 / 170 (0.59%)	0 / 1 (0.00%)	0 / 28 (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
Infections and infestations
Cytomegalovirus infection
subjects affected / exposed	0 / 31 (0.00%)	1 / 170 (0.59%)	0 / 1 (0.00%)	0 / 28 (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
Brain abscess
subjects affected / exposed	0 / 31 (0.00%)	1 / 170 (0.59%)	0 / 1 (0.00%)	0 / 28 (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
Diverticulitis
subjects affected / exposed	0 / 31 (0.00%)	1 / 170 (0.59%)	0 / 1 (0.00%)	0 / 28 (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
Empyema
subjects affected / exposed	0 / 31 (0.00%)	0 / 170 (0.00%)	0 / 1 (0.00%)	1 / 28 (3.57%)
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
Encephalitis
subjects affected / exposed	1 / 31 (3.23%)	0 / 170 (0.00%)	0 / 1 (0.00%)	0 / 28 (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
Gastroenteritis
subjects affected / exposed	0 / 31 (0.00%)	1 / 170 (0.59%)	0 / 1 (0.00%)	0 / 28 (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
Pneumonia
subjects affected / exposed	0 / 31 (0.00%)	10 / 170 (5.88%)	0 / 1 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	3 / 13	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Klebsiella sepsis
subjects affected / exposed	0 / 31 (0.00%)	1 / 170 (0.59%)	0 / 1 (0.00%)	0 / 28 (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
Oral fungal infection
subjects affected / exposed	0 / 31 (0.00%)	1 / 170 (0.59%)	0 / 1 (0.00%)	0 / 28 (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
Osteomyelitis
subjects affected / exposed	0 / 31 (0.00%)	1 / 170 (0.59%)	0 / 1 (0.00%)	0 / 28 (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
Herpes zoster
subjects affected / exposed	0 / 31 (0.00%)	1 / 170 (0.59%)	0 / 1 (0.00%)	0 / 28 (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
Pneumonia bacterial
subjects affected / exposed	1 / 31 (3.23%)	0 / 170 (0.00%)	0 / 1 (0.00%)	0 / 28 (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 pneumococcal
subjects affected / exposed	0 / 31 (0.00%)	1 / 170 (0.59%)	0 / 1 (0.00%)	0 / 28 (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
Respiratory tract infection
subjects affected / exposed	0 / 31 (0.00%)	2 / 170 (1.18%)	0 / 1 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Septic shock
subjects affected / exposed	0 / 31 (0.00%)	1 / 170 (0.59%)	0 / 1 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	1 / 31 (3.23%)	1 / 170 (0.59%)	0 / 1 (0.00%)	2 / 28 (7.14%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
Sepsis
subjects affected / exposed	1 / 31 (3.23%)	3 / 170 (1.76%)	0 / 1 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
Metabolism and nutrition disorders
Acidosis
subjects affected / exposed	0 / 31 (0.00%)	0 / 170 (0.00%)	0 / 1 (0.00%)	1 / 28 (3.57%)
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
Dehydration
subjects affected / exposed	0 / 31 (0.00%)	3 / 170 (1.76%)	0 / 1 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Diabetes mellitus
subjects affected / exposed	1 / 31 (3.23%)	0 / 170 (0.00%)	0 / 1 (0.00%)	0 / 28 (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
Diabetic ketoacidosis
subjects affected / exposed	0 / 31 (0.00%)	1 / 170 (0.59%)	0 / 1 (0.00%)	1 / 28 (3.57%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypoglycaemia
subjects affected / exposed	0 / 31 (0.00%)	0 / 170 (0.00%)	0 / 1 (0.00%)	1 / 28 (3.57%)
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	0 / 31 (0.00%)	0 / 170 (0.00%)	0 / 1 (0.00%)	1 / 28 (3.57%)
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
Hypercalcaemia
subjects affected / exposed	0 / 31 (0.00%)	2 / 170 (1.18%)	0 / 1 (0.00%)	1 / 28 (3.57%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypokalaemia
subjects affected / exposed	0 / 31 (0.00%)	1 / 170 (0.59%)	0 / 1 (0.00%)	2 / 28 (7.14%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hyponatraemia
subjects affected / exposed	0 / 31 (0.00%)	3 / 170 (1.76%)	0 / 1 (0.00%)	1 / 28 (3.57%)
occurrences causally related to treatment / all	0 / 0	1 / 4	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypomagnesaemia
subjects affected / exposed	0 / 31 (0.00%)	1 / 170 (0.59%)	0 / 1 (0.00%)	0 / 28 (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

