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Clinical Trial Results:
A Phase III Multicenter, Randomized, Open-Label Study Evaluating the Efficacy and Safety of Atezolizumab (MPDL3280A, Anti-PD-L1 Antibody) in Combination With Carboplatin+Nab-Paclitaxel for Chemotherapy-Naive Patients With Stage IV Non-Squamous Non-Small Cell Lung Cancer

Summary
EudraCT number	2014-003206-32
Trial protocol	DE BE IT FR ES
Global end of trial date

Results information
Results version number	v1
This version publication date	29 Mar 2019
First version publication date	29 Mar 2019
Other versions	v2 , v3

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

GO29537

ISRCTN number

US NCT number

NCT02367781

WHO universal trial number (UTN)

Sponsor organisation name

F. Hoffmann-La Roche AG

Sponsor organisation address

Grenzacherstrasse 124, Basel, Switzerland, CH-4070

Public contact

F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, 41 616878333, global.trial_information@roche.com

Scientific contact

F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, 41 616878333, lobal.trial_information@roche.com

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

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

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

Analysis stage

Interim

Date of interim/final analysis

15 Mar 2018

Is this the analysis of the primary completion data?

Yes

Primary completion date

15 Mar 2018

Global end of trial reached?

Main objective of the trial

This randomized Phase III, multicenter, open-label study is designed to evaluate the safety and efficacy of atezolizumab (an engineered anti-programmed death-ligand 1 [PD-L1] antibody) in combination with carboplatin+nab-paclitaxel compared with treatment with carboplatin+nab-paclitaxel in chemotherapy-naive subjects with Stage IV non-squamous NSCLC.

Protection of trial subjects

All study subjects were required to read and sign an Informed Consent Form.

Background therapy

Evidence for comparator

Actual start date of recruitment

16 Apr 2015

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Israel: 35

Country: Number of subjects enrolled

Belgium: 21

Country: Number of subjects enrolled

Germany: 132

Country: Number of subjects enrolled

Spain: 71

Country: Number of subjects enrolled

France: 45

Country: Number of subjects enrolled

Italy: 52

Country: Number of subjects enrolled

Canada: 52

Country: Number of subjects enrolled

United States: 315

Worldwide total number of subjects

723

EEA total number of subjects

321

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)

362

From 65 to 84 years

358

85 years and over

Subject disposition

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Recruitment details

Screening details

Subjects in this study included: histologically or cytologically confirmed, Stage IV non-squamous NSCLC; and no prior treatment for Stage IV non-squamous NSCLC.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Arm A (Atezolizumab+Nab-Paclitaxel+Carboplatin)

Arm description

Subjects will receive intravenous (IV) infusion of atezolizumab and carboplatin on Day 1 of each 21-day cycle, and nab-paclitaxel on Days 1, 8, and 15 of each 21-day cycle for 4 or 6 cycles or until loss of clinical benefit whichever occurs first during induction treatment phase. Subjects will receive IV infusion of atezolizumab during maintenance treatment phase until loss of clinical benefit.

Arm type

Experimental

Investigational medicinal product name

Atezolizumab

Investigational medicinal product code

Other name

Tecentriq, MPDL3280A, RO5541267

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Atezolizumab will be administered as IV infusion at a dose of 1200 milligrams (mg) on Day 1 of each 21-day cycle.

Investigational medicinal product name

Nab-Paclitaxel

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Nab-paclitaxel will be administered as IV infusion at a dose of 100 milligrams per square meter (mg/m^2) on Days 1, 8, and 15 of each 21-day cycle.

Investigational medicinal product name

Carboplatin

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Carboplatin will be administered at area under the concentration curve (AUC) 6 milligrams per milliliter per minute (mg/mL/min) on Day 1 of each 21-day cycle.

Arm B (Nab-Paclitaxel+Carboplatin)

Arm description

Subjects will receive IV infusion of carboplatin on Day 1 and nab-paclitaxel on Days 1, 8, and 15 of each 21-day cycle for 4 or 6 cycles or until disease progression whichever occurs first during induction treatment phase. Subjects will receive best supportive care during maintenance treatment phase. Switch maintenance to pemetrexed is also permitted. Subjects who were consented prior to approval of protocol Version 5 will be given the option to cross over to receive atezolizumab as monotherapy until disease progression.

Arm type

Active comparator

Investigational medicinal product name

Nab-paclitaxel

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Nab-paclitaxel will be administered as IV infusion at a dose of 100 milligrams per square meter (mg/m^2) on Days 1, 8, and 15 of each 21-day cycle.

Investigational medicinal product name

Carboplatin

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intracavernous use

Dosage and administration details

Carboplatin will be administered at area under the concentration curve (AUC) 6 milligrams per milliliter per minute (mg/mL/min) on Day 1 of each 21-day cycle.

Investigational medicinal product name

Pemetrexed

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Switch maintenance to pemetrexed can be administered within 6 weeks of Day 1 of the last induction cycle.

Number of subjects in period 1	Arm A (Atezolizumab+Nab-Paclitaxel+Carboplatin)	Arm B (Nab-Paclitaxel+Carboplatin)
Started	483	240
Completed	0	0
Not completed	483	240
Adverse event, serious fatal	240	136
Prolonged Hospitalization	1	-
Consent withdrawn by subject	19	10
Physician decision	1	-
Non-Compliance	1	-
On-going in study	214	88
Lost to follow-up	-	1
Death Prior to First Dose	1	-
Administrative-Change Facility	1	-
Randomized in Error	5	4
Protocol deviation	-	1

Baseline characteristics

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Reporting group title

Arm A (Atezolizumab+Nab-Paclitaxel+Carboplatin)

Reporting group description

Reporting group title

Arm B (Nab-Paclitaxel+Carboplatin)

Reporting group description

Reporting group values	Arm A (Atezolizumab+Nab-Paclitaxel+Carboplatin)	Arm B (Nab-Paclitaxel+Carboplatin)	Total
Number of subjects	483	240	723
Age categorical
Units: Subjects
In utero	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0
Newborns (0-27 days)	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0
Children (2-11 years)	0	0	0
Adolescents (12-17 years)	0	0	0
Adults (18-64 years)	245	117	362
From 65-84 years	236	122	358
85 years and over	2	1	3
Age continuous
Units: years
arithmetic mean (standard deviation)	63.8 ( 9.5 )	64.4 ( 8.9 )	-
Gender categorical
Units: Subjects
Female	206	102	308
Male	277	138	415

End points

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Reporting group title

Arm A (Atezolizumab+Nab-Paclitaxel+Carboplatin)

Reporting group description

Reporting group title

Arm B (Nab-Paclitaxel+Carboplatin)

Reporting group description

Primary: Progression-Free Survival (PFS) as Determined by the Investigator Using Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) in the ITT-WT Population

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End point title

Progression-Free Survival (PFS) as Determined by the Investigator Using Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) in the ITT-WT Population

End point description

PFS is reported for the ITT-WT population. The term "wild type" (WT) refers to randomized subjects who do not have a sensitizing EGFR mutation or ALK translocation.

End point type

Primary

End point timeframe

Up to approximately 35 months after first patient enrolled

End point values	Arm A (Atezolizumab+Nab-Paclitaxel+Carboplatin)	Arm B (Nab-Paclitaxel+Carboplatin)
Number of subjects analysed	451	228
Units: Months
median (confidence interval 95%)
PFS in the ITT-WT Population	7.0 (6.2 to 7.3)	5.5 (4.4 to 5.9)

Statistical Analysis for PFS in the ITT-WT

Comparison groups

Arm A (Atezolizumab+Nab-Paclitaxel+Carboplatin) v Arm B (Nab-Paclitaxel+Carboplatin)

Number of subjects included in analysis

679

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Stratified Log Rank Test

Parameter type

Hazard ratio (HR)

Point estimate

0.64

Confidence interval

level

95%

sides

2-sided

lower limit

0.54

upper limit

0.77

Primary: Overall Survival (OS) in the ITT-WT Population

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End point title

Overall Survival (OS) in the ITT-WT Population

End point description

OS is reported for the ITT-WT population. The term "wild type" (WT) refers to randomized subjects who do not have a sensitizing EGFR mutation or ALK translocation.

