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Clinical Trial Results:
A Phase 3, Randomized, Open-Label Study of the Efficacy and Safety of Crizotinib Versus Pemetrexed/Cisplatin or Pemetrexed/Carboplatin in Previously Untreated Subjects With Non-Squamous Carcinoma of the Lung Harboring a Translocation or Inversion Event Involving the Anaplastic Lymphoma Kinase (ALK) Gene Locus.

Summary
EudraCT number	2010-021336-33
Trial protocol	DE ES FI IE AT IT GB BE NL DK PT NO
Global end of trial date	30 Nov 2016

Results information
Results version number	v1(current)
This version publication date	14 Oct 2017
First version publication date	14 Oct 2017
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

A8081014

ISRCTN number

US NCT number

NCT01154140

WHO universal trial number (UTN)

Sponsor organisation name

Pfizer, Inc.

Sponsor organisation address

235 E 42nd Street, New York, United States, NY 10017

Public contact

Pfizer ClinicalTrials.gov Call Center, Pfizer Inc., 001 18007181021, ClinicalTrials.gov_Inquiries@pfizer.com

Scientific contact

Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., 001 18007181021, ClinicalTrials.gov_Inquiries@pfizer.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

16 Aug 2017

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

30 Nov 2016

Was the trial ended prematurely?

Main objective of the trial

To demonstrate that crizotinib (Arm A) is superior to first-line chemotherapy, pemetrexed/cisplatin or pemetrexed/carboplatin (Arm B), in prolonging progression free survival in subjects with advanced non-small cell lung cancer (NSCLC) whose tumors harbor a translocation or inversion event involving the ALK gene locus.

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 Council for Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were followed.

Background therapy

Evidence for comparator

Actual start date of recruitment

13 Jan 2011

Long term follow-up planned

Yes

Long term follow-up rationale

Efficacy

Long term follow-up duration

72 Months

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Australia: 25

Country: Number of subjects enrolled

Belgium: 6

Country: Number of subjects enrolled

Brazil: 6

Country: Number of subjects enrolled

Canada: 6

Country: Number of subjects enrolled

China: 39

Country: Number of subjects enrolled

Finland: 1

Country: Number of subjects enrolled

France: 15

Country: Number of subjects enrolled

Germany: 6

Country: Number of subjects enrolled

Hong Kong: 3

Country: Number of subjects enrolled

Ireland: 1

Country: Number of subjects enrolled

Italy: 36

Country: Number of subjects enrolled

Japan: 32

Country: Number of subjects enrolled

Korea, Republic of: 55

Country: Number of subjects enrolled

Luxembourg: 2

Country: Number of subjects enrolled

Mexico: 4

Country: Number of subjects enrolled

Netherlands: 1

Country: Number of subjects enrolled

Norway: 1

Country: Number of subjects enrolled

Portugal: 1

Country: Number of subjects enrolled

Russian Federation: 10

Country: Number of subjects enrolled

Singapore: 14

Country: Number of subjects enrolled

South Africa: 1

Country: Number of subjects enrolled

Spain: 35

Country: Number of subjects enrolled

Switzerland: 5

Country: Number of subjects enrolled

Taiwan: 2

Country: Number of subjects enrolled

Ukraine: 6

Country: Number of subjects enrolled

United Kingdom: 2

Country: Number of subjects enrolled

United States: 28

Worldwide total number of subjects

343

EEA total number of subjects

107

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)

288

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Screening details

Subjects with histologically or cytologically proven diagnosis of locally advanced, recurrent, or metastatic non squamous NSCLC and tumors with measurable disease were enrolled. Subjects were to be positive for translocation or inversion events involving the ALK gene locus as determined by an ALK break apart Fluorescence In-Situ Hybridization test.

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

Crizotinib

Arm description

Crizotinib 250 milligram (mg) capsule, orally twice daily was administered in treatment cycle of 21 days. Subjects could continue crizotinib treatment beyond the time of Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 defined progressive disease (PD), as determined by independent radiology review (IRR), at the discretion of the investigator if the subject was perceived to be experiencing clinical benefit.

Arm type

Experimental

Investigational medicinal product name

Crizotinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Crizotinib 250 mg capsule administered orally twice daily in cycles of 21 days.

Chemotherapy

Arm description

Standard doses of chemotherapy (pemetrexed/cisplatin or pemetrexed/carboplatin) were administered intravenously on Day 1 of each cycle for a maximum of 6 cycles. Pemetrexed 500 mg per meter square (m)^2 intravenous (IV) infusion according to standard of care was administered over 10 minutes (min); either cisplatin 75 mg/m^2 IV infusion was administered approximately 30 min after the end of the pemetrexed infusion or carboplatin was administered at a dose calculated to produce an area under the concentration time curve (AUC) of 5 or 6 milligram*minute per millilitre (mg*min/mL), approximately 30 min after end of pemetrexed infusion.

Arm type

Active comparator

Investigational medicinal product name

Pemetrexed

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

Pemetrexed 500 mg/m^2 IV infusion administered over 10 min according to standard of care.

Investigational medicinal product name

Carboplatin

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

Carboplatin IV infusion administered at a dose calculated to produce an AUC of 5 or 6 mg*min/mL over 30 min according to standard of care.

Investigational medicinal product name

Cisplatin

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

Cisplatin 75 mg/m^2 IV infusion administered over 30 min according to standard of care.

Number of subjects in period 1	Crizotinib	Chemotherapy
Started	172	171
Treated	171	169
Completed	81	69
Not completed	91	102
Adverse event, serious fatal	71	81
Consent withdrawn by subject	12	13
Unspecified	3	1
Randomized,not treated	1	2
Lost to follow-up	4	5

Baseline characteristics

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Reporting group title

Crizotinib

Reporting group description

Reporting group title

Chemotherapy

Reporting group description

Reporting group values	Crizotinib	Chemotherapy	Total
Number of subjects	172	171	343
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)	149	139	288
From 65-84 years	23	32	55
85 years and over	0	0	0
Age Continuous
Units: years
arithmetic mean (standard deviation)	50.9 ( 11.9 )	52.9 ( 13.1 )	-
Gender, Male/Female
Units: Subjects
Female	104	108	212
Male	68	63	131

End points

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Reporting group title

Crizotinib

Reporting group description

Reporting group title

Chemotherapy

Reporting group description

Primary: Progression-Free Survival (PFS) Based on IRR

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End point title

Progression-Free Survival (PFS) Based on IRR

End point description

PFS was defined as the time from the date of randomization in study until the date of first documented objective tumor progression (according to RECIST v1.1 as determined by IRR) or death (due to any cause), whichever occurred first. PFS was calculated as (first event date − randomization date +1)/30.44. Objective progression was defined as a 20 percent (%) increase in the sum of the diameters of target measurable lesions taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study), with a minimum absolute increase of 5 millimeter (mm) or clear progression of pre-existing non-target lesions or the appearance of any new clear lesions. Full Analysis (FA)= subjects who were randomized with study treatment assignment designated according to the initial randomization.

End point type

Primary

End point timeframe

Randomization to objective progression, death or last tumor assessment without progression before any additional anti-cancer therapy (up to 35 months)

End point values	Crizotinib	Chemotherapy
Number of subjects analysed	172	171
Units: months
median (confidence interval 95%)	10.9 (8.3 to 13.9)	7 (6.8 to 8.2)

Crizotinib vs Chemotherapy

Comparison groups

Crizotinib v Chemotherapy

Number of subjects included in analysis

343

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

< 0.0001 ^[1]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.454

Confidence interval

level

95%

sides

2-sided

lower limit

0.346

upper limit

0.596

Notes
[1] - P-value was obtained from 1-sided log rank test, stratified by eastern cooperative oncology group performance status (ECOG PS),race,brain metastases. 1-sided log-rank test at 0.0247 level of significance was used to compare PFS between the 2 arms.

Secondary: Overall Survival (OS)

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End point title

Overall Survival (OS)

End point description

OS (in months) was defined as the duration from start of study treatment to date of death due to any cause. OS =(date of death minus the date of randomization of study medication plus 1) divided by 30.4. For subjects who were alive, overall survival was censored on last date the subjects were known to be alive. FA population included all subjects who were randomized with study treatment assignment designated according to the initial randomization.

End point type

Secondary

End point timeframe

From randomization to death or last date known alive for those not known to have died (up to 72 months)

End point values	Crizotinib	Chemotherapy
Number of subjects analysed	172	171
Units: months
median (confidence interval 95%)	99999 (45.8 to 99999)	47.5 (32.2 to 99999)

Crizotinib vs Chemotherapy

Comparison groups

Crizotinib v Chemotherapy

Number of subjects included in analysis

343

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.0489 ^[2]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.76

Confidence interval

level

95%

sides

2-sided

lower limit

0.548

upper limit

1.053

Notes
[2] - P-value was obtained from 1-sided log rank test, stratified by ECOG PS, race group and brain metastases.