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

Non-serious adverse events	PART 1: PD-L1+ Status	PART 2: PD-L1 Status Independent	PART 1: Not Evaluable/Indeterminate PD-L1 Status	PART 1: PD-L1- Status
Total subjects affected by non serious adverse events
subjects affected / exposed	31 / 31 (100.00%)	161 / 170 (94.71%)	1 / 1 (100.00%)	27 / 28 (96.43%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumour pain
subjects affected / exposed	3 / 31 (9.68%)	1 / 170 (0.59%)	0 / 1 (0.00%)	1 / 28 (3.57%)
occurrences all number	3	1	0	1
Vascular disorders
Hypertension
subjects affected / exposed	0 / 31 (0.00%)	7 / 170 (4.12%)	0 / 1 (0.00%)	5 / 28 (17.86%)
occurrences all number	0	11	0	10
Hot flush
subjects affected / exposed	1 / 31 (3.23%)	2 / 170 (1.18%)	0 / 1 (0.00%)	2 / 28 (7.14%)
occurrences all number	1	2	0	4
Hypotension
subjects affected / exposed	3 / 31 (9.68%)	7 / 170 (4.12%)	0 / 1 (0.00%)	4 / 28 (14.29%)
occurrences all number	4	8	0	4
General disorders and administration site conditions
Asthenia
subjects affected / exposed	1 / 31 (3.23%)	20 / 170 (11.76%)	0 / 1 (0.00%)	2 / 28 (7.14%)
occurrences all number	1	30	0	2
Chills
subjects affected / exposed	2 / 31 (6.45%)	9 / 170 (5.29%)	0 / 1 (0.00%)	2 / 28 (7.14%)
occurrences all number	2	9	0	2
Fatigue
subjects affected / exposed	18 / 31 (58.06%)	43 / 170 (25.29%)	0 / 1 (0.00%)	16 / 28 (57.14%)
occurrences all number	19	51	0	19
Gait disturbance
subjects affected / exposed	0 / 31 (0.00%)	1 / 170 (0.59%)	0 / 1 (0.00%)	2 / 28 (7.14%)
occurrences all number	0	1	0	2
Malaise
subjects affected / exposed	2 / 31 (6.45%)	4 / 170 (2.35%)	0 / 1 (0.00%)	0 / 28 (0.00%)
occurrences all number	2	5	0	0
Oedema peripheral
subjects affected / exposed	4 / 31 (12.90%)	18 / 170 (10.59%)	0 / 1 (0.00%)	3 / 28 (10.71%)
occurrences all number	4	22	0	3
Pyrexia
subjects affected / exposed	5 / 31 (16.13%)	27 / 170 (15.88%)	0 / 1 (0.00%)	5 / 28 (17.86%)
occurrences all number	6	38	0	6
Non-cardiac chest pain
subjects affected / exposed	1 / 31 (3.23%)	12 / 170 (7.06%)	0 / 1 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	13	0	0
Immune system disorders
Hypersensitivity
subjects affected / exposed	0 / 31 (0.00%)	2 / 170 (1.18%)	0 / 1 (0.00%)	2 / 28 (7.14%)
occurrences all number	0	5	0	3
Reproductive system and breast disorders
Pelvic pain
subjects affected / exposed	2 / 31 (6.45%)	0 / 170 (0.00%)	0 / 1 (0.00%)	0 / 28 (0.00%)
occurrences all number	2	0	0	0
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	4 / 31 (12.90%)	45 / 170 (26.47%)	0 / 1 (0.00%)	10 / 28 (35.71%)
occurrences all number	6	58	0	13
Dyspnoea
subjects affected / exposed	8 / 31 (25.81%)	45 / 170 (26.47%)	0 / 1 (0.00%)	12 / 28 (42.86%)
occurrences all number	9	56	0	12
Wheezing
subjects affected / exposed	0 / 31 (0.00%)	2 / 170 (1.18%)	0 / 1 (0.00%)	2 / 28 (7.14%)
occurrences all number	0	2	0	2
Sinus congestion