End point type

Primary

End point timeframe

Up to approximately 35 months after first patient enrolled

End point values	Arm A (Atezolizumab+Nab-Paclitaxel+Carboplatin)	Arm B (Nab-Paclitaxel+Carboplatin)
Number of subjects analysed	451	228
Units: Months
median (confidence interval 95%)	18.6 (16.0 to 21.2)	13.9 (12.0 to 18.7)

Statistical Analysis for OS in the ITT-WT

Comparison groups

Arm A (Atezolizumab+Nab-Paclitaxel+Carboplatin) v Arm B (Nab-Paclitaxel+Carboplatin)

Number of subjects included in analysis

679

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0331

Method

Startified Log-Rank Test

Parameter type

Hazard ratio (HR)

Point estimate

0.79

Confidence interval

level

95%

sides

2-sided

lower limit

0.64

upper limit

0.98

Secondary: PFS as Determined by the Investigator Using Recist v1.1 in the ITT Population

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End point title

PFS as Determined by the Investigator Using Recist v1.1 in the ITT Population

End point description

End point type

Secondary

End point timeframe

Up to approximately 56 months after first subject enrolled

End point values	Arm A (Atezolizumab+Nab-Paclitaxel+Carboplatin)	Arm B (Nab-Paclitaxel+Carboplatin)
Number of subjects analysed	0 ^[1]	0 ^[2]
Units: Months
median (confidence interval 95%)	( to )	( to )

Notes
[1] - Data will be analyzed at the time of study completion.
[2] - Data will be analyzed at the time of study completion.

No statistical analyses for this end point

Secondary: OS as Determined by the Investigator Using Recist v1.1 in the ITT Population

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End point title

OS as Determined by the Investigator Using Recist v1.1 in the ITT Population

End point description

End point type

Secondary

End point timeframe

Up to approximately 56 months after first subject enrolled

End point values	Arm A (Atezolizumab+Nab-Paclitaxel+Carboplatin)	Arm B (Nab-Paclitaxel+Carboplatin)
Number of subjects analysed	0 ^[3]	0 ^[4]
Units: Months
median (standard deviation)	( )	( )

Notes
[3] - Data will be analyzed at the time of study completion.
[4] - Data will be analyzed at the time of study completion.

No statistical analyses for this end point

Secondary: Percentage of Participants With an Objective Response (OR) (Complete Response [CR] or Partial Response [PR]) as Determined by the Investigator Using RECIST v1.1 in the ITT-WT Population

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End point title

Percentage of Participants With an Objective Response (OR) (Complete Response [CR] or Partial Response [PR]) as Determined by the Investigator Using RECIST v1.1 in the ITT-WT Population

End point description

End point type

Secondary

End point timeframe

Up to approximately 56 months after first subject enrolled

End point values	Arm A (Atezolizumab+Nab-Paclitaxel+Carboplatin)	Arm B (Nab-Paclitaxel+Carboplatin)
Number of subjects analysed	0 ^[5]	0 ^[6]
Units: Percentage of participants
number (confidence interval 95%)	( to )	( to )

Notes
[5] - Data will be analyzed at the time of study completion.
[6] - Data will be analyzed at the time of study completion.

No statistical analyses for this end point

Secondary: Duration of Response (DOR) as Determined by the Investigator Using RECIST v1.1 in ITT-WT Population

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End point title

Duration of Response (DOR) as Determined by the Investigator Using RECIST v1.1 in ITT-WT Population

End point description

End point type

Secondary

End point timeframe

Up to approximately 56 months after first subject enrolled

End point values	Arm A (Atezolizumab+Nab-Paclitaxel+Carboplatin)	Arm B (Nab-Paclitaxel+Carboplatin)
Number of subjects analysed	0 ^[7]	0 ^[8]
Units: Months
median (standard deviation)	( )	( )

Notes
[7] - Data will be analyzed at the time of study completion.
[8] - Data will be analyzed at the time of study completion.

No statistical analyses for this end point

Secondary: Percentage of Subjects Who are Alive at Year 1 and 2 in ITT-WT Population

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End point title

Percentage of Subjects Who are Alive at Year 1 and 2 in ITT-WT Population

End point description

Percentage of subjects who are alive is reported for the ITT-WT population. The term "wild type" (WT) refers to randomized subjects who do not have a sensitizing EGFR mutation or ALK translocation.

End point type

Secondary

End point timeframe

Up to approximately 56 months after first subject enrolled

End point values	Arm A (Atezolizumab+Nab-Paclitaxel+Carboplatin)	Arm B (Nab-Paclitaxel+Carboplatin)
Number of subjects analysed	0 ^[9]	0 ^[10]
Units: Percentage
number (not applicable)

Notes
[9] - Data will be analyzed at the time of study completion.
[10] - Data will be analyzed at the time of study completion.

No statistical analyses for this end point

Secondary: Time to Deterioration (TTD) in Patient-Reported Lung Cancer Symptoms in the ITT-WT Population

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End point title

Time to Deterioration (TTD) in Patient-Reported Lung Cancer Symptoms in the ITT-WT Population

End point description

Defined as time from randomization to confirmed deterioration (10-point change) on the combined European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire−Core (EORTC QLQ-C30) and supplemental lung cancer module (EORTC QLQ-LC13) symptom subscales.

End point type

Secondary

End point timeframe

Up to approximately 56 months after first subject enrolled

End point values	Arm A (Atezolizumab+Nab-Paclitaxel+Carboplatin)	Arm B (Nab-Paclitaxel+Carboplatin)
Number of subjects analysed	0 ^[11]	0 ^[12]
Units: Months
median (confidence interval 95%)	( to )	( to )

Notes
[11] - Data will be analyzed at the time of study completion.
[12] - Data will be analyzed at the time of study completion.

No statistical analyses for this end point

Secondary: Change From Baseline in Patient-Reported Lung Cancer Symptoms Score Using the Symptoms in Lung Cancer (SILC) Scale

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End point title

Change From Baseline in Patient-Reported Lung Cancer Symptoms Score Using the Symptoms in Lung Cancer (SILC) Scale

End point description

End point type

Secondary

End point timeframe

Up to approximately 56 months after first subject enrolled date

End point values	Arm A (Atezolizumab+Nab-Paclitaxel+Carboplatin)	Arm B (Nab-Paclitaxel+Carboplatin)
Number of subjects analysed	0 ^[13]	0 ^[14]
Units: Units on a scale
arithmetic mean (standard deviation)	( )	( )

Notes
[13] - Data will be analyzed at the time of study completion.
[14] - Data will be analyzed at the time of study completion.

No statistical analyses for this end point

Secondary: Percentage of Participants With Adverse Events

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End point title

Percentage of Participants With Adverse Events

End point description

End point type

Secondary

End point timeframe

Up to approximately 56 months after first subject enrolled date

End point values	Arm A (Atezolizumab+Nab-Paclitaxel+Carboplatin)	Arm B (Nab-Paclitaxel+Carboplatin)
Number of subjects analysed	0 ^[15]	0 ^[16]
Units: Percentage
number (not applicable)

Notes
[15] - Data will be analyzed at the time of study completion.
[16] - Data will be analyzed at the time of study completion.

No statistical analyses for this end point

Secondary: Percentage of Participants With Anti-Therapeutic Antibodies (ATAs) to Atezolizumab

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End point title

Percentage of Participants With Anti-Therapeutic Antibodies (ATAs) to Atezolizumab

End point description

End point type

Secondary

End point timeframe

Up to approximately 56 months after first subject enrolled

End point values	Arm A (Atezolizumab+Nab-Paclitaxel+Carboplatin)	Arm B (Nab-Paclitaxel+Carboplatin)
Number of subjects analysed	0 ^[17]	0 ^[18]
Units: Percentage
number (not applicable)

Notes
[17] - Data will be analyzed at the time of study completion.
[18] - Data will be analyzed at the time of study completion.