Secondary: Overall Survival Probability at Month 12 and 18

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End point title

Overall Survival Probability at Month 12 and 18

End point description

Overall survival probability at Month 12 and 18 was defined as the probability of overall survival at 12 and 18 months respectively, where the OS was defined as the duration from start of study treatment to date of death due to any cause. The survival probability was estimated using the Kaplan-Meier method. FA population included all subjects who were randomized with study treatment assignment designated according to the initial randomization.

End point type

Secondary

End point timeframe

Month 12, 18

End point values	Crizotinib	Chemotherapy
Number of subjects analysed	172	171
Units: percent probability
number (confidence interval 95%)
Month 12	83.5 (77 to 88.3)	78.4 (71.3 to 83.9)
Month 18	71.5 (64 to 77.7)	66.6 (58.8 to 73.2)

No statistical analyses for this end point

Secondary: Objective Response Rate (ORR): Percentage of Subjects With Objective Response as Assessed by IRR

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End point title

Objective Response Rate (ORR): Percentage of Subjects With Objective Response as Assessed by IRR

End point description

ORR was defined as percentage of subjects with complete response (CR) or partial response (PR) according to RECIST v1.1 determined by IRR. CR was defined as complete disappearance of all target lesions and non-target disease. All nodes, both target and non-target, must decrease to normal (short axis less than [<] 10 mm). No new lesions and disappearance of all non-target lesions. PR was defined as greater than or equal to (>=) 30% decrease taking as reference the baseline sum of lesion dimensions. The short axis was used in the sum for target nodes, while the longest diameter was used in the sum for all other target lesions. No clear progression of non-target disease. No new lesions. FA population included all subjects who were randomized with study treatment assignment designated according to the initial randomization.

End point type

Secondary

End point timeframe

Randomization to objective progression, death or last tumor assessment without progression before any additional anti-cancer therapy (up to 35 months)

End point values	Crizotinib	Chemotherapy
Number of subjects analysed	172	171
Units: percentage of subjects
number (confidence interval 95%)	74.4 (67.2 to 80.8)	45 (37.4 to 52.8)

Crizotinib vs Chemotherapy

Statistical analysis description

If the PFS endpoint was significant, ORR was to be considered significant if the 2-sided p-value from Pearson chi-square test was (less than or equal to)<= 0.0494.

Comparison groups

Crizotinib v Chemotherapy

Number of subjects included in analysis

343

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

< 0.0001 ^[3]

Method

Pearson chi-square test

Parameter type

Difference in percentage

Point estimate

29.4

Confidence interval

level

95%

sides

2-sided

lower limit

19.5

upper limit

39.3

Notes
[3] - P-value was obtained from a Pearson chi-square test

Secondary: Duration of Response (DR) Based on IRR

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End point title

Duration of Response (DR) Based on IRR

End point description

Time from first documentation of objective tumor response(CR or PR)to first documentation of PD or death due to any cause,whichever occurred first as per RECISTv1.1 determined by IRR.CR:complete disappearance of all target and non-target disease.All nodes(target, non-target)must decrease to normal(short axis <10 mm).No new lesions,disappearance of all non-target lesions.PR:>=30% decrease taking as reference the baseline sum of lesion dimensions.Short axis was used in sum for target nodes,while longest diameter was used in sum for all or target lesions.No clear progression of non-target disease.c)PD:20 % increase in the sum of the diameters of target measurable lesions taking as reference the smallest sum on study(includes the baseline sum if that is the smallest on study)with a minimum absolute increase of 5 mm or clear progression of pre-existing non-target lesions or the appearance of any new clear lesions.FA set.N=subjects with objective tumor response evaluable for the endpoint.

End point type

Secondary

End point timeframe

From objective response to date of progression, death or last tumor assessment without progression before any additional anti-cancer therapy (up to 35 months)

End point values	Crizotinib	Chemotherapy
Number of subjects analysed	128	77
Units: weeks
median (confidence interval 95%)	49 (35.1 to 60)	22.9 (18 to 25.1)

No statistical analyses for this end point

Secondary: Time to tumor response (TTR) Based on IRR

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End point title

Time to tumor response (TTR) Based on IRR

End point description

TTR was defined as the time from randomization to first documentation of objective tumor response (CR or PR) according to RECIST v1.1 determined by IRR. CR: complete disappearance of all target lesions and non-target disease. All nodes, both target and non-target, must decrease to normal (short axis <10 mm). No new lesions and disappearance of all non-target lesions. PR: >=30% decrease taking as reference the baseline sum of lesion dimensions. Short axis was used in sum for target nodes, while longest diameter was used in sum for all or target lesions. No clear progression of non-target disease. No new lesions. FA population included all subjects who were randomized with study treatment assignment designated according to the initial randomization. Here "N" signifies subjects with objective tumor response and were evaluable for this endpoint.

End point type

Secondary

End point timeframe

Randomization to first documentation of objective tumor response (up to 35 months)

End point values	Crizotinib	Chemotherapy
Number of subjects analysed	128	77
Units: weeks
median (full range (min-max))	6.1 (2.7 to 41.4)	12.1 (5.1 to 36.7)

No statistical analyses for this end point

Secondary: Percentage of Subjects With Disease Control at Week 12 Based on IRR

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End point title

Percentage of Subjects With Disease Control at Week 12 Based on IRR

End point description

Disease control rate at week 12 is defined as the percent of subjects with CR, PR, or stable disease (SD) at week 12 according to RECIST v1.1 determined by IRR. The best response of SD would be assigned if SD criteria was met at least once after randomization at a minimum interval of 6 weeks. CR: complete disappearance of all target lesions and non-target disease, with exception of nodal disease. All nodes, both target and non-target, must decrease to normal (short axis <10 mm). No new lesions and disappearance of all non-target lesions. PR: >=30% decrease taking as reference the baseline sum of lesion dimensions. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters. Short axis was used in sum for target nodes, while longest diameter was used in sum for all or target lesions. No clear progression of non-target disease. No new lesions. FA analysis set.

End point type

Secondary

End point timeframe

Week 12

End point values	Crizotinib	Chemotherapy
Number of subjects analysed	172	171
Units: percentage of subjects
number (confidence interval 95%)	78.5 (71.6 to 84.4)	68.4 (60.9 to 75.3)

Crizotinib vs Chemotherapy

Statistical analysis description

The confidence interval for the difference in percentage was based on normal distribution

Comparison groups

Crizotinib v Chemotherapy

Number of subjects included in analysis

343

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.0381

Method

Pearson chi-square test

Parameter type

Difference in percentage

Point estimate

10.067

Confidence interval

level

95%

sides

2-sided

lower limit

0.8

upper limit

19.4

Secondary: Time to progression (TTP) Based on IRR

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End point title

Time to progression (TTP) Based on IRR

End point description

TTP was defined as the time from the date of randomization to the date of the first documentation of objective tumor progression according to RECIST v1.1 determined by IRR. Objective tumor progression was defined as 20% increase in the sum of the diameters of target measurable lesions taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study), with a minimum absolute increase of 5 mm or clear progression of pre-existing non-target lesions, or the appearance of any new clear lesions. If tumor progression data included more than 1 date, the first date was used. TTP (in months) was calculated as (first event date − randomization date +1)/30.44. FA population included all subjects who were randomized with study treatment assignment designated according to the initial randomization.

End point type

Secondary

End point timeframe

Randomization to objective progression or last tumor assessment without progression before any additional anti-cancer therapy (up to 35 months)

End point values	Crizotinib	Chemotherapy
Number of subjects analysed	172	171
Units: months
median (confidence interval 95%)	13.6 (8.5 to 15)	7 (6.8 to 8.3)

Crizotinib vs Chemotherapy

Statistical analysis description

Analysis was based on the Cox Proportional hazards model assuming proportional hazards, a HR less than 1 indicated a reduction in hazard rate in favor of Crizotinib.

Comparison groups

Crizotinib v Chemotherapy

Number of subjects included in analysis

343

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

< 0.0001 ^[4]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.441

Confidence interval

level

95%

sides

2-sided

lower limit

0.335

upper limit

0.582

Notes
[4] - P-value was obtained from 1-sided unstratified log-rank test.