subjects affected / exposed	1 / 31 (3.23%)	1 / 170 (0.59%)	0 / 1 (0.00%)	2 / 28 (7.14%)
occurrences all number	1	1	0	2
Productive cough
subjects affected / exposed	3 / 31 (9.68%)	17 / 170 (10.00%)	0 / 1 (0.00%)	3 / 28 (10.71%)
occurrences all number	4	21	0	4
Pneumonitis
subjects affected / exposed	5 / 31 (16.13%)	10 / 170 (5.88%)	0 / 1 (0.00%)	2 / 28 (7.14%)
occurrences all number	5	10	0	2
Oropharyngeal pain
subjects affected / exposed	1 / 31 (3.23%)	3 / 170 (1.76%)	0 / 1 (0.00%)	2 / 28 (7.14%)
occurrences all number	1	3	0	2
Nasal congestion
subjects affected / exposed	0 / 31 (0.00%)	3 / 170 (1.76%)	0 / 1 (0.00%)	3 / 28 (10.71%)
occurrences all number	0	3	0	4
Dyspnoea exertional
subjects affected / exposed	4 / 31 (12.90%)	3 / 170 (1.76%)	0 / 1 (0.00%)	3 / 28 (10.71%)
occurrences all number	4	4	0	3
Epistaxis
subjects affected / exposed	0 / 31 (0.00%)	5 / 170 (2.94%)	0 / 1 (0.00%)	3 / 28 (10.71%)
occurrences all number	0	5	0	4
Haemoptysis
subjects affected / exposed	4 / 31 (12.90%)	8 / 170 (4.71%)	0 / 1 (0.00%)	0 / 28 (0.00%)
occurrences all number	4	12	0	0
Hypoxia
subjects affected / exposed	7 / 31 (22.58%)	1 / 170 (0.59%)	0 / 1 (0.00%)	1 / 28 (3.57%)
occurrences all number	7	1	0	2
Psychiatric disorders
Anxiety
subjects affected / exposed	4 / 31 (12.90%)	5 / 170 (2.94%)	0 / 1 (0.00%)	0 / 28 (0.00%)
occurrences all number	4	6	0	0
Confusional state
subjects affected / exposed	2 / 31 (6.45%)	5 / 170 (2.94%)	0 / 1 (0.00%)	0 / 28 (0.00%)
occurrences all number	3	5	0	0
Depression
subjects affected / exposed	1 / 31 (3.23%)	8 / 170 (4.71%)	0 / 1 (0.00%)	2 / 28 (7.14%)
occurrences all number	1	8	0	2
Insomnia
subjects affected / exposed	2 / 31 (6.45%)	12 / 170 (7.06%)	0 / 1 (0.00%)	5 / 28 (17.86%)
occurrences all number	2	12	0	7
Investigations
Alanine aminotransferase increased
subjects affected / exposed	7 / 31 (22.58%)	30 / 170 (17.65%)	0 / 1 (0.00%)	2 / 28 (7.14%)
occurrences all number	8	43	0	2
Amylase increased
subjects affected / exposed	6 / 31 (19.35%)	29 / 170 (17.06%)	0 / 1 (0.00%)	5 / 28 (17.86%)
occurrences all number	8	64	0	6
Aspartate aminotransferase increased
subjects affected / exposed	7 / 31 (22.58%)	33 / 170 (19.41%)	0 / 1 (0.00%)	1 / 28 (3.57%)
occurrences all number	9	48	0	3
Platelet count decreased
subjects affected / exposed	2 / 31 (6.45%)	4 / 170 (2.35%)	0 / 1 (0.00%)	0 / 28 (0.00%)
occurrences all number	2	4	0	0
Blood bicarbonate decreased
subjects affected / exposed	0 / 31 (0.00%)	0 / 170 (0.00%)	0 / 1 (0.00%)	2 / 28 (7.14%)
occurrences all number	0	0	0	3
Blood bilirubin increased
subjects affected / exposed	1 / 31 (3.23%)	1 / 170 (0.59%)	0 / 1 (0.00%)	2 / 28 (7.14%)
occurrences all number	2	1	0	2
Blood creatinine increased
subjects affected / exposed	3 / 31 (9.68%)	22 / 170 (12.94%)	0 / 1 (0.00%)	3 / 28 (10.71%)
occurrences all number	5	35	0	7
International normalised ratio increased