No statistical analyses for this end point

Secondary: Maximum Observed Serum Concentration (Cmax) of Atezolizumab in Atezolizumab+Carboplatin+Nab-Paclitaxel Arm

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End point title

Maximum Observed Serum Concentration (Cmax) of Atezolizumab in Atezolizumab+Carboplatin+Nab-Paclitaxel Arm ^[19]

End point description

Predose samples will be collected on the same day of treatment administration. The infusion duration of atezolizumab will be of 30-60 minutes.

End point type

Secondary

End point timeframe

Predose on Day (D) 1 of Cycle (Cy) 1,2,3,4,8,16 and every 8 cycles thereafter up to end of treatment (EOT) (approximately 56 months), 0.5 hours (h) post-infusion on D1 of Cy1,3, at 120 days after EOT (up to approximately 56 months)

Notes
[19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Cmax of Atezolizumab is only relevant for arm with Atezolizumab.

End point values	Arm A (Atezolizumab+Nab-Paclitaxel+Carboplatin)
Number of subjects analysed	0 ^[20]
Units: mcg/mL
geometric mean (standard deviation)	( )

Notes
[20] - Data will be analyzed at the time of study completion.

No statistical analyses for this end point

Secondary: Minimum Observed Serum Concentration (Cmin) of Atezolizumab Prior to Infusion in Atezolizumab+Carboplatin+Nab-Paclitaxel Arm

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End point title

Minimum Observed Serum Concentration (Cmin) of Atezolizumab Prior to Infusion in Atezolizumab+Carboplatin+Nab-Paclitaxel Arm ^[21]

End point description

Predose samples will be collected on the same day of treatment administration.

End point type

Secondary

End point timeframe

Predose on D1 of Cy 1, 2, 3, 4, 8, 16 and every 8 cycles thereafter up to EOT (up to approximately 56 months), at 120 days after EOT (up to approximately 56 months) ]

Notes
[21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Cmin of Atezolizumab is only relevant for arm with Atezolizumab.

End point values	Arm A (Atezolizumab+Nab-Paclitaxel+Carboplatin)
Number of subjects analysed	0 ^[22]
Units: mcg/mL
geometric mean (standard deviation)	( )

Notes
[22] - Data will be analyzed at the time of study completion.

No statistical analyses for this end point

Secondary: Plasma Concentration of Carboplatin

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End point title

Plasma Concentration of Carboplatin

End point description

End point type

Secondary

End point timeframe

Predose (same day of treatment administration), 5-10 minutes before end of carboplatin infusion, 1 h after carboplatin infusion (infusion duration=15 to 30 minutes) on D1 of Cy1,3 (1Cy=21 days)(up to approximately 56 months)

End point values	Arm A (Atezolizumab+Nab-Paclitaxel+Carboplatin)	Arm B (Nab-Paclitaxel+Carboplatin)
Number of subjects analysed	0 ^[23]	0 ^[24]
Units: mcg/mL
geometric mean (standard deviation)	( )	( )

Notes
[23] - Data will be analyzed at the time of study completion.
[24] - Data will be analyzed at the time of study completion.

No statistical analyses for this end point

Secondary: Plasma Concentrations of Nab-Paclitaxel Reported as Total Paclitaxel

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End point title

Plasma Concentrations of Nab-Paclitaxel Reported as Total Paclitaxel

End point description

End point type

Secondary

End point timeframe

Predose (same day of treatment administration), 5-10 minutes before end of nab-paclitaxel infusion, 1 h after nab-paclitaxel infusion (infusion duration=30 minutes) on D1 of Cy1,3 (1Cy=21 days)(up to approximately 56 months)

End point values	Arm A (Atezolizumab+Nab-Paclitaxel+Carboplatin)	Arm B (Nab-Paclitaxel+Carboplatin)
Number of subjects analysed	0 ^[25]	0 ^[26]
Units: mcg/mL
geometric mean (standard deviation)	( )	( )

Notes
[25] - Data will be analyzed at the time of study completion.
[26] - Data will be analyzed at the time of study completion.

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

From the first study drug administration to the data cutoff date: 15 March 2018

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

18.0

Reporting group title

Arm B (Nab-Paclitaxel+Carboplatin)

Reporting group description

Reporting group title

Arm A (Atezolizumab+Nab-Paclitaxel+Carboplatin)