Secondary: Time to Intracranial Progression (IC-TTP) Based on IRR

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End point title

Time to Intracranial Progression (IC-TTP) Based on IRR

End point description

IC-TTP was defined similarly to TTP, but only considering intracranial disease (excluding extracranial disease) and the progression was determined based on either new brain metastases or progression of existing brain metastases. TTP was defined as the time from the date of randomization to the date of the first documentation of objective tumor progression according to RECIST v1.1 determined by IRR. Objective tumor progression was defined as 20% increase in the sum of the diameters of target measurable lesions taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study), with a minimum absolute increase of 5 mm or clear progression of pre-existing non-target lesions, or the appearance of any new clear lesions. FA population included all subjects who were randomized with study treatment assignment designated according to the initial randomization.

End point type

Secondary

End point timeframe

Randomization to objective intracranial progression or last tumor assessment without progression before any additional anti-cancer therapy (up to 35 months)

End point values	Crizotinib	Chemotherapy
Number of subjects analysed	172	171
Units: months
median (confidence interval 95%)	99999 (99999 to 99999)	17.8 (13.9 to 99999)

Crizotinib vs Chemotherapy

Statistical analysis description

Analysis was based on the Cox Proportional hazards model assuming proportional hazards, a HR less than 1 indicated a reduction in hazard rate in favor of Crizotinib.

Comparison groups

Crizotinib v Chemotherapy

Number of subjects included in analysis

343

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.0347 ^[5]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.595

Confidence interval

level

95%

sides

2-sided

lower limit

0.338

upper limit

1.048

Notes
[5] - P-value was obtained from 1-sided unstratified log-rank test.

Secondary: Time to Extracranial Progression (EC-TTP) Based on IRR

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End point title

Time to Extracranial Progression (EC-TTP) Based on IRR

End point description

EC-TTP was defined similarly to TTP, but only considering extracranial disease (excluding intracranial disease) and the progression was determined based on either new extracranial lesions or progression of existing extracranial lesions. TTP was defined as the time from the date of randomization to the date of the first documentation of objective tumor progression according to RECIST v1.1 determined by IRR. Objective tumor progression was defined as 20% increase in the sum of the diameters of target measurable lesions taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study), with a minimum absolute increase of 5 mm or clear progression of pre-existing non-target lesions, or the appearance of any new clear lesions. FA population included all subjects who were randomized with study treatment assignment designated according to the initial randomization.

End point type

Secondary

End point timeframe

Randomization to objective extracranial progression or last tumor assessment without progression before any additional anti-cancer therapy (up to 35 months)

End point values	Crizotinib	Chemotherapy
Number of subjects analysed	172	171
Units: months
median (confidence interval 95%)	15.2 (12.6 to 21.9)	7.2 (6.9 to 8.5)

Crizotinib vs Chemotherapy

Statistical analysis description

Analysis was based on the Cox Proportional hazards model assuming proportional hazards, a HR less than 1 indicated a reduction in hazard rate in favor of Crizotinib.

Comparison groups

Crizotinib v Chemotherapy

Number of subjects included in analysis

343

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

< 0.0001 ^[6]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.387

Confidence interval

level

95%

sides

2-sided

lower limit

0.286

upper limit

0.524

Notes
[6] - P-value was obtained from 1-sided unstratified log-rank test.

Secondary: Percentage of Subjects With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)

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End point title

Percentage of Subjects With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)

End point description

An AE was any untoward medical occurrence in a subject who received study drug without regard to possibility of causal relationship. SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent are events between first dose of study drug and up to 28 days after last dose of study drug that were absent before treatment or that worsened relative to pretreatment state. AEs included both SAEs and non-SAEs. The safety analysis population included all randomized subjects who received at least 1 dose of study treatment, with treatment assignments designated according to actual study treatment received during the first cycle.

End point type

Secondary

End point timeframe

Baseline up to follow up period (up to 72 months)

End point values	Crizotinib	Chemotherapy
Number of subjects analysed	171	169
Units: percentage of subjects
number (not applicable)
AEs	99.4	99.4
SAEs	41.5	29

No statistical analyses for this end point

Secondary: Percentage of Subjects With Treatment Emergent Treatment-Related Adverse Events (AEs) and Serious Adverse Events (SAEs)

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End point title

Percentage of Subjects With Treatment Emergent Treatment-Related Adverse Events (AEs) and Serious Adverse Events (SAEs)

End point description

Treatment-related AE was any untoward medical occurrence attributed to study drug in a subject who received study drug. SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent were events between first dose of study drug and up to 28 days after last dose of study drug that were absent before treatment or that worsened relative to pre-treatment state. Relatedness to study drug was assessed by the investigator. The safety analysis population included all randomized subjects who received at least 1 dose of study treatment, with treatment assignments designated according to actual study treatment received during the first cycle.

End point type

Secondary

End point timeframe

Baseline up to follow up period (up to 72 months)

End point values	Crizotinib	Chemotherapy
Number of subjects analysed	171	169
Units: percentage of subjects
number (not applicable)
AEs	98.2	92.3
SAEs	12.9	8.9

No statistical analyses for this end point

Secondary: Percentage of Subjects With Adverse Events (AEs) According to Maximum Severity

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End point title

Percentage of Subjects With Adverse Events (AEs) According to Maximum Severity

End point description

An AE was any untoward medical occurrence in a subject who received study drug without regard to possibility of causal relationship. AE was assessed according to maximum severity grading based on National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events [CTCAE] Version 3.0. Grade 1 =mild; Grade 2 =moderate; within normal limits, Grade 3 =severe or medically significant but not immediately life-threatening; Grade 4 =life-threatening or disabling; urgent intervention indicated; Grade 5 =death. The safety analysis population included all randomized subjects who received at least 1 dose of study treatment, with treatment assignments designated according to actual study treatment received during the first cycle.

End point type

Secondary

End point timeframe

Baseline up to follow up period (up to 72 months)

End point values	Crizotinib	Chemotherapy
Number of subjects analysed	171	169
Units: percentage of subjects
number (not applicable)
Grade 1	7	9.5
Grade 2	28.7	34.3
Grade 3	41.5	44.4
Grade 4	8.8	8.9
Grade 5	13.5	2.4

No statistical analyses for this end point

Secondary: Plasma Predose Concentration (Ctrough) of Crizotinib and its Metabolite PF-06260182

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End point title

Plasma Predose Concentration (Ctrough) of Crizotinib and its Metabolite PF-06260182 ^[7]

End point description

Ctrough is the concentration prior to study drug administration on Day 1 of Cycle 2 onwards. PF-06260182 is the metabolite of Crizotinib. The Pharmacokinetic concentration population included all subjects in the safety analysis population who had at least 1 plasma concentration of crizotinib or its metabolite.N= subjects who were evaluable for this measure. n= subjects who were evaluable at specified time points. This analysis was performed in crizotinib arm only.

End point type

Secondary

End point timeframe

Predose at Day 1 of Cycle 2, 3 and 5

Notes
[7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was planned to be reported for Crizotinib arm only.

End point values	Crizotinib
Number of subjects analysed	162
Units: nanogram per milliliter
geometric mean (geometric coefficient of variation)
Crizotinib Ctrough: Cycle 2 Day 1 (n= 91)	324.2 ( 39 )
Crizotinib Ctrough: Cycle 3 Day 1 (n= 85)	320.9 ( 40 )
Crizotinib Ctrough: Cycle 5 Day 1 (n= 82)	308.2 ( 39 )
PF-06260182 Ctrough: Cycle 2 Day 1 (n= 100)	98.4 ( 46 )
PF-06260182 Ctrough: Cycle 3 Day 1 (n= 94)	99 ( 49 )
PF-06260182 Ctrough: Cycle 5 Day 1 (n= 86)	92.9 ( 55 )

No statistical analyses for this end point

Secondary: Percentage of Subjects For Each Anaplastic Lymphoma Kinase (ALK) Gene Fusion Variants

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End point title

Percentage of Subjects For Each Anaplastic Lymphoma Kinase (ALK) Gene Fusion Variants

End point description

The Response Genetics, Inc. Echinoderm Microtubule Associated Protein Like 4 (EML4) ALK reverse transcriptase polymerase chain reaction (RT PCR) gene fusion test was used for the analysis of tissue samples for the ALK gene fusion variants (either no rearrangement, or 1 of 9 results reflecting 8 specific rearrangements [V1, V2, V3a, V3b,V3a/b, V4, V5a, V6, V7]). Percentage of subjects who tested positive for ALK gene fusion variants were reported in this endpoint. The ALK variant evaluable population included subjects from the FA population who had a result from ALK gene fusion variant testing of either no rearrangement, or 1 of 9 results reflecting 8 specific rearrangements (V1, V2, V3a, V3b, V3a/b, V4, V5a, V6, and V7).