subjects affected / exposed	2 / 31 (6.45%)	0 / 170 (0.00%)	0 / 1 (0.00%)	0 / 28 (0.00%)
occurrences all number	2	0	0	0
Lipase increased
subjects affected / exposed	6 / 31 (19.35%)	28 / 170 (16.47%)	0 / 1 (0.00%)	7 / 28 (25.00%)
occurrences all number	7	45	0	10
Blood alkaline phosphatase increased
subjects affected / exposed	3 / 31 (9.68%)	22 / 170 (12.94%)	0 / 1 (0.00%)	1 / 28 (3.57%)
occurrences all number	3	34	0	2
Weight decreased
subjects affected / exposed	3 / 31 (9.68%)	20 / 170 (11.76%)	0 / 1 (0.00%)	2 / 28 (7.14%)
occurrences all number	3	22	0	2
White blood cell count decreased
subjects affected / exposed	2 / 31 (6.45%)	3 / 170 (1.76%)	0 / 1 (0.00%)	0 / 28 (0.00%)
occurrences all number	4	6	0	0
Injury, poisoning and procedural complications
Fall
subjects affected / exposed	2 / 31 (6.45%)	5 / 170 (2.94%)	0 / 1 (0.00%)	2 / 28 (7.14%)
occurrences all number	2	5	0	4
Cardiac disorders
Sinus tachycardia
subjects affected / exposed	2 / 31 (6.45%)	2 / 170 (1.18%)	0 / 1 (0.00%)	0 / 28 (0.00%)
occurrences all number	3	2	0	0
Nervous system disorders
Dizziness
subjects affected / exposed	5 / 31 (16.13%)	12 / 170 (7.06%)	0 / 1 (0.00%)	3 / 28 (10.71%)
occurrences all number	6	15	0	5
Amnesia
subjects affected / exposed	3 / 31 (9.68%)	1 / 170 (0.59%)	0 / 1 (0.00%)	1 / 28 (3.57%)
occurrences all number	3	1	0	1
Neuropathy peripheral
subjects affected / exposed	2 / 31 (6.45%)	1 / 170 (0.59%)	0 / 1 (0.00%)	1 / 28 (3.57%)
occurrences all number	2	1	0	1
Dysgeusia
subjects affected / exposed	0 / 31 (0.00%)	8 / 170 (4.71%)	0 / 1 (0.00%)	2 / 28 (7.14%)
occurrences all number	0	9	0	2
Headache
subjects affected / exposed	4 / 31 (12.90%)	25 / 170 (14.71%)	0 / 1 (0.00%)	5 / 28 (17.86%)
occurrences all number	7	32	0	7
Peroneal nerve palsy
subjects affected / exposed	0 / 31 (0.00%)	0 / 170 (0.00%)	0 / 1 (0.00%)	2 / 28 (7.14%)
occurrences all number	0	0	0	2
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	5 / 31 (16.13%)	37 / 170 (21.76%)	0 / 1 (0.00%)	6 / 28 (21.43%)
occurrences all number	7	56	0	6
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	2 / 31 (6.45%)	8 / 170 (4.71%)	0 / 1 (0.00%)	3 / 28 (10.71%)
occurrences all number	2	12	0	3
Abdominal pain upper
subjects affected / exposed	1 / 31 (3.23%)	7 / 170 (4.12%)	0 / 1 (0.00%)	2 / 28 (7.14%)
occurrences all number	1	8	0	2
Colitis
subjects affected / exposed	0 / 31 (0.00%)	4 / 170 (2.35%)	0 / 1 (0.00%)	2 / 28 (7.14%)
occurrences all number	0	4	0	2
Constipation
subjects affected / exposed	6 / 31 (19.35%)	25 / 170 (14.71%)	0 / 1 (0.00%)	9 / 28 (32.14%)
occurrences all number	6	31	0	9
Stomatitis
subjects affected / exposed	1 / 31 (3.23%)	8 / 170 (4.71%)	0 / 1 (0.00%)	2 / 28 (7.14%)
occurrences all number	1	8	0	3
Dry mouth
subjects affected / exposed	1 / 31 (3.23%)	12 / 170 (7.06%)	0 / 1 (0.00%)	1 / 28 (3.57%)
occurrences all number	1	12	0	1
Dyspepsia
subjects affected / exposed	0 / 31 (0.00%)	7 / 170 (4.12%)	0 / 1 (0.00%)	4 / 28 (14.29%)