Reporting group description

Serious adverse events	Arm B (Nab-Paclitaxel+Carboplatin)	Arm A (Atezolizumab+Nab-Paclitaxel+Carboplatin)
Total subjects affected by serious adverse events
subjects affected / exposed	88 / 232 (37.93%)	240 / 473 (50.74%)
number of deaths (all causes)	134	240
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
TUMOUR PAIN
subjects affected / exposed	0 / 232 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular disorders
ARTERIAL OCCLUSIVE DISEASE
subjects affected / exposed	2 / 232 (0.86%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	1 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
DEEP VEIN THROMBOSIS
subjects affected / exposed	0 / 232 (0.00%)	2 / 473 (0.42%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
EMBOLISM
subjects affected / exposed	1 / 232 (0.43%)	2 / 473 (0.42%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
FEMORAL ARTERY ANEURYSM
subjects affected / exposed	0 / 232 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
HYPOTENSION
subjects affected / exposed	1 / 232 (0.43%)	2 / 473 (0.42%)
occurrences causally related to treatment / all	1 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
JUGULAR VEIN THROMBOSIS
subjects affected / exposed	0 / 232 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
PHLEBITIS
subjects affected / exposed	0 / 232 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
VASCULAR STENOSIS
subjects affected / exposed	0 / 232 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Surgical and medical procedures
ABORTION INDUCED
subjects affected / exposed	0 / 232 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
General disorders and administration site conditions
ASTHENIA
subjects affected / exposed	0 / 232 (0.00%)	3 / 473 (0.63%)
occurrences causally related to treatment / all	0 / 0	3 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
CHEST PAIN
subjects affected / exposed	0 / 232 (0.00%)	5 / 473 (1.06%)
occurrences causally related to treatment / all	0 / 0	1 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
DEATH
subjects affected / exposed	4 / 232 (1.72%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 4	1 / 1
deaths causally related to treatment / all	0 / 4	1 / 1
DRUG INTERACTION
subjects affected / exposed	0 / 232 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
FATIGUE
subjects affected / exposed	2 / 232 (0.86%)	2 / 473 (0.42%)
occurrences causally related to treatment / all	2 / 2	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
GENERAL PHYSICAL HEALTH DETERIORATION
subjects affected / exposed	2 / 232 (0.86%)	4 / 473 (0.85%)
occurrences causally related to treatment / all	2 / 2	1 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
GENERALISED OEDEMA
subjects affected / exposed	0 / 232 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
INFLUENZA LIKE ILLNESS
subjects affected / exposed	0 / 232 (0.00%)	2 / 473 (0.42%)
occurrences causally related to treatment / all	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
MUCOSAL INFLAMMATION
subjects affected / exposed	0 / 232 (0.00%)	2 / 473 (0.42%)
occurrences causally related to treatment / all	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
NON−CARDIAC CHEST PAIN
subjects affected / exposed	0 / 232 (0.00%)	3 / 473 (0.63%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
OEDEMA PERIPHERAL
subjects affected / exposed	1 / 232 (0.43%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
PAIN
subjects affected / exposed	0 / 232 (0.00%)	2 / 473 (0.42%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
PERFORMANCE STATUS DECREASED
subjects affected / exposed	0 / 232 (0.00%)	2 / 473 (0.42%)
occurrences causally related to treatment / all	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
PYREXIA
subjects affected / exposed	2 / 232 (0.86%)	8 / 473 (1.69%)
occurrences causally related to treatment / all	1 / 2	6 / 9
deaths causally related to treatment / all	0 / 0	0 / 0
SUDDEN DEATH
subjects affected / exposed	1 / 232 (0.43%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Immune system disorders
ANAPHYLACTIC REACTION
subjects affected / exposed	0 / 232 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Reproductive system and breast disorders
VAGINAL HAEMORRHAGE
subjects affected / exposed	0 / 232 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
ACUTE RESPIRATORY FAILURE
subjects affected / exposed	0 / 232 (0.00%)	2 / 473 (0.42%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
ASPIRATION
subjects affected / exposed	0 / 232 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
ASTHMA
subjects affected / exposed	0 / 232 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
CHRONIC OBSTRUCTIVE PULMONARY DISEASE
subjects affected / exposed	3 / 232 (1.29%)	12 / 473 (2.54%)
occurrences causally related to treatment / all	1 / 4	0 / 17
deaths causally related to treatment / all	0 / 1	0 / 0
COUGH
subjects affected / exposed	1 / 232 (0.43%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
DYSPNOEA
subjects affected / exposed	1 / 232 (0.43%)	11 / 473 (2.33%)
occurrences causally related to treatment / all	0 / 1	1 / 11
deaths causally related to treatment / all	0 / 0	0 / 0
EPISTAXIS
subjects affected / exposed	1 / 232 (0.43%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
HAEMOPTYSIS
subjects affected / exposed	3 / 232 (1.29%)	5 / 473 (1.06%)
occurrences causally related to treatment / all	0 / 4	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
LUNG DISORDER
subjects affected / exposed	0 / 232 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
ORGANISING PNEUMONIA
subjects affected / exposed	0 / 232 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
OROPHARYNGEAL DISCOMFORT
subjects affected / exposed	0 / 232 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
PLEURAL EFFUSION
subjects affected / exposed	0 / 232 (0.00%)	8 / 473 (1.69%)
occurrences causally related to treatment / all	0 / 0	0 / 8
deaths causally related to treatment / all	0 / 0	0 / 0
PNEUMONITIS
subjects affected / exposed	3 / 232 (1.29%)	7 / 473 (1.48%)
occurrences causally related to treatment / all	1 / 3	7 / 7
deaths causally related to treatment / all	0 / 1	2 / 2
PNEUMOTHORAX
subjects affected / exposed	2 / 232 (0.86%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
PNEUMOTHORAX SPONTANEOUS
subjects affected / exposed	0 / 232 (0.00%)	2 / 473 (0.42%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
PULMONARY EMBOLISM
subjects affected / exposed	5 / 232 (2.16%)	14 / 473 (2.96%)
occurrences causally related to treatment / all	1 / 5	0 / 15
deaths causally related to treatment / all	0 / 1	0 / 4
PULMONARY HAEMORRHAGE
subjects affected / exposed	0 / 232 (0.00%)	2 / 473 (0.42%)
occurrences causally related to treatment / all	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
RESPIRATORY DISTRESS
subjects affected / exposed	0 / 232 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
RESPIRATORY FAILURE
subjects affected / exposed	2 / 232 (0.86%)	3 / 473 (0.63%)
occurrences causally related to treatment / all	1 / 2	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Psychiatric disorders
CONFUSIONAL STATE
subjects affected / exposed	0 / 232 (0.00%)	2 / 473 (0.42%)
occurrences causally related to treatment / all	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
DISORIENTATION
subjects affected / exposed	0 / 232 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
MENTAL STATUS CHANGES
subjects affected / exposed	0 / 232 (0.00%)	4 / 473 (0.85%)
occurrences causally related to treatment / all	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Investigations
ALANINE AMINOTRANSFERASE INCREASED
subjects affected / exposed	0 / 232 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
ASPARTATE AMINOTRANSFERASE INCREASED
subjects affected / exposed	0 / 232 (0.00%)	2 / 473 (0.42%)
occurrences causally related to treatment / all	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
BLOOD ALKALINE PHOSPHATASE INCREASED
subjects affected / exposed	0 / 232 (0.00%)	2 / 473 (0.42%)
occurrences causally related to treatment / all	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
BLOOD CREATININE INCREASED
subjects affected / exposed	0 / 232 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
BLOOD GLUCOSE INCREASED
subjects affected / exposed	0 / 232 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
LYMPHOCYTE COUNT DECREASED
subjects affected / exposed	0 / 232 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
NEUTROPHIL COUNT DECREASED
subjects affected / exposed	0 / 232 (0.00%)	6 / 473 (1.27%)
occurrences causally related to treatment / all	0 / 0	6 / 6
deaths causally related to treatment / all	0 / 0	0 / 0
PLATELET COUNT DECREASED
subjects affected / exposed	1 / 232 (0.43%)	2 / 473 (0.42%)
occurrences causally related to treatment / all	1 / 1	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
WHITE BLOOD CELL COUNT DECREASED
subjects affected / exposed	0 / 232 (0.00%)	4 / 473 (0.85%)
occurrences causally related to treatment / all	0 / 0	4 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Injury, poisoning and procedural complications
FALL
subjects affected / exposed	1 / 232 (0.43%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
FEMORAL NECK FRACTURE
subjects affected / exposed	1 / 232 (0.43%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
FEMUR FRACTURE
subjects affected / exposed	0 / 232 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