End point type

Secondary

End point timeframe

28 days prior to day 1 of study treatment

End point values	Crizotinib	Chemotherapy
Number of subjects analysed	70	78
Units: percentage of subjects
number (not applicable)
V1	27.1	25.6
V2	7.1	7.7
V3a	1.4	1.3
V3a/b	4.3	6.4
No rearrangement	60	59

No statistical analyses for this end point

Secondary: Objective Response Rate (ORR) of Anaplastic Lymphoma Kinase (ALK) Variant Groups Based on IRR

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End point title

Objective Response Rate (ORR) of Anaplastic Lymphoma Kinase (ALK) Variant Groups Based on IRR

End point description

The Response Genetics, Inc. EML4 ALK RTPCR gene fusion test was used for the analysis of tissue samples for the ALK gene fusion variants (either no rearrangement, or 1 of 9 results reflecting 8 specific rearrangements [V1, V2, V3a, V3b,V3a/b, V4, V5a, V6, V7]). Percentage of subjects with confirmed CR or PR according to RECIST v1.1 determined by IRR, by type of ALK gene fusion variant were reported in this outcome measure. CR: complete disappearance of all target lesions and non-target disease. All nodes, both target and non-target, must decrease to normal (short axis<10 mm).No new lesions and disappearance of all non-target lesions.PR:>=30% decrease taking as reference the baseline sum of lesion dimensions. Short axis was used in sum for target nodes, while longest diameter was used in sum for all or target lesions. No clear progression of non-target disease. No new lesions. The ALK variant evaluable set. Here, n signifies those subjects who were evaluable at specified time points.

End point type

Secondary

End point timeframe

Randomization to objective progression, death or last tumor assessment without progression before any additional anti-cancer therapy (up to 35 months)

End point values	Crizotinib	Chemotherapy
Number of subjects analysed	70	78
Units: percentage of subjects
number (confidence interval 95%)
V1 (n =19,20)	84.2 (60.4 to 96.6)	45 (23.1 to 68.5)
V2 (n =5,6)	100 (47.8 to 100)	33.3 (4.3 to 77.7)
V3a (n =1,1)	0 (-99999 to 99999)	100 (2.5 to 100)
V3a/b (n =3,5)	100 (29.2 to 100)	60 (14.7 to 94.7)
No rearrangement (n =42,46)	71.4 (55.4 to 84.3)	43.5 (28.9 to 58.9)

No statistical analyses for this end point

Secondary: Time to Deterioration (TTD) in Chest Pain, Dyspnea or Cough

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End point title

Time to Deterioration (TTD) in Chest Pain, Dyspnea or Cough

End point description

TTD in pain in chest, dyspnea, or cough from the Quality of Life Questionnaire Core 30 (QLQ-LC13) was a composite endpoint defined as the time from randomization to the earliest time the subject scale scores showed a 10 point or greater increase after baseline in any of the 3 symptoms. For those who had not shown deterioration, the data was censored at the last date when the subjects completed an assessment (QLQ-LC13) for pain, dyspnea, or cough or at last visit date prior to crossover for subjects randomized to chemotherapy who crossed over to crizotinib. A 10-point or higher change in the score was perceived by subjects as clinically significant. The transformed score of pain, dyspnea, and cough symptom scales of EORTC (European Organization for the Research and Treatment of Cancer) QLQ-LC13 range from 0 to 100, where higher scores indicate greater symptom severity. The patient reported outcome (PRO) evaluable analysis set.

End point type

Secondary

End point timeframe

From randomization of treatment up to deterioration while on study treatment (up to 35 months)

End point values	Crizotinib	Chemotherapy
Number of subjects analysed	166	163
Units: months
median (confidence interval 95%)	2.1 (0.8 to 4.2)	0.5 (0.4 to 0.7)

Crizotinib vs Chemotherapy

Statistical analysis description

HR was calculated based on the Cox Proportional hazards model. Assuming proportional hazards, a HR less than 1 indicated a reduction in hazard rate in favor of crizotinib.

Comparison groups

Crizotinib v Chemotherapy

Number of subjects included in analysis

329

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.0002 ^[8]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.591

Confidence interval

level

95%

sides

2-sided

lower limit

0.452

upper limit

0.773

Notes
[8] - Two-sided p-value from the unstratified log rank test was used.

Secondary: Change From Baseline in Functioning and Global Quality of Life (QOL) as Assessed by the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC-QLQ-C30)

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End point title

Change From Baseline in Functioning and Global Quality of Life (QOL) as Assessed by the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC-QLQ-C30)

End point description

EORTC QLQ-C30: included 5 functional scales (physical, role, cognitive, emotional and social), global health status/global quality of life scale, 3 symptom scales (fatigue, pain, nausea and vomiting), 6 single items that assess the additional symptoms (dyspnea, appetite loss, sleep disturbance, constipation, diarrhea) and financial difficulties. All scales and single-item measures range from 0 to 100. A high score for a functional scale represents a high/healthy level of functioning, for the global health status/QoL represents a high QoL (better subject state), and for a symptom scale/item represents a high level of symptoms/problems (worse subject state). PRO evaluable population included all subjects from the FA population who completed a baseline and at least 1 postbaseline PRO assessment prior to end of randomized study treatment.

End point type

Secondary

End point timeframe

Baseline, From Cycle 1 Day 1 up to end of study treatment or crossover to crizotinib arm (up to 35 months)

End point values	Crizotinib	Chemotherapy
Number of subjects analysed	166	163
Units: units on a scale
arithmetic mean (confidence interval 95%)
QLQ-C30 Global QoL	5.9815 (3.92 to 8.05)	-7.8488 (-10.15 to -5.55)
QLQ-C30 Cognitive Functioning	1.1836 (-0.66 to 3.03)	-2.1696 (-4.21 to -0.13)
QLQ-C30 Emotional Functioning	8.7431 (6.77 to 10.72)	1.2266 (-0.95 to 3.4)
QLQ-C30 Physical Functioning	5.937 (3.94 to 7.93)	-4.4664 (-6.59 to -2.34)
QLQ-C30 Role Functioning	4.8122 (1.92 to 7.71)	-10.7391 (-13.87 to -7.61)
QLQ-C30 Social Functioning	4.379 (1.6 to 7.15)	-4.3851 (-7.37 to -1.4)

Crizotinib vs Chemotherapy

Statistical analysis description

QLQ-C30 Global QoL: Analysis was from a repeated measures mixed-effects model with an intercept term, treatment, treatment-by-time interaction, and baseline EORTC QLQ-C30 subscale baseline score (intercept and time from first dose are included as random effects).

Comparison groups

Crizotinib v Chemotherapy

Number of subjects included in analysis

329

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

13.8303

Confidence interval

level

95%

sides

2-sided

lower limit

10.74

upper limit

16.92

Crizotinib vs Chemotherapy

Statistical analysis description

QLQ-C30 cognitive functioning: Analysis was from a repeated measures mixed-effects model with an intercept term, treatment, treatment-by-time interaction, and baseline EORTC QLQ-C30 subscale baseline score (intercept and time from first dose are included as random effects).

Comparison groups

Crizotinib v Chemotherapy

Number of subjects included in analysis

329

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.017

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

3.3532

Confidence interval

level

95%

sides

2-sided

lower limit

0.6

upper limit

6.11

Crizotinib vs Chemotherapy

Statistical analysis description

QLQ-C30 emotional functioning: Analysis was from a repeated measures mixed-effects model with an intercept term, treatment, treatment-by-time interaction, and baseline EORTC QLQ-C30 subscale baseline score (intercept and time from first dose are included as random effects).

Comparison groups

Crizotinib v Chemotherapy

Number of subjects included in analysis

329

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

7.5165

Confidence interval

level

95%

sides

2-sided

lower limit

4.57

upper limit

10.46

Crizotinib vs Chemotherapy

Statistical analysis description

QLQ-C30 physical functioning: Analysis was from a repeated measures mixed-effects model with an intercept term, treatment, treatment-by-time interaction, and baseline EORTC QLQ-C30 subscale baseline score (intercept and time from first dose are included as random effects).

Comparison groups

Crizotinib v Chemotherapy

Number of subjects included in analysis

329

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

10.4035

Confidence interval

level

95%

sides

2-sided

lower limit

7.48

upper limit

13.32

Crizotinib vs Chemotherapy

Statistical analysis description

QLQ-C30 role functioning: Analysis was from a repeated measures mixed-effects model with an intercept term, treatment, treatment-by-time interaction, and baseline EORTC QLQ-C30 subscale baseline score (intercept and time from first dose are included as random effects).

Comparison groups

Crizotinib v Chemotherapy

Number of subjects included in analysis

329

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

15.5513

Confidence interval

level

95%

sides

2-sided

lower limit

11.29

upper limit

19.81

Crizotinib vs Chemotherapy

Statistical analysis description

QLQ-C30 social functioning: Analysis was from a repeated measures mixed-effects model with an intercept term, treatment, treatment-by-time interaction, and baseline EORTC QLQ-C30 subscale baseline score (intercept and time from first dose are included as random effects).