occurrences all number	0	7	0	4
Dysphagia
subjects affected / exposed	0 / 31 (0.00%)	14 / 170 (8.24%)	0 / 1 (0.00%)	3 / 28 (10.71%)
occurrences all number	0	16	0	3
Flatulence
subjects affected / exposed	0 / 31 (0.00%)	3 / 170 (1.76%)	0 / 1 (0.00%)	2 / 28 (7.14%)
occurrences all number	0	3	0	2
Gastrooesophageal reflux disease
subjects affected / exposed	3 / 31 (9.68%)	4 / 170 (2.35%)	0 / 1 (0.00%)	2 / 28 (7.14%)
occurrences all number	3	5	0	2
Nausea
subjects affected / exposed	12 / 31 (38.71%)	48 / 170 (28.24%)	0 / 1 (0.00%)	11 / 28 (39.29%)
occurrences all number	14	57	0	14
Diarrhoea
subjects affected / exposed	7 / 31 (22.58%)	65 / 170 (38.24%)	0 / 1 (0.00%)	12 / 28 (42.86%)
occurrences all number	9	108	0	20
Vomiting
subjects affected / exposed	4 / 31 (12.90%)	20 / 170 (11.76%)	0 / 1 (0.00%)	6 / 28 (21.43%)
occurrences all number	5	23	0	6
Skin and subcutaneous tissue disorders
Alopecia
subjects affected / exposed	3 / 31 (9.68%)	2 / 170 (1.18%)	0 / 1 (0.00%)	1 / 28 (3.57%)
occurrences all number	3	2	0	1
Pruritus
subjects affected / exposed	6 / 31 (19.35%)	43 / 170 (25.29%)	1 / 1 (100.00%)	10 / 28 (35.71%)
occurrences all number	10	78	1	13
Night sweats
subjects affected / exposed	2 / 31 (6.45%)	5 / 170 (2.94%)	0 / 1 (0.00%)	0 / 28 (0.00%)
occurrences all number	2	6	0	0
Dry skin
subjects affected / exposed	1 / 31 (3.23%)	15 / 170 (8.82%)	0 / 1 (0.00%)	3 / 28 (10.71%)
occurrences all number	1	15	0	4
Rash maculo-papular
subjects affected / exposed	3 / 31 (9.68%)	4 / 170 (2.35%)	0 / 1 (0.00%)	6 / 28 (21.43%)
occurrences all number	3	4	0	8
Rash
subjects affected / exposed	7 / 31 (22.58%)	42 / 170 (24.71%)	0 / 1 (0.00%)	8 / 28 (28.57%)
occurrences all number	10	74	0	9
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	1 / 31 (3.23%)	3 / 170 (1.76%)	0 / 1 (0.00%)	2 / 28 (7.14%)
occurrences all number	1	3	0	2
Haematuria
subjects affected / exposed	0 / 31 (0.00%)	3 / 170 (1.76%)	0 / 1 (0.00%)	3 / 28 (10.71%)
occurrences all number	0	3	0	4
Pollakiuria
subjects affected / exposed	0 / 31 (0.00%)	2 / 170 (1.18%)	0 / 1 (0.00%)	4 / 28 (14.29%)
occurrences all number	0	3	0	4
Endocrine disorders
Hyperthyroidism
subjects affected / exposed	1 / 31 (3.23%)	16 / 170 (9.41%)	0 / 1 (0.00%)	2 / 28 (7.14%)
occurrences all number	1	16	0	2
Hypothyroidism
subjects affected / exposed	4 / 31 (12.90%)	15 / 170 (8.82%)	0 / 1 (0.00%)	5 / 28 (17.86%)
occurrences all number	4	15	0	5
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	5 / 31 (16.13%)	25 / 170 (14.71%)	0 / 1 (0.00%)	3 / 28 (10.71%)
occurrences all number	6	34	0	5
Back pain
subjects affected / exposed	5 / 31 (16.13%)	18 / 170 (10.59%)	0 / 1 (0.00%)	2 / 28 (7.14%)
occurrences all number	5	24	0	3
Flank pain
subjects affected / exposed	0 / 31 (0.00%)	2 / 170 (1.18%)	0 / 1 (0.00%)	3 / 28 (10.71%)
occurrences all number	0	2	0	3
Muscular weakness