INFUSION RELATED REACTION
subjects affected / exposed	0 / 232 (0.00%)	3 / 473 (0.63%)
occurrences causally related to treatment / all	0 / 0	4 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
PUBIS FRACTURE
subjects affected / exposed	0 / 232 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
SPINAL COMPRESSION FRACTURE
subjects affected / exposed	1 / 232 (0.43%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
SPINAL FRACTURE
subjects affected / exposed	0 / 232 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
UPPER LIMB FRACTURE
subjects affected / exposed	1 / 232 (0.43%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders
ACUTE MYOCARDIAL INFARCTION
subjects affected / exposed	1 / 232 (0.43%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
ANGINA UNSTABLE
subjects affected / exposed	0 / 232 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
ATRIAL FIBRILLATION
subjects affected / exposed	1 / 232 (0.43%)	3 / 473 (0.63%)
occurrences causally related to treatment / all	0 / 1	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
ATRIAL FLUTTER
subjects affected / exposed	0 / 232 (0.00%)	2 / 473 (0.42%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
BRADYCARDIA
subjects affected / exposed	0 / 232 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
CARDIAC ANEURYSM
subjects affected / exposed	1 / 232 (0.43%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
CARDIAC ARREST
subjects affected / exposed	0 / 232 (0.00%)	3 / 473 (0.63%)
occurrences causally related to treatment / all	0 / 0	1 / 3
deaths causally related to treatment / all	0 / 0	1 / 2
CARDIAC FAILURE
subjects affected / exposed	0 / 232 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
CARDIAC FAILURE CHRONIC
subjects affected / exposed	1 / 232 (0.43%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
CARDIAC TAMPONADE
subjects affected / exposed	0 / 232 (0.00%)	3 / 473 (0.63%)
occurrences causally related to treatment / all	0 / 0	2 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
CARDIO−RESPIRATORY ARREST
subjects affected / exposed	0 / 232 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
MYOCARDIAL INFARCTION
subjects affected / exposed	1 / 232 (0.43%)	3 / 473 (0.63%)
occurrences causally related to treatment / all	1 / 1	1 / 3
deaths causally related to treatment / all	0 / 0	1 / 3
PALPITATIONS
subjects affected / exposed	0 / 232 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
PERICARDIAL EFFUSION
subjects affected / exposed	0 / 232 (0.00%)	6 / 473 (1.27%)
occurrences causally related to treatment / all	0 / 0	1 / 6
deaths causally related to treatment / all	0 / 0	0 / 0
SUPRAVENTRICULAR TACHYCARDIA
subjects affected / exposed	0 / 232 (0.00%)	2 / 473 (0.42%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
VENTRICULAR TACHYCARDIA
subjects affected / exposed	0 / 232 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	1 / 1
Nervous system disorders
ATAXIA
subjects affected / exposed	0 / 232 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
CAROTID ARTERY STENOSIS
subjects affected / exposed	1 / 232 (0.43%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
CEREBROVASCULAR ACCIDENT
subjects affected / exposed	2 / 232 (0.86%)	3 / 473 (0.63%)
occurrences causally related to treatment / all	0 / 3	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
DIZZINESS
subjects affected / exposed	0 / 232 (0.00%)	2 / 473 (0.42%)
occurrences causally related to treatment / all	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
EMBOLIC STROKE
subjects affected / exposed	0 / 232 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
EPILEPSY
subjects affected / exposed	1 / 232 (0.43%)	2 / 473 (0.42%)
occurrences causally related to treatment / all	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
HEADACHE
subjects affected / exposed	0 / 232 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
HEMIPARESIS
subjects affected / exposed	1 / 232 (0.43%)	2 / 473 (0.42%)
occurrences causally related to treatment / all	0 / 1	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
ISCHAEMIC STROKE
subjects affected / exposed	0 / 232 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
LETHARGY
subjects affected / exposed	0 / 232 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
PARAESTHESIA
subjects affected / exposed	0 / 232 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
SEIZURE
subjects affected / exposed	0 / 232 (0.00%)	2 / 473 (0.42%)
occurrences causally related to treatment / all	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
TOXIC NEUROPATHY
subjects affected / exposed	0 / 232 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
SYNCOPE
subjects affected / exposed	1 / 232 (0.43%)	3 / 473 (0.63%)
occurrences causally related to treatment / all	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
VASOGENIC CEREBRAL OEDEMA
subjects affected / exposed	1 / 232 (0.43%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Blood and lymphatic system disorders
AGRANULOCYTOSIS
subjects affected / exposed	1 / 232 (0.43%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
ANAEMIA
subjects affected / exposed	8 / 232 (3.45%)	13 / 473 (2.75%)
occurrences causally related to treatment / all	6 / 8	12 / 15
deaths causally related to treatment / all	0 / 0	0 / 0
FEBRILE NEUTROPENIA
subjects affected / exposed	5 / 232 (2.16%)	9 / 473 (1.90%)
occurrences causally related to treatment / all	5 / 5	10 / 10
deaths causally related to treatment / all	0 / 0	0 / 0
HAEMOLYTIC URAEMIC SYNDROME
subjects affected / exposed	0 / 232 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
LEUKOPENIA
subjects affected / exposed	0 / 232 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
NEUTROPENIA
subjects affected / exposed	2 / 232 (0.86%)	14 / 473 (2.96%)
occurrences causally related to treatment / all	2 / 2	16 / 16
deaths causally related to treatment / all	0 / 0	0 / 0
PANCYTOPENIA
subjects affected / exposed	1 / 232 (0.43%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
THROMBOCYTOPENIA
subjects affected / exposed	0 / 232 (0.00%)	6 / 473 (1.27%)
occurrences causally related to treatment / all	0 / 0	6 / 6
deaths causally related to treatment / all	0 / 0	0 / 0
Ear and labyrinth disorders
VERTIGO
subjects affected / exposed	0 / 232 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
ABDOMINAL PAIN
subjects affected / exposed	1 / 232 (0.43%)	2 / 473 (0.42%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
ABDOMINAL PAIN LOWER
subjects affected / exposed	0 / 232 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
ABDOMINAL PAIN UPPER
subjects affected / exposed	0 / 232 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
AUTOIMMUNE COLITIS
subjects affected / exposed	0 / 232 (0.00%)	2 / 473 (0.42%)
occurrences causally related to treatment / all	0 / 0	3 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
COLITIS
subjects affected / exposed	0 / 232 (0.00%)	2 / 473 (0.42%)
occurrences causally related to treatment / all	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
CONSTIPATION
subjects affected / exposed	1 / 232 (0.43%)	3 / 473 (0.63%)
occurrences causally related to treatment / all	0 / 1	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
DIARRHOEA
subjects affected / exposed	2 / 232 (0.86%)	14 / 473 (2.96%)
occurrences causally related to treatment / all	1 / 2	12 / 14
deaths causally related to treatment / all	0 / 0	0 / 0
DUODENAL ULCER
subjects affected / exposed	0 / 232 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
GASTRITIS
subjects affected / exposed	1 / 232 (0.43%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
GASTROINTESTINAL HAEMORRHAGE
subjects affected / exposed	0 / 232 (0.00%)	2 / 473 (0.42%)
occurrences causally related to treatment / all	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
GASTROINTESTINAL VASCULAR MALFORMATION HAEMORRHAGIC
subjects affected / exposed	1 / 232 (0.43%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
GASTROOESOPHAGEAL REFLUX DISEASE
subjects affected / exposed	0 / 232 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
ILEUS PARALYTIC
subjects affected / exposed	1 / 232 (0.43%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
LARGE INTESTINAL OBSTRUCTION
subjects affected / exposed	0 / 232 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
LARGE INTESTINAL STENOSIS
subjects affected / exposed	1 / 232 (0.43%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
MELAENA
subjects affected / exposed	0 / 232 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
NAUSEA
subjects affected / exposed	4 / 232 (1.72%)	5 / 473 (1.06%)
occurrences causally related to treatment / all	3 / 5	4 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
OESOPHAGEAL FOOD IMPACTION
subjects affected / exposed	0 / 232 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
SMALL INTESTINAL OBSTRUCTION
subjects affected / exposed	2 / 232 (0.86%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
STOMATITIS
subjects affected / exposed	0 / 232 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
UPPER GASTROINTESTINAL HAEMORRHAGE
subjects affected / exposed	0 / 232 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
VOMITING
subjects affected / exposed	4 / 232 (1.72%)	6 / 473 (1.27%)
occurrences causally related to treatment / all	3 / 5	4 / 7
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatobiliary disorders
AUTOIMMUNE HEPATITIS