Comparison groups

Crizotinib v Chemotherapy

Number of subjects included in analysis

329

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

8.7641

Confidence interval

level

95%

sides

2-sided

lower limit

4.69

upper limit

12.84

Secondary: Change From Baseline Scores in QLQ-C30 Symptoms as Assessed by the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC-QLQ-C30)

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End point title

Change From Baseline Scores in QLQ-C30 Symptoms as Assessed by the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC-QLQ-C30)

End point description

EORTC QLQ-C30: included 5 functional scales (physical, role, cognitive, emotional and social), global health status/global quality of life scale, 3 symptom scales (fatigue, pain, nausea and vomiting), 6 single items that assess the additional symptoms (dyspnea, appetite loss, sleep disturbance, constipation, diarrhea) and financial difficulties. All scales and single-item measures range from 0 to 100. A high score for a functional scale represents a high/healthy level of functioning, for the global health status/QoL represents a high QoL (better subject state), and for a symptom scale/item represents a high level of symptoms/problems (worse subject state). The PRO evaluable population included all subjects from the FA population who completed a baseline and at least 1 postbaseline PRO assessment prior to crossover to crizotinib or end of randomized study treatment.

End point type

Secondary

End point timeframe

Baseline, From Cycle 1 Day 1 up to end of study treatment or crossover to crizotinib arm (up to 35 months)

End point values	Crizotinib	Chemotherapy
Number of subjects analysed	166	163
Units: units on a scale
arithmetic mean (confidence interval 95%)
QLQ-C30 Appetite loss	-5.4906 (-8.52 to -2.47)	8.007 (4.63 to 11.38)
QLQ-C30 Constipation	6.4858 (3.46 to 9.51)	10.9194 (7.5 to 14.34)
QLQ-C30 Diarrhea	12.9558 (10.67 to 15.24)	0.4652 (-2.2 to 3.13)
QLQ-C30 Dysponea	-14.9019 (-17.4 to -12.4)	-1.4398 (-4.21 to 1.33)
QLQ-C30 Fatigue	-7.3476 (-9.72 to -4.98)	7.6511 (5.05 to 10.25)
QLQ-C30 Financial Difficulties	-0.5984 (-3.13 to 1.93)	0.2203 (-2.54 to 2.98)
QLQ-C30 Insomnia	-10.3095 (-13.1 to -7.52)	-0.2665 (-3.38 to 2.84)
QLQ-C30 Nausea and Vomiting	3.7742 (1.54 to 6.01)	7.2188 (4.66 to 9.78)
QLQ-C30 Pain	-11.0993 (-13.27 to -8.92)	-1.1716 (-3.66 to 1.31)

Crizotinib vs Chemotherapy

Statistical analysis description

QLQ-C30 appetite loss: Analysis was from a repeated measures mixed-effects model with an intercept term, treatment, treatment-by-time interaction, and baseline EORTC QLQ-C30 subscale baseline score (intercept and time from first dose are included as random effects).

Comparison groups

Crizotinib v Chemotherapy

Number of subjects included in analysis

329

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

-13.4976

Confidence interval

level

95%

sides

2-sided

lower limit

-18.03

upper limit

-8.97

Crizotinib vs Chemotherapy

Statistical analysis description

QLQ-C30 constipation: Analysis was from a repeated measures mixed-effects model with an intercept term, treatment, treatment-by-time interaction, and baseline EORTC QLQ-C30 subscale baseline score (intercept and time from first dose are included as random effects).

Comparison groups

Crizotinib v Chemotherapy

Number of subjects included in analysis

329

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.057

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

-4.4336

Confidence interval

level

95%

sides

2-sided

lower limit

-9

upper limit

0.13

Crizotinib vs Chemotherapy

Statistical analysis description

QLQ-C30 diarrhea: Analysis was from a repeated measures mixed-effects model with an intercept term, treatment, treatment-by-time interaction, and baseline EORTC QLQ-C30 subscale baseline score (intercept and time from first dose are included as random effects).

Comparison groups

Crizotinib v Chemotherapy

Number of subjects included in analysis

329

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

12.4906

Confidence interval

level

95%

sides

2-sided

lower limit

8.98

upper limit

Crizotinib vs Chemotherapy

Statistical analysis description

QLQ-C30 dysponea: Analysis was from a repeated measures mixed-effects model with an intercept term, treatment, treatment-by-time interaction, and baseline EORTC QLQ-C30 subscale baseline score (intercept and time from first dose are included as random effects).

Comparison groups

Crizotinib v Chemotherapy

Number of subjects included in analysis

329

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

-13.4622

Confidence interval

level

95%

sides

2-sided

lower limit

-17.2

upper limit

-9.73

Crizotinib vs Chemotherapy

Statistical analysis description

QLQ-C30 fatigue: Analysis was from a repeated measures mixed-effects model with an intercept term, treatment, treatment-by-time interaction, and baseline EORTC QLQ-C30 subscale baseline score (intercept and time from first dose are included as random effects).

Comparison groups

Crizotinib v Chemotherapy

Number of subjects included in analysis

329

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

-14.9987

Confidence interval

level

95%

sides

2-sided

lower limit

-18.52

upper limit

-11.48

Crizotinib vs Chemotherapy

Statistical analysis description

QLQ-C30 financial difficulties: Analysis was from a repeated measures mixed-effects model with an intercept term, treatment, treatment-by-time interaction, and baseline EORTC QLQ-C30 subscale baseline score (intercept and time from first dose are included as random effects).

Comparison groups

Crizotinib v Chemotherapy

Number of subjects included in analysis

329

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.6681

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

-0.8186

Confidence interval

level

95%

sides

2-sided

lower limit

-4.56

upper limit

2.92

Crizotinib vs Chemotherapy

Statistical analysis description

QLQ-C30 insomnia: Analysis was from a repeated measures mixed-effects model with an intercept term, treatment, treatment-by-time interaction, and baseline EORTC QLQ-C30 subscale baseline score (intercept and time from first dose are included as random effects).

Comparison groups

Crizotinib v Chemotherapy

Number of subjects included in analysis

329

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

-10.043

Confidence interval

level

95%

sides

2-sided

lower limit

-14.22

upper limit

-5.87

Crizotinib vs Chemotherapy

Statistical analysis description

QLQ-C30 nausea and vomiting: Analysis was from a repeated measures mixed-effects model with an intercept term, treatment, treatment-by-time interaction, and baseline EORTC QLQ-C30 subscale baseline score (intercept and time from first dose are included as random effects).

Comparison groups

Crizotinib v Chemotherapy

Number of subjects included in analysis

329

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.0468

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

-3.4446

Confidence interval

level

95%

sides

2-sided

lower limit

-6.84

upper limit

-0.05

Crizotinib vs Chemotherapy

Statistical analysis description

QLQ-C30 pain: Analysis was from a repeated measures mixed-effects model with an intercept term, treatment, treatment-by-time interaction, and baseline EORTC QLQ-C30 subscale baseline score (intercept and time from first dose are included as random effects).

Comparison groups

Crizotinib v Chemotherapy

Number of subjects included in analysis

329

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

-9.9277

Confidence interval

level

95%

sides

2-sided

lower limit

-13.23

upper limit

-6.62

Secondary: Change From Baseline in Lung Cancer Symptom Scores as Assessed by the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire-Lung Cancer 13 (QLQ- LC13)

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End point title

Change From Baseline in Lung Cancer Symptom Scores as Assessed by the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire-Lung Cancer 13 (QLQ- LC13)

End point description

QLQ-LC13 consists of 1 multi-item scale and 9 single items that assess the specific symptoms (dyspnea, cough, hemoptysis, and site-specific pain), side effects (sore mouth, dysphagia, neuropathy, and alopecia), and pain medication use of patients with lung cancer receiving chemotherapy. All multi-item scales and single-item measures range from 0 to 100, where higher score indicates greater degree of symptom severity. The PRO evaluable population included all subjects from the FA population who completed a baseline and at least 1 postbaseline PRO assessment prior to crossover to crizotinib or end of randomized study treatment.