subjects affected / exposed	2 / 31 (6.45%)	2 / 170 (1.18%)	0 / 1 (0.00%)	7 / 28 (25.00%)
occurrences all number	3	2	0	8
Neck pain
subjects affected / exposed	2 / 31 (6.45%)	7 / 170 (4.12%)	0 / 1 (0.00%)	2 / 28 (7.14%)
occurrences all number	2	7	0	2
Pain in extremity
subjects affected / exposed	1 / 31 (3.23%)	9 / 170 (5.29%)	0 / 1 (0.00%)	1 / 28 (3.57%)
occurrences all number	1	9	0	1
Myalgia
subjects affected / exposed	2 / 31 (6.45%)	14 / 170 (8.24%)	0 / 1 (0.00%)	2 / 28 (7.14%)
occurrences all number	2	16	0	2
Infections and infestations
Upper respiratory tract infection
subjects affected / exposed	0 / 31 (0.00%)	5 / 170 (2.94%)	0 / 1 (0.00%)	3 / 28 (10.71%)
occurrences all number	0	5	0	3
Conjunctivitis
subjects affected / exposed	2 / 31 (6.45%)	2 / 170 (1.18%)	0 / 1 (0.00%)	0 / 28 (0.00%)
occurrences all number	2	3	0	0
Nasopharyngitis
subjects affected / exposed	2 / 31 (6.45%)	9 / 170 (5.29%)	0 / 1 (0.00%)	0 / 28 (0.00%)
occurrences all number	2	11	0	0
Sinusitis
subjects affected / exposed	2 / 31 (6.45%)	3 / 170 (1.76%)	0 / 1 (0.00%)	0 / 28 (0.00%)
occurrences all number	3	3	0	0
Urinary tract infection
subjects affected / exposed	5 / 31 (16.13%)	4 / 170 (2.35%)	0 / 1 (0.00%)	5 / 28 (17.86%)
occurrences all number	5	4	0	5
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	9 / 31 (29.03%)	38 / 170 (22.35%)	0 / 1 (0.00%)	9 / 28 (32.14%)
occurrences all number	9	48	0	10
Dehydration
subjects affected / exposed	2 / 31 (6.45%)	2 / 170 (1.18%)	0 / 1 (0.00%)	3 / 28 (10.71%)
occurrences all number	2	2	0	4
Hypercalcaemia
subjects affected / exposed	0 / 31 (0.00%)	6 / 170 (3.53%)	0 / 1 (0.00%)	2 / 28 (7.14%)
occurrences all number	0	6	0	2
Hyperglycaemia
subjects affected / exposed	2 / 31 (6.45%)	19 / 170 (11.18%)	0 / 1 (0.00%)	0 / 28 (0.00%)
occurrences all number	3	28	0	0
Hyponatraemia
subjects affected / exposed	4 / 31 (12.90%)	16 / 170 (9.41%)	0 / 1 (0.00%)	4 / 28 (14.29%)
occurrences all number	6	21	0	5
Hypoalbuminaemia
subjects affected / exposed	2 / 31 (6.45%)	12 / 170 (7.06%)	0 / 1 (0.00%)	3 / 28 (10.71%)
occurrences all number	4	19	0	4
Hypocalcaemia
subjects affected / exposed	3 / 31 (9.68%)	2 / 170 (1.18%)	0 / 1 (0.00%)	1 / 28 (3.57%)
occurrences all number	6	3	0	2
Hypoglycaemia
subjects affected / exposed	0 / 31 (0.00%)	0 / 170 (0.00%)	0 / 1 (0.00%)	3 / 28 (10.71%)
occurrences all number	0	0	0	3
Hypokalaemia
subjects affected / exposed	5 / 31 (16.13%)	12 / 170 (7.06%)	0 / 1 (0.00%)	4 / 28 (14.29%)
occurrences all number	13	13	0	7
Hypomagnesaemia
subjects affected / exposed	2 / 31 (6.45%)	8 / 170 (4.71%)	0 / 1 (0.00%)	3 / 28 (10.71%)
occurrences all number	3	16	0	5
Hyperkalaemia
subjects affected / exposed	1 / 31 (3.23%)	5 / 170 (2.94%)	0 / 1 (0.00%)	2 / 28 (7.14%)
occurrences all number	1	5	0	2
Hypophosphataemia
subjects affected / exposed	1 / 31 (3.23%)	1 / 170 (0.59%)	0 / 1 (0.00%)	2 / 28 (7.14%)
occurrences all number	1	1	0	3