subjects affected / exposed	0 / 232 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
BILE DUCT STONE
subjects affected / exposed	0 / 232 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
CHOLECYSTITIS ACUTE
subjects affected / exposed	0 / 232 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
CHOLESTASIS
subjects affected / exposed	1 / 232 (0.43%)	2 / 473 (0.42%)
occurrences causally related to treatment / all	0 / 1	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
HEPATIC CIRRHOSIS
subjects affected / exposed	0 / 232 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	1 / 1
HEPATITIS
subjects affected / exposed	0 / 232 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
HEPATOCELLULAR INJURY
subjects affected / exposed	0 / 232 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
IMMUNE−MEDIATED HEPATITIS
subjects affected / exposed	0 / 232 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
DRUG ERUPTION
subjects affected / exposed	1 / 232 (0.43%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
RASH
subjects affected / exposed	0 / 232 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
SKIN ULCER
subjects affected / exposed	0 / 232 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Renal and urinary disorders
ACUTE KIDNEY INJURY
subjects affected / exposed	0 / 232 (0.00%)	4 / 473 (0.85%)
occurrences causally related to treatment / all	0 / 0	3 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
NEPHRITIS
subjects affected / exposed	0 / 232 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
NEPHROLITHIASIS
subjects affected / exposed	0 / 232 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
NEPHROPATHY TOXIC
subjects affected / exposed	0 / 232 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
POSTRENAL FAILURE
subjects affected / exposed	0 / 232 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
RENAL FAILURE
subjects affected / exposed	2 / 232 (0.86%)	5 / 473 (1.06%)
occurrences causally related to treatment / all	1 / 2	3 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
TUBULOINTERSTITIAL NEPHRITIS
subjects affected / exposed	0 / 232 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Endocrine disorders
ADRENAL INSUFFICIENCY
subjects affected / exposed	0 / 232 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
HYPOTHYROIDISM
subjects affected / exposed	0 / 232 (0.00%)	3 / 473 (0.63%)
occurrences causally related to treatment / all	0 / 0	3 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
ARTHRALGIA
subjects affected / exposed	0 / 232 (0.00%)	2 / 473 (0.42%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
BACK PAIN
subjects affected / exposed	0 / 232 (0.00%)	3 / 473 (0.63%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
BONE PAIN
subjects affected / exposed	0 / 232 (0.00%)	3 / 473 (0.63%)
occurrences causally related to treatment / all	0 / 0	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
MUSCULAR WEAKNESS
subjects affected / exposed	0 / 232 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
MUSCULOSKELETAL CHEST PAIN
subjects affected / exposed	0 / 232 (0.00%)	2 / 473 (0.42%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
MYALGIA
subjects affected / exposed	0 / 232 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
SPINAL PAIN
subjects affected / exposed	1 / 232 (0.43%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
APPENDICITIS PERFORATED
subjects affected / exposed	0 / 232 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
ATYPICAL PNEUMONIA
subjects affected / exposed	0 / 232 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
BACTERAEMIA
subjects affected / exposed	0 / 232 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
BACTERIAL COLITIS
subjects affected / exposed	0 / 232 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
BACTERIAL SEPSIS
subjects affected / exposed	0 / 232 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
BRONCHITIS
subjects affected / exposed	1 / 232 (0.43%)	5 / 473 (1.06%)
occurrences causally related to treatment / all	0 / 1	1 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
CAMPYLOBACTER INFECTION
subjects affected / exposed	0 / 232 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
CATHETER SITE INFECTION
subjects affected / exposed	0 / 232 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
CELLULITIS
subjects affected / exposed	0 / 232 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
CLOSTRIDIUM DIFFICILE INFECTION
subjects affected / exposed	0 / 232 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
CONJUNCTIVITIS
subjects affected / exposed	0 / 232 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
CYSTITIS
subjects affected / exposed	0 / 232 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
DEVICE RELATED INFECTION
subjects affected / exposed	1 / 232 (0.43%)	2 / 473 (0.42%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
DIVERTICULITIS
subjects affected / exposed	1 / 232 (0.43%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
ENCEPHALITIS
subjects affected / exposed	0 / 232 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
ERYSIPELAS
subjects affected / exposed	0 / 232 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
FEBRILE INFECTION
subjects affected / exposed	0 / 232 (0.00%)	2 / 473 (0.42%)
occurrences causally related to treatment / all	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
GANGRENE
subjects affected / exposed	1 / 232 (0.43%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
INFECTION
subjects affected / exposed	1 / 232 (0.43%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
INFECTIOUS PLEURAL EFFUSION
subjects affected / exposed	0 / 232 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
INFLUENZA
subjects affected / exposed	1 / 232 (0.43%)	5 / 473 (1.06%)
occurrences causally related to treatment / all	0 / 1	1 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
LUNG INFECTION
subjects affected / exposed	1 / 232 (0.43%)	14 / 473 (2.96%)
occurrences causally related to treatment / all	0 / 1	5 / 15
deaths causally related to treatment / all	0 / 0	0 / 0
NASOPHARYNGITIS
subjects affected / exposed	0 / 232 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
NEUTROPENIC INFECTION
subjects affected / exposed	1 / 232 (0.43%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
PNEUMONIA
subjects affected / exposed	14 / 232 (6.03%)	28 / 473 (5.92%)
occurrences causally related to treatment / all	3 / 16	6 / 36
deaths causally related to treatment / all	0 / 2	0 / 5
PULMONARY SEPSIS
subjects affected / exposed	0 / 232 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
RESPIRATORY TRACT INFECTION
subjects affected / exposed	1 / 232 (0.43%)	3 / 473 (0.63%)
occurrences causally related to treatment / all	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
SEPSIS
subjects affected / exposed	2 / 232 (0.86%)	6 / 473 (1.27%)
occurrences causally related to treatment / all	1 / 2	1 / 6
deaths causally related to treatment / all	1 / 2	0 / 1
SEPTIC SHOCK
subjects affected / exposed	2 / 232 (0.86%)	5 / 473 (1.06%)
occurrences causally related to treatment / all	0 / 2	3 / 5
deaths causally related to treatment / all	0 / 1	1 / 1
STAPHYLOCOCCAL SEPSIS
subjects affected / exposed	0 / 232 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
TRACHEOBRONCHITIS
subjects affected / exposed	0 / 232 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
UPPER RESPIRATORY TRACT INFECTION
subjects affected / exposed	0 / 232 (0.00%)	2 / 473 (0.42%)
occurrences causally related to treatment / all	0 / 0	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
URINARY TRACT INFECTION
subjects affected / exposed	1 / 232 (0.43%)	4 / 473 (0.85%)
occurrences causally related to treatment / all	1 / 1	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
UROSEPSIS
subjects affected / exposed	1 / 232 (0.43%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Metabolism and nutrition disorders
DECREASED APPETITE
subjects affected / exposed	2 / 232 (0.86%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
DEHYDRATION
subjects affected / exposed	2 / 232 (0.86%)	3 / 473 (0.63%)
occurrences causally related to treatment / all	0 / 2	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
DIABETES MELLITUS
subjects affected / exposed	0 / 232 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
DIABETIC KETOACIDOSIS
subjects affected / exposed	1 / 232 (0.43%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
HYPERGLYCAEMIA
subjects affected / exposed	0 / 232 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
HYPERKALAEMIA
subjects affected / exposed	0 / 232 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
HYPOALBUMINAEMIA
subjects affected / exposed	0 / 232 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
HYPOCALCAEMIA
subjects affected / exposed	0 / 232 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
HYPOKALAEMIA
subjects affected / exposed	2 / 232 (0.86%)	3 / 473 (0.63%)
occurrences causally related to treatment / all	1 / 2	2 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
HYPOMAGNESAEMIA
subjects affected / exposed	0 / 232 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
HYPONATRAEMIA
subjects affected / exposed	0 / 232 (0.00%)	3 / 473 (0.63%)
occurrences causally related to treatment / all	0 / 0	2 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
TYPE 2 DIABETES MELLITUS
subjects affected / exposed	1 / 232 (0.43%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0