End point type

Secondary

End point timeframe

Baseline, From Cycle 1 day 1 up to end of study treatment or crossover to crizotinib arm (up to 35 months)

End point values	Crizotinib	Chemotherapy
Number of subjects analysed	166	163
Units: units on a scale
arithmetic mean (confidence interval 95%)
QLQ-LC13 Alopecia	-4.4879 (-6.99 to -1.99)	0.3271 (-2.4 to 3.06)
QLQ-LC13 Coughing	-16.4819 (-18.92 to -14.05)	-8.0893 (-10.83 to -5.35)
QLQ-LC13 Dysphagia	0.7618 (-0.82 to 2.35)	0.0966 (-1.76 to 1.95)
QLQ-LC13 Dyspnoea	-9.2029 (-11.2 to -7.2)	-0.1948 (-2.36 to 1.97)
QLQ-LC13 Haemoptysis	-3.2197 (-3.83 to -2.61)	-2.3369 (-3.05 to -1.62)
QLQ-LC13 Pain in Arm or Shoulder	-10.1693 (-12.26 to -8.08)	-4.1218 (-6.51 to -1.74)
QLQ-LC13 Pain in Chest	-8.1437 (-10.31 to -5.98)	-0.0479 (-2.48 to 2.38)
QLQ-LC13 Pain in Other Parts	-8.0757 (-10.28 to -5.87)	-1.304 (-3.97 to 1.36)
QLQ-LC13 Peripheral Neuropathy	3.1779 (1.04 to 5.31)	-0.1742 (-2.6 to 2.25)
QLQ-LC13 Sore Mouth	2.2472 (0.36 to 4.13)	4.3993 (2.27 to 6.53)

Crizotinib vs Chemotherapy

Statistical analysis description

QLQ-LC13 alopecia: Analysis was from a repeated measures mixed-effects model with an intercept term, treatment, treatment-by-time interaction, and baseline EORTC QLQ-LC13 subscale baseline score (intercept and time from first dose are included as random effects).

Comparison groups

Crizotinib v Chemotherapy

Number of subjects included in analysis

329

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.0108

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

-4.8149

Confidence interval

level

95%

sides

2-sided

lower limit

-8.52

upper limit

-1.11

Crizotinib vs Chemotherapy

Statistical analysis description

QLQ-LC13 coughing: Analysis was from a repeated measures mixed-effects model with an intercept term, treatment, treatment-by-time interaction, and baseline EORTC QLQ-LC13 subscale baseline score (intercept and time from first dose are included as random effects).

Comparison groups

Crizotinib v Chemotherapy

Number of subjects included in analysis

329

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

-8.3926

Confidence interval

level

95%

sides

2-sided

lower limit

-12.06

upper limit

-4.72

Crizotinib vs Chemotherapy

Statistical analysis description

QLQ-LC13 dysphagia: Analysis was from a repeated measures mixed-effects model with an intercept term, treatment, treatment-by-time interaction, and baseline EORTC QLQ-LC13 subscale baseline score (intercept and time from first dose are included as random effects).

Comparison groups

Crizotinib v Chemotherapy

Number of subjects included in analysis

329

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.5938

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

0.6651

Confidence interval

level

95%

sides

2-sided

lower limit

-1.78

upper limit

3.11

Crizotinib vs Chemotherapy

Statistical analysis description

QLQ-LC13 dyspnoea: Analysis was from a repeated measures mixed-effects model with an intercept term, treatment, treatment-by-time interaction, and baseline EORTC QLQ-LC13 subscale baseline score (intercept and time from first dose are included as random effects).

Comparison groups

Crizotinib v Chemotherapy

Number of subjects included in analysis

329

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

-9.008

Confidence interval

level

95%

sides

2-sided

lower limit

-11.96

upper limit

-6.06

Crizotinib vs Chemotherapy

Statistical analysis description

QLQ-LC13 haemoptysis: Analysis was from a repeated measures mixed-effects model with an intercept term, treatment, treatment-by-time interaction, and baseline EORTC QLQ-LC13 subscale baseline score (intercept and time from first dose are included as random effects).

Comparison groups

Crizotinib v Chemotherapy

Number of subjects included in analysis

329

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.0656

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

-0.8828

Confidence interval

level

95%

sides

2-sided

lower limit

-1.82

upper limit

0.06

Crizotinib vs Chemotherapy

Statistical analysis description

QLQ-LC13 pain in arm or shoulder: Analysis was from a repeated measures mixed-effects model with an intercept term, treatment, treatment-by-time interaction, and baseline EORTC QLQ-LC13 subscale baseline score (intercept and time from first dose are included as random effects).

Comparison groups

Crizotinib v Chemotherapy

Number of subjects included in analysis

329

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.0002

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

-6.0475

Confidence interval

level

95%

sides

2-sided

lower limit

-9.22

upper limit

-2.88

Crizotinib vs Chemotherapy

Statistical analysis description

QLQ-LC13 pain in chest: Analysis was from a repeated measures mixed-effects model with an intercept term, treatment, treatment-by-time interaction, and baseline EORTC QLQ-LC13 subscale baseline score (intercept and time from first dose are included as random effects).

Comparison groups

Crizotinib v Chemotherapy

Number of subjects included in analysis

329

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

-8.0959

Confidence interval

level

95%

sides

2-sided

lower limit

-11.35

upper limit

-4.84

Crizotinib vs Chemotherapy

Statistical analysis description

QLQ-LC13 pain in other parts: Analysis was from a repeated measures mixed-effects model with an intercept term, treatment, treatment-by-time interaction, and baseline EORTC QLQ-LC13 subscale baseline score (intercept and time from first dose are included as random effects).

Comparison groups

Crizotinib v Chemotherapy

Number of subjects included in analysis

329

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.0001

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

-6.7717

Confidence interval

level

95%

sides

2-sided

lower limit

-10.24

upper limit

-3.31

Crizotinib vs Chemotherapy

Statistical analysis description

QLQ-LC13 peripheral neuropathy: Analysis was from a repeated measures mixed-effects model with an intercept term, treatment, treatment-by-time interaction, and baseline EORTC QLQ-LC13 subscale baseline score (intercept and time from first dose are included as random effects).

Comparison groups

Crizotinib v Chemotherapy

Number of subjects included in analysis

329

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.0427

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

3.3521

Confidence interval

level

95%

sides

2-sided

lower limit

0.11

upper limit

6.59

Crizotinib vs Chemotherapy

Statistical analysis description

QLQ-LC13 sore mouth: Analysis was from a repeated measures mixed-effects model with an intercept term, treatment, treatment-by-time interaction, and baseline EORTC QLQ-LC13 subscale baseline score (intercept and time from first dose are included as random effects).

Comparison groups

Crizotinib v Chemotherapy

Number of subjects included in analysis

329

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.1382

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

-2.1521

Confidence interval

level

95%

sides

2-sided

lower limit

-5

upper limit

0.69

Secondary: Change From Baseline in General Health Status as Assessed by EuroQol 5D (EQ-5D)- Visual Analog Scale (VAS)

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End point title

Change From Baseline in General Health Status as Assessed by EuroQol 5D (EQ-5D)- Visual Analog Scale (VAS)

End point description

EQ-5D: subject rated questionnaire to assess health-related quality of life in terms of a single index value. VAS component: subjects rated their current health state on a scale from 0 (worst imaginable health state) to 100 (best imaginable health state); higher scores indicate a better health. The PRO evaluable population included all subjects from the FA population who completed a baseline and at least 1 postbaseline PRO assessment prior to crossover to crizotinib or end of randomized study treatment. Here, "N" signifies participants who were evaluable for this outcome measure.

End point type

Secondary

End point timeframe

Baseline, From Cycle 1 day 1 up to end of study treatment or crossover to crizotinib arm (up to 35 months)

End point values	Crizotinib	Chemotherapy
Number of subjects analysed	160	160
Units: units on a scale
arithmetic mean (confidence interval 95%)	4.5323 (2.44 to 6.62)	0.5415 (-1.85 to 2.93)

Crizotinib vs Chemotherapy

Statistical analysis description

Analysis was based on a repeated measures mixed-effects model with an intercept term, treatment, treatment-by-time interaction, and baseline EQ-5D VAS subscale baseline score (intercept and time from first dose were included as random effects).

Comparison groups

Crizotinib v Chemotherapy

Number of subjects included in analysis

320

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.0139

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

3.9908

Confidence interval

level

95%

sides

2-sided

lower limit

0.81

upper limit

7.17

Secondary: Percentage of Subjects with Hospital Admissions-Healthcare Resource Utilization (HCRU)

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End point title

Percentage of Subjects with Hospital Admissions-Healthcare Resource Utilization (HCRU)

End point description

Healthcare resource utilization was to be evaluated using the assessment of the following: date and duration of index admission, duration of hospitalization and date of discharge. FA population included all subjects who were randomized with study treatment assignment designated according to the initial randomization.