More information

Top of page

Were there any global substantial amendments to the protocol? Yes

03 Nov 2016

Schedule of Activities Update

29 Mar 2017

Endpoints Update

02 Mar 2018

Inclusion Criteria Update

03 May 2019

Endpoints update

18 Dec 2019

Inclusion/Exclusion Criteria Update

Were there any global interruptions to the trial? No

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

None reported

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Clinical trials

Clinical Trial Results: An Exploratory Study of the Biologic Effects and Biomarkers of Nivolumab in combination with Ipilimumab in Subjects with Treatment-Naive Stage IV or recurrent Non-Small Cell Lung Cancer (NSCLC) (CheckMate 592: CHECKpoint pathway and nivoluMAb clinical Trial Evaluation 592)

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Objective Response Rate (ORR) per Investigator by Blood TMB (bTMB) within PD-L1 Subgroup (TMB Cut-point = 16 mutations/MB)

Primary: Objective Response Rate (ORR) per Investigator by Blood TMB (bTMB) within PD-L1 Subgroup (TMB Cut-point = 16 mutations/MB)

Primary: Objective Response Rate (ORR) per Investigator by Blood TMB (bTMB) within PD-L1 Subgroup (Blood TMB Cut-point = 21-mutations/MB)

Primary: Objective Response Rate (ORR) per Investigator by Blood TMB (bTMB) within PD-L1 Subgroup (Blood TMB Cut-point = 21-mutations/MB)

Primary: Objective Response Rate (ORR) per Investigator by Tissue TMB within PD-L1 Subgroup (Tissue TMB Cut-point = 10-mutations/MB)

Primary: Objective Response Rate (ORR) per Investigator by Tissue TMB within PD-L1 Subgroup (Tissue TMB Cut-point = 10-mutations/MB)

Secondary: Objective Response Rate (ORR) for All Treated Participants by Investigator per RECIST 1.1

Secondary: Objective Response Rate (ORR) for All Treated Participants by Investigator per RECIST 1.1

Secondary: Disease Control Rate (DCR) for Part 1

Secondary: Disease Control Rate (DCR) for Part 1

Secondary: Duration of Response (DOR) for Part 1

Secondary: Duration of Response (DOR) for Part 1

Secondary: Time to Response (TTR) for Part 1

Secondary: Time to Response (TTR) for Part 1

Secondary: Progression Free Survival (PFS)

Secondary: Progression Free Survival (PFS)

Secondary: Number of Participants with Select Adverse Events (AEs) for Study Part 2

Secondary: Number of Participants with Select Adverse Events (AEs) for Study Part 2

Secondary: Number of Participants with Serious Adverse Events (SAEs) for Study Part 2

Secondary: Number of Participants with Serious Adverse Events (SAEs) for Study Part 2

Secondary: Number of Participants with Adverse Events (AEs) for Study Part 2

Secondary: Number of Participants with Adverse Events (AEs) for Study Part 2

Secondary: Overall Survival (OS)

Secondary: Overall Survival (OS)

Post-hoc: Extended Collection of Objective Response Rate (ORR) per Investigator by Blood TMB (bTMB) (TMB Cut-point = 16 mutations/MB)

Post-hoc: Extended Collection of Objective Response Rate (ORR) per Investigator by Blood TMB (bTMB) (TMB Cut-point = 16 mutations/MB)

Post-hoc: Extended Collection of Objective Response Rate (ORR) per Investigator by Blood TMB (bTMB) (Blood TMB Cut-point = 21-mutations/MB)

Post-hoc: Extended Collection of Objective Response Rate (ORR) per Investigator by Blood TMB (bTMB) (Blood TMB Cut-point = 21-mutations/MB)

Post-hoc: Extended Collection of Objective Response Rate (ORR) per Investigator by Tissue TMB (Tissue TMB Cut-point = 10-mutations/MB)

Post-hoc: Extended Collection of Objective Response Rate (ORR) per Investigator by Tissue TMB (Tissue TMB Cut-point = 10-mutations/MB)

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
An Exploratory Study of the Biologic Effects and Biomarkers of Nivolumab in combination with Ipilimumab in Subjects with Treatment-Naive Stage IV or recurrent Non-Small Cell Lung Cancer (NSCLC) (CheckMate 592: CHECKpoint pathway and nivoluMAb clinical Trial Evaluation 592)