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

Non-serious adverse events	Arm B (Nab-Paclitaxel+Carboplatin)	Arm A (Atezolizumab+Nab-Paclitaxel+Carboplatin)
Total subjects affected by non serious adverse events
subjects affected / exposed	226 / 232 (97.41%)	466 / 473 (98.52%)
Vascular disorders
HYPOTENSION
subjects affected / exposed	13 / 232 (5.60%)	32 / 473 (6.77%)
occurrences all number	14	40
HYPERTENSION
subjects affected / exposed	8 / 232 (3.45%)	24 / 473 (5.07%)
occurrences all number	10	29
General disorders and administration site conditions
ASTHENIA
subjects affected / exposed	38 / 232 (16.38%)	84 / 473 (17.76%)
occurrences all number	53	121
CHEST PAIN
subjects affected / exposed	12 / 232 (5.17%)	26 / 473 (5.50%)
occurrences all number	12	31
FATIGUE
subjects affected / exposed	109 / 232 (46.98%)	222 / 473 (46.93%)
occurrences all number	133	276
OEDEMA PERIPHERAL
subjects affected / exposed	25 / 232 (10.78%)	64 / 473 (13.53%)
occurrences all number	28	71
PAIN
subjects affected / exposed	7 / 232 (3.02%)	26 / 473 (5.50%)
occurrences all number	8	30
PYREXIA
subjects affected / exposed	21 / 232 (9.05%)	75 / 473 (15.86%)
occurrences all number	29	96
Respiratory, thoracic and mediastinal disorders
COUGH
subjects affected / exposed	38 / 232 (16.38%)	125 / 473 (26.43%)
occurrences all number	41	145
DYSPNOEA
subjects affected / exposed	46 / 232 (19.83%)	126 / 473 (26.64%)
occurrences all number	54	158
EPISTAXIS
subjects affected / exposed	27 / 232 (11.64%)	68 / 473 (14.38%)
occurrences all number	30	83
HAEMOPTYSIS
subjects affected / exposed	7 / 232 (3.02%)	26 / 473 (5.50%)
occurrences all number	7	33
PRODUCTIVE COUGH
subjects affected / exposed	8 / 232 (3.45%)	33 / 473 (6.98%)
occurrences all number	8	37
Psychiatric disorders
ANXIETY
subjects affected / exposed	8 / 232 (3.45%)	28 / 473 (5.92%)
occurrences all number	8	28
DEPRESSION
subjects affected / exposed	5 / 232 (2.16%)	25 / 473 (5.29%)
occurrences all number	5	25
INSOMNIA
subjects affected / exposed	31 / 232 (13.36%)	68 / 473 (14.38%)
occurrences all number	33	74
Investigations
ALANINE AMINOTRANSFERASE INCREASED
subjects affected / exposed	14 / 232 (6.03%)	24 / 473 (5.07%)
occurrences all number	18	34
BLOOD CREATININE INCREASED
subjects affected / exposed	7 / 232 (3.02%)	25 / 473 (5.29%)
occurrences all number	12	29
NEUTROPHIL COUNT DECREASED
subjects affected / exposed	35 / 232 (15.09%)	93 / 473 (19.66%)
occurrences all number	61	187
PLATELET COUNT DECREASED
subjects affected / exposed	38 / 232 (16.38%)	107 / 473 (22.62%)
occurrences all number	61	177
WEIGHT DECREASED
subjects affected / exposed	28 / 232 (12.07%)	53 / 473 (11.21%)
occurrences all number	29	58
WHITE BLOOD CELL COUNT DECREASED
subjects affected / exposed	18 / 232 (7.76%)	49 / 473 (10.36%)
occurrences all number	28	80
Nervous system disorders
DIZZINESS
subjects affected / exposed	25 / 232 (10.78%)	74 / 473 (15.64%)
occurrences all number	36	85
DYSGEUSIA
subjects affected / exposed	14 / 232 (6.03%)	57 / 473 (12.05%)
occurrences all number	14	60
HEADACHE
subjects affected / exposed	23 / 232 (9.91%)	77 / 473 (16.28%)
occurrences all number	26	92
NEUROPATHY PERIPHERAL
subjects affected / exposed	21 / 232 (9.05%)	53 / 473 (11.21%)
occurrences all number	25	55
PARAESTHESIA
subjects affected / exposed	12 / 232 (5.17%)	40 / 473 (8.46%)
occurrences all number	13	48
PERIPHERAL SENSORY NEUROPATHY
subjects affected / exposed	23 / 232 (9.91%)	60 / 473 (12.68%)
occurrences all number	29	69
Blood and lymphatic system disorders
ANAEMIA
subjects affected / exposed	116 / 232 (50.00%)	255 / 473 (53.91%)
occurrences all number	132	346
LEUKOPENIA
subjects affected / exposed	18 / 232 (7.76%)	51 / 473 (10.78%)
occurrences all number	28	91
NEUTROPENIA
subjects affected / exposed	105 / 232 (45.26%)	212 / 473 (44.82%)
occurrences all number	194	422
THROMBOCYTOPENIA
subjects affected / exposed	60 / 232 (25.86%)	130 / 473 (27.48%)
occurrences all number	95	206
Gastrointestinal disorders
ABDOMINAL PAIN
subjects affected / exposed	17 / 232 (7.33%)	51 / 473 (10.78%)
occurrences all number	20	62
CONSTIPATION
subjects affected / exposed	71 / 232 (30.60%)	168 / 473 (35.52%)
occurrences all number	89	213
DIARRHOEA
subjects affected / exposed	71 / 232 (30.60%)	193 / 473 (40.80%)
occurrences all number	100	300
DYSPEPSIA
subjects affected / exposed	7 / 232 (3.02%)	30 / 473 (6.34%)
occurrences all number	8	31
NAUSEA
subjects affected / exposed	106 / 232 (45.69%)	231 / 473 (48.84%)
occurrences all number	148	345
STOMATITIS
subjects affected / exposed	12 / 232 (5.17%)	37 / 473 (7.82%)
occurrences all number	14	41
VOMITING
subjects affected / exposed	43 / 232 (18.53%)	125 / 473 (26.43%)
occurrences all number	67	214
Skin and subcutaneous tissue disorders
ALOPECIA
subjects affected / exposed	63 / 232 (27.16%)	151 / 473 (31.92%)
occurrences all number	63	153
DRY SKIN
subjects affected / exposed	12 / 232 (5.17%)	24 / 473 (5.07%)
occurrences all number	12	27
PRURITUS
subjects affected / exposed	12 / 232 (5.17%)	53 / 473 (11.21%)
occurrences all number	12	63
RASH
subjects affected / exposed	16 / 232 (6.90%)	66 / 473 (13.95%)
occurrences all number	18	77
Endocrine disorders
HYPOTHYROIDISM
subjects affected / exposed	1 / 232 (0.43%)	50 / 473 (10.57%)
occurrences all number	1	54
Musculoskeletal and connective tissue disorders
ARTHRALGIA
subjects affected / exposed	24 / 232 (10.34%)	70 / 473 (14.80%)
occurrences all number	26	89
BACK PAIN
subjects affected / exposed	16 / 232 (6.90%)	79 / 473 (16.70%)
occurrences all number	16	87
MUSCULAR WEAKNESS
subjects affected / exposed	14 / 232 (6.03%)	22 / 473 (4.65%)
occurrences all number	16	24
MUSCULOSKELETAL PAIN
subjects affected / exposed	10 / 232 (4.31%)	45 / 473 (9.51%)
occurrences all number	10	53
MYALGIA
subjects affected / exposed	10 / 232 (4.31%)	41 / 473 (8.67%)
occurrences all number	11	48
PAIN IN EXTREMITY
subjects affected / exposed	14 / 232 (6.03%)	52 / 473 (10.99%)
occurrences all number	14	58
Infections and infestations
BRONCHITIS
subjects affected / exposed	6 / 232 (2.59%)	26 / 473 (5.50%)
occurrences all number	7	27
NASOPHARYNGITIS
subjects affected / exposed	9 / 232 (3.88%)	29 / 473 (6.13%)
occurrences all number	9	39
PNEUMONIA
subjects affected / exposed	5 / 232 (2.16%)	27 / 473 (5.71%)
occurrences all number	5	28
UPPER RESPIRATORY TRACT INFECTION
subjects affected / exposed	12 / 232 (5.17%)	33 / 473 (6.98%)
occurrences all number	15	47
URINARY TRACT INFECTION
subjects affected / exposed	19 / 232 (8.19%)	59 / 473 (12.47%)
occurrences all number	20	79
Metabolism and nutrition disorders
DECREASED APPETITE
subjects affected / exposed	58 / 232 (25.00%)	142 / 473 (30.02%)
occurrences all number	64	164
DEHYDRATION
subjects affected / exposed	24 / 232 (10.34%)	47 / 473 (9.94%)
occurrences all number	30	68
HYPOKALAEMIA
subjects affected / exposed	24 / 232 (10.34%)	71 / 473 (15.01%)
occurrences all number	29	90
HYPOMAGNESAEMIA
subjects affected / exposed	39 / 232 (16.81%)	94 / 473 (19.87%)
occurrences all number	48	125
HYPONATRAEMIA
subjects affected / exposed	8 / 232 (3.45%)	26 / 473 (5.50%)
occurrences all number	10	41

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Were there any global substantial amendments to the protocol? Yes