End point type

Secondary

End point timeframe

Baseline up to follow up period (up to 72 months)

End point values	Crizotinib	Chemotherapy
Number of subjects analysed	172	171
Units: percentage of subjects
number (not applicable)	40.12	36.26

No statistical analyses for this end point

Secondary: Percentage of Subjects With Laboratory Test Abnormalities By Maximum Severity: National Cancer Institute Common Terminology Criteria for Adverse Event (Version 4.0) Grade 1 to 4 Hematological Test Abnormalities

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End point title

Percentage of Subjects With Laboratory Test Abnormalities By Maximum Severity: National Cancer Institute Common Terminology Criteria for Adverse Event (Version 4.0) Grade 1 to 4 Hematological Test Abnormalities

End point description

Anemia (grade[g]1:Less than[<]Lower limit of normal[LLN] to 10gram per[/]deciliter[g/dL],g2:<10 to 8g/dL,g3:<8g/dL,g4:lifethreatening); platelet (g1:<LLN to 75*10^3/mm]^3,g2:<75*10^3/mm^3 to 50*10^3/mm^3,g3:<50*10^3/mm^3 to 25*10^3/mm^3,g4:<25*10^3/mm^3);lymphopenia(g1:<LLN to 8*10^2/mm^3,g2:<8*10^2 to 5*10^2/mm^3,g3:<5*10^2 to 2*10^2/mm^3,g4:<2*10^2/mm^3); neutrophil(g1:<LLN to 15*10^2/mm^3,g2:<15*10^2 to 10*10^2/mm^3,g3:<10*10^2 to 5*10^2/mm^3,g4:<5*10^2/mm^3);WBC(g1:<LLN to 3*10^3/mm^3,g2:<3*10^3 to 2*10^3/mm^3,g3:<2*10^3 to 1*10^3/mm^3,g4:<1*10^3/mm^3); haemoglobin (Hgb) (g1:increase in Hgb level>0 to 2 g/dL above ULN or above baseline if baseline is above ULN,g2:increase in Hgb level>2 to 4g/dL above ULN or above baseline if baseline is above ULN,g3:increase in Hgb level>4 g/dL above ULN or above baseline if baseline is above ULN). Subject>=1 abnormality given. Safety analysis set. N=subjects evaluable for this endpoint.

End point type

Secondary

End point timeframe

Baseline up to follow up period (up to 72 months)

End point values	Crizotinib	Chemotherapy
Number of subjects analysed	170	165
Units: percentage of subjects
number (not applicable)
Anemia: Grade 1	47.1	46.7
Anemia: Grade 2	13.5	27.9
Anemia: Grade 3	0.6	10.9
Hemoglobin increased: Grade 1	6.5	3
Hemoglobin increased: Grade 2	0.6	0
Lymphocyte count increased: Grade 2	3.5	1.2
Lymphopenia: Grade 1	34.1	26.1
Lymphopenia: Grade 2	24.7	33.9
Lymphopenia: Grade 3	10.6	13.9
Lymphopenia: Grade 4	2.4	1.8
Neutrophils (Absolute): Grade 1	20.6	14.5
Neutrophils (Absolute): Grade 2	20	26.7
Neutrophils (Absolute): Grade 3	14.1	13.9
Neutrophils (Absolute): Grade 4	0.6	3.6
Platelets: Grade 1	9.4	21.8
Platelets: Grade 2	2.4	7.9
Platelets: Grade 3	0.6	7.9
Platelets: Grade 4	0	0.6
White blood cells: Grade 1	23.5	34.5
White blood cells: Grade 2	22.5	24.2
White blood cells: Grade 3	2.9	9.1
White blood cells: Grade 4	0	0.6

No statistical analyses for this end point

Secondary: Percentage of Subjects With Laboratory Test Abnormalities By Maximum Severity: National Cancer Institute Common Terminology Criteria for Adverse Event (Version 4.0) Grade 1 to 4 Chemistry Test Abnormalities

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End point title

End point description

ALT/AST([g]1:>ULN-3*ULN,g2:>3-5*ULN,g3:>5-20*ULN,g4:>20*ULN);AP(g1:>ULN-2.5*ULN,g2:>2.5-5*ULN,g3:>5-20*ULN,g4:>20*ULN);CR(g1:>ULN-1.5*ULN,g2:>1.5-3*ULN,g3:>3-6*ULN,g4:>6*ULN);hyperglycemia(g1:>ULN-160,g2:>160-250,g3:>250-500,g4:>500mg/dL);bilirubin(total) (g1:>ULN-1.5*ULN,g2:>1.5-3*ULN,g3:>3-10*ULN,g4:>10*ULN);hypoglycaemia (g1:<LLN-55,g2:<55-40,g3:<40-30,g4:<30mg/dL);hyperkalemia (g1:>ULN-5.5,g2:>5.5-6,g3:>6-7,g4:>7mmol/L);hypokalemia (g1:<LLN-3,g2:<LLN-3,g3:<3-2.5,g4:<2.5mmol/L);hypermagnesemia (g1:>ULN-3,g3:>3-8,g4:>8mg/dL);hypocalcemia (g1:<LLN-8,g2:<8-7,g3:<7-6,g4:<6mg/dL);hypercalcemia (g1:>ULN-11.5,g2:>11.5-12.5,g3:>12.5-13.5,g4:>13.5mg/dL);hypomagnesemia (g1:<LLN-1.2,g2:<1.2-0.9,g3:<0.9-0.7,g4:<0.7mg/dL);hyponatremia (g1:<LLN-130,g3:<130-120,g4:<120mmol/L);hypoalbuminemia (g1:<LLN-3,g2:<3-2,g3:<2,g4:lifethreatening);hypophosphatemia (g1:<LLN-2.5,g2:<2.5-2,g3:<2-1,g4:<1mg/dL).Safety set.N= subjects evaluable for this endpoint,n=subjects evaluable at specific time points.

End point type

Secondary

End point timeframe

Baseline up to follow up period (up to 72 months)

End point values	Crizotinib	Chemotherapy
Number of subjects analysed	171	165
Units: percentage of subjects
number (not applicable)
Alanine aminotransferase: Grade 1 (n =171, 165)	64.3	34.5
Alanine aminotransferase: Grade 2 (n =171, 165)	10.5	7.3
Alanine aminotransferase: Grade 3 (n =171, 165)	12.3	1.8
Alanine aminotransferase: Grade 4 (n =171, 165)	2.3	0
Alkaline phosphatase: Grade 1 (n =171, 165)	55.6	33.9
Alkaline phosphatase: Grade 2 (n =171, 165)	8.8	4.8
Alkaline phosphatase: Grade 3 (n =171, 165)	0.6	1.2
Aspartate Aminotransferase: Grade 1 (n =171, 165)	57.9	32.1
Aspartate Aminotransferase: Grade 2 (n =171, 165)	6.4	1.8
Aspartate Aminotransferase: Grade 3 (n =171, 165)	7.6	1.2
Aspartate Aminotransferase: Grade 4 (n =171, 165)	0.6	0
Bilirubin: Grade 1 (n =171, 165)	10.5	7.3
Bilirubin: Grade 2 (n =171, 165)	5.8	1.2
Bilirubin: Grade 3 (n =171, 165)	0	0.6
Creatinine: Grade 1 (n =171, 165)	50.3	78.8
Creatinine: Grade 2 (n =171, 165)	47.4	15.8
Creatinine: Grade 3 (n =171, 165)	1.2	0
Hypercalcemia: Grade 1 (n =171, 165)	0.6	9.1
Hypercalcemia: Grade 4 (n =171, 165)	0.6	0
Hyperglycemia: Grade 1 (n =171, 165)	50.3	42.4
Hyperglycemia: Grade 2 (n =171, 165)	15.8	23.6
Hyperglycemia: Grade 3 (n =171, 165)	4.1	3.6
Hyperkalemia: Grade 1 (n =171, 165)	17.5	12.1
Hyperkalemia: Grade 2 (n =171, 165)	5.8	3
Hyperkalemia: Grade 3 (n =171, 165)	2.3	1.8
Hyperkalemia: Grade 4 (n =171, 165)	0.6	0
Hypermagnesemia: Grade 1 (n =170, 162)	17.6	8
Hypermagnesemia: Grade 3 (n =170, 162)	1.8	0
Hypernatremia: Grade 1 (n =171, 165)	21.1	5.5
Hypernatremia: Grade 2 (n =171, 165)	0.6	0
Hypernatremia: Grade 4 (n =171, 165)	0.6	0
Hypoalbuminemia: Grade 1 (n =171, 164)	35.1	22.6
Hypoalbuminemia: Grade 2 (n =171, 164)	44.4	14.6
Hypoalbuminemia: Grade 3 (n =171, 164)	1.2	0.6
Hypocalcemia: Grade 1 (n =171, 165)	39.8	24.8
Hypocalcemia: Grade 2 (n =171, 165)	38	4.8
Hypocalcemia: Grade 3 (n =171, 165)	2.3	0.6
Hypoglycemia: Grade 1 (n =171, 165)	19.9	3.6
Hypoglycemia: Grade 2 (n =171, 165)	4.7	1.8
Hypoglycemia: Grade 4 (n =171, 165)	0	0.6
Hypokalemia: Grade 1 (n =171, 165)	14.6	9.1
Hypokalemia: Grade 3 (n =171, 165)	2.3	3
Hypokalemia: Grade 4 (n =171, 165)	0	0.6
Hypomagnesemia: Grade 1 (n =170, 162)	12.4	26.5
Hypomagnesemia: Grade 2 (n =170, 162)	0	1.9
Hyponatremia: Grade 1 (n =171, 165)	25.7	22.4
Hyponatremia: Grade 3 (n =171, 165)	4.1	5.5
Hyponatremia: Grade 4 (n =171, 165)	0.6	1.2
Hypophosphatemia: Grade 1 (n =169, 161)	5.3	3.1
Hypophosphatemia: Grade 2 (n =169, 161)	27.2	13
Hypophosphatemia: Grade 3 (n =169, 161)	13	6.8
Hypophosphatemia: Grade 4 (n =169, 161)	1.2	0