24 Aug 2015

Protocol was amended to include change to the name of the test product from MPDL3280A to atezolizumab. The evaluations of progression-free survival at 6 months and at 1 year and overall survival at 3 years have been added as exploratory objectives to further evaluate the clinical benefit of atezolizumab at these time points. The contraception requirements in the inclusion and exclusion criteria and the pregnancy-reporting information have been updated to be consistent with safety information for nab-paclitaxel. The study inclusion criteria have been modified, on the basis of data from an expanding safety database, to allow for patients with treated, asymptomatic cerebellar metastases to be enrolled provided specific criteria are met. The exclusion criteria for history of autoimmune disease has been broadened, on the basis of data from an expanding safety database, to allow for patients with eczema, psoriasis, or lichen simplex chronicus of vitiligo with dermatologic manifestations only to be permitted provided that they meet the specific conditions. The study exclusion criterion regarding treatment with systemic immunostimulatory agents within 6 weeks or 5 half-lives of the drug (whichever is shorter) prior to randomization has been modified to 4 weeks prior to randomization for consistency with more recent atezolizumab protocols. The exclusion criterion specifying that patients with a history of allergic reaction to intravenous contrast that requires steroid pretreatment should have baseline and subsequent tumor assessments performed via magnetic resonance imaging (MRI) has been removed because this is in conflict with Section 4.5.5. Patients with contraindications to contrast may have assessments done with non-contrast computed tomography or MRI.

11 Nov 2015

Protocol was amended to clarify that a wash-out period of at least 4 weeks or five half-lives, whichever is longer, of any systemic immunomodulatory agent is required prior to enrollment.

15 Jun 2016

Protocol was amended to add a co-primary endpoint of overall survival (OS) to the progression-free survival (PFS) primary endpoint. For patients consented and randomized to Arm B after Ethics Committee or Institutional Review Board approval of Protocol GO29537, Version 5 at each respective site, the option for crossover to atezolizumab maintenance therapy has been removed to enable the comparative analyses of the two treatment arms. Patients randomized to Arm B who were consented under previous versions of this protocol prior to the approval of Version 5 will continue to have the option for crossover to atezolizumab maintenance therapy. The total number of patients to be randomized in the study has increased from 550 patients to 650 patients to ensure that the study is adequately powered for the comparative analyses. Erlotinib switch maintenance therapy has been removed from the protocol. A secondary efficacy objective and outcome measure has been added to evaluate the efficacy of atezolizumab + carboplatin + nab-paclitaxel compared with carboplatin + nab-paclitaxel as measured by investigator-assessed time to response (TTR) according to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) for both the intent-to-treat (ITT) and programmed death−ligand 1(PD-L1)−selected populations.

01 Mar 2017

Protocol was amended to include change to the primary analysis populations for the co-primary endpoints of progression-free survival (PFS) and overall survival (OS). OS will be analyzed in the intent-to-treat (ITT) population. PFS will be analyzed in the ITT population and a population with a defined level of expression of a PD-L1 and T-effector gene signature in tumor tissue as determined by an RNA-based assay. Patients with known sensitizing EGFR mutations or ALK translocations will be excluded from the primary analysis populations. The analyses of PFS and OS in all randomized patients will be conducted as secondary analyses. Additional censoring rule for the primary endpoint of PFS for U.S. registration purposes has been removed. The statistical testing procedures have been amended to reflect the change in analysis populations. All endpoints (secondary and exploratory) based on the review by an Independent Review Facility (IRF) have been removed.

24 Oct 2018

Protocol was amended to correct the end of study definition corrected. This correction ensures that the study continues until last patient, last visit or until the Sponsor terminates the study. The inclusion criterion that addresses female contraception has been modified to specify when women must refrain from donating eggs.

29 Mar 2019

Protocol was amended to clarify the inclusion criterion on contraception. In addition, reporting for serious adverse events and adverse events of special interest has been extended to 90 days after last dose of study treatment or until initiation of a new anticancer therapy, whichever occurs first.

Were there any global interruptions to the trial? No

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

None reported

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Clinical trials

Clinical Trial Results: A Phase III Multicenter, Randomized, Open-Label Study Evaluating the Efficacy and Safety of Atezolizumab (MPDL3280A, Anti-PD-L1 Antibody) in Combination With Carboplatin+Nab-Paclitaxel for Chemotherapy-Naive Patients With Stage IV Non-Squamous Non-Small Cell Lung Cancer

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Progression-Free Survival (PFS) as Determined by the Investigator Using Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) in the ITT-WT Population

Primary: Progression-Free Survival (PFS) as Determined by the Investigator Using Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) in the ITT-WT Population

Primary: Overall Survival (OS) in the ITT-WT Population

Primary: Overall Survival (OS) in the ITT-WT Population

Secondary: PFS as Determined by the Investigator Using Recist v1.1 in the ITT Population

Secondary: PFS as Determined by the Investigator Using Recist v1.1 in the ITT Population

Secondary: OS as Determined by the Investigator Using Recist v1.1 in the ITT Population

Secondary: OS as Determined by the Investigator Using Recist v1.1 in the ITT Population

Secondary: Percentage of Participants With an Objective Response (OR) (Complete Response [CR] or Partial Response [PR]) as Determined by the Investigator Using RECIST v1.1 in the ITT-WT Population

Secondary: Percentage of Participants With an Objective Response (OR) (Complete Response [CR] or Partial Response [PR]) as Determined by the Investigator Using RECIST v1.1 in the ITT-WT Population

Secondary: Duration of Response (DOR) as Determined by the Investigator Using RECIST v1.1 in ITT-WT Population

Secondary: Duration of Response (DOR) as Determined by the Investigator Using RECIST v1.1 in ITT-WT Population

Secondary: Percentage of Subjects Who are Alive at Year 1 and 2 in ITT-WT Population

Secondary: Percentage of Subjects Who are Alive at Year 1 and 2 in ITT-WT Population

Secondary: Time to Deterioration (TTD) in Patient-Reported Lung Cancer Symptoms in the ITT-WT Population

Secondary: Time to Deterioration (TTD) in Patient-Reported Lung Cancer Symptoms in the ITT-WT Population

Secondary: Change From Baseline in Patient-Reported Lung Cancer Symptoms Score Using the Symptoms in Lung Cancer (SILC) Scale

Secondary: Change From Baseline in Patient-Reported Lung Cancer Symptoms Score Using the Symptoms in Lung Cancer (SILC) Scale

Secondary: Percentage of Participants With Adverse Events

Secondary: Percentage of Participants With Adverse Events

Secondary: Percentage of Participants With Anti-Therapeutic Antibodies (ATAs) to Atezolizumab

Secondary: Percentage of Participants With Anti-Therapeutic Antibodies (ATAs) to Atezolizumab

Secondary: Maximum Observed Serum Concentration (Cmax) of Atezolizumab in Atezolizumab+Carboplatin+Nab-Paclitaxel Arm

Secondary: Maximum Observed Serum Concentration (Cmax) of Atezolizumab in Atezolizumab+Carboplatin+Nab-Paclitaxel Arm

Secondary: Minimum Observed Serum Concentration (Cmin) of Atezolizumab Prior to Infusion in Atezolizumab+Carboplatin+Nab-Paclitaxel Arm

Secondary: Minimum Observed Serum Concentration (Cmin) of Atezolizumab Prior to Infusion in Atezolizumab+Carboplatin+Nab-Paclitaxel Arm

Secondary: Plasma Concentration of Carboplatin

Secondary: Plasma Concentration of Carboplatin

Secondary: Plasma Concentrations of Nab-Paclitaxel Reported as Total Paclitaxel

Secondary: Plasma Concentrations of Nab-Paclitaxel Reported as Total Paclitaxel

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A Phase III Multicenter, Randomized, Open-Label Study Evaluating the Efficacy and Safety of Atezolizumab (MPDL3280A, Anti-PD-L1 Antibody) in Combination With Carboplatin+Nab-Paclitaxel for Chemotherapy-Naive Patients With Stage IV Non-Squamous Non-Small Cell Lung Cancer