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Baseline up to follow up period (up to 72 months)

Adverse event reporting additional description

The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

19.1

Reporting group title

Chemotherapy

Reporting group description

Standard doses of chemotherapy (pemetrexed/cisplatin or pemetrexed/carboplatin) were administered intravenously, where pemetrexed 500 mg/m^2 IV infusion according to standard of care was administered over 10 min; cisplatin 75mg/m^2 IV infusion was administered approximately 30 min after the end of the pemetrexed infusion and carboplatin was administered at a dose calculated to produce an AUC of 5 or 6 mg*min/mL, approximately 30 minutes after end of pemetrexed infusion.

Reporting group title

Crizotinib

Reporting group description

Crizotinib 250 mg capsule, orally twice daily was administered in treatment cycle of 21 days (up to a maximum of 50 cycles). Subjects could continue crizotinib treatment beyond the time of RECIST v1.1 defined PD, as determined by IRR, at the discretion of the investigator if the subject was perceived to be experiencing clinical benefit.

Serious adverse events	Chemotherapy	Crizotinib
Total subjects affected by serious adverse events
subjects affected / exposed	49 / 169 (28.99%)	71 / 171 (41.52%)
number of deaths (all causes)	81	71
number of deaths resulting from adverse events	4	23
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Thyroid adenoma
subjects affected / exposed	1 / 169 (0.59%)	0 / 171 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular disorders
Deep vein thrombosis
subjects affected / exposed	1 / 169 (0.59%)	1 / 171 (0.58%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Orthostatic hypotension
subjects affected / exposed	0 / 169 (0.00%)	1 / 171 (0.58%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Aortic dissection
subjects affected / exposed	0 / 169 (0.00%)	1 / 171 (0.58%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Embolism
subjects affected / exposed	0 / 169 (0.00%)	1 / 171 (0.58%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Phlebitis
subjects affected / exposed	0 / 169 (0.00%)	1 / 171 (0.58%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Superior vena cava syndrome
subjects affected / exposed	0 / 169 (0.00%)	1 / 171 (0.58%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pregnancy, puerperium and perinatal conditions
Unintended pregnancy
Additional description: This adverse event is gender specific.
subjects affected / exposed ^[1]	0 / 108 (0.00%)	1 / 104 (0.96%)
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
Chest pain
subjects affected / exposed	1 / 169 (0.59%)	1 / 171 (0.58%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Disease progression
subjects affected / exposed	1 / 169 (0.59%)	18 / 171 (10.53%)
occurrences causally related to treatment / all	0 / 1	0 / 19
deaths causally related to treatment / all	1 / 1	18 / 18
Fatigue
subjects affected / exposed	0 / 169 (0.00%)	1 / 171 (0.58%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
General physical health deterioration
subjects affected / exposed	2 / 169 (1.18%)	0 / 171 (0.00%)
occurrences causally related to treatment / all	4 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Oedema peripheral
subjects affected / exposed	0 / 169 (0.00%)	1 / 171 (0.58%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	2 / 169 (1.18%)	1 / 171 (0.58%)
occurrences causally related to treatment / all	2 / 2	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Asthenia
subjects affected / exposed	0 / 169 (0.00%)	2 / 171 (1.17%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Death
subjects affected / exposed	0 / 169 (0.00%)	1 / 171 (0.58%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	1 / 1
Reproductive system and breast disorders
Uterine prolapse
subjects affected / exposed ^[2]	0 / 108 (0.00%)	1 / 104 (0.96%)
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 / 169 (0.00%)	1 / 171 (0.58%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	1 / 1
Asthma
subjects affected / exposed	1 / 169 (0.59%)	0 / 171 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	4 / 169 (2.37%)	7 / 171 (4.09%)
occurrences causally related to treatment / all	0 / 4	2 / 9
deaths causally related to treatment / all	0 / 0	0 / 0
Haemoptysis
subjects affected / exposed	2 / 169 (1.18%)	0 / 171 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0
Pneumothorax
subjects affected / exposed	1 / 169 (0.59%)	0 / 171 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Lung infiltration
subjects affected / exposed	1 / 169 (0.59%)	0 / 171 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Interstitial lung disease
subjects affected / exposed	1 / 169 (0.59%)	1 / 171 (0.58%)
occurrences causally related to treatment / all	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	5 / 169 (2.96%)	2 / 171 (1.17%)
occurrences causally related to treatment / all	0 / 5	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
Pleurisy
subjects affected / exposed	1 / 169 (0.59%)	0 / 171 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonitis
subjects affected / exposed	0 / 169 (0.00%)	1 / 171 (0.58%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	7 / 169 (4.14%)	5 / 171 (2.92%)
occurrences causally related to treatment / all	2 / 7	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary oedema
subjects affected / exposed	1 / 169 (0.59%)	0 / 171 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
acute respiratory distress syndrome
subjects affected / exposed	0 / 169 (0.00%)	1 / 171 (0.58%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Psychiatric disorders
Completed suicide
subjects affected / exposed	1 / 169 (0.59%)	0 / 171 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0
Hypomania
subjects affected / exposed	0 / 169 (0.00%)	1 / 171 (0.58%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Investigations
Alanine aminotransferase increased
subjects affected / exposed	0 / 169 (0.00%)	1 / 171 (0.58%)
occurrences causally related to treatment / all	0 / 0	3 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Aspartate aminotransferase increased
subjects affected / exposed	0 / 169 (0.00%)	1 / 171 (0.58%)
occurrences causally related to treatment / all	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Injury, poisoning and procedural complications
Overdose
subjects affected / exposed	1 / 169 (0.59%)	0 / 171 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Rib fracture
subjects affected / exposed	1 / 169 (0.59%)	0 / 171 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders
Atrial fibrillation
subjects affected / exposed	1 / 169 (0.59%)	1 / 171 (0.58%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Atrioventricular block
subjects affected / exposed	0 / 169 (0.00%)	1 / 171 (0.58%)
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	1 / 169 (0.59%)	0 / 171 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pericarditis
subjects affected / exposed	1 / 169 (0.59%)	0 / 171 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Syncope
subjects affected / exposed	2 / 169 (1.18%)	0 / 171 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac arrest
subjects affected / exposed	1 / 169 (0.59%)	0 / 171 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0
Myocardial ischaemia
subjects affected / exposed	1 / 169 (0.59%)	0 / 171 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Bradycardia
subjects affected / exposed	0 / 169 (0.00%)	1 / 171 (0.58%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac tamponade
subjects affected / exposed	0 / 169 (0.00%)	2 / 171 (1.17%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorders
Altered state of consciousness
subjects affected / exposed	0 / 169 (0.00%)	1 / 171 (0.58%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Central nervous system lesion
subjects affected / exposed	0 / 169 (0.00%)	1 / 171 (0.58%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Headache
subjects affected / exposed	0 / 169 (0.00%)	3 / 171 (1.75%)
occurrences causally related to treatment / all	0 / 0	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Loss of consciousness
subjects affected / exposed	0 / 169 (0.00%)	1 / 171 (0.58%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Multiple sclerosis
subjects affected / exposed	0 / 169 (0.00%)	1 / 171 (0.58%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Partial seizures
subjects affected / exposed	1 / 169 (0.59%)	0 / 171 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Transient ischaemic attack
subjects affected / exposed	1 / 169 (0.59%)	0 / 171 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cervicobrachial syndrome
subjects affected / exposed	0 / 169 (0.00%)	1 / 171 (0.58%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Dizziness
subjects affected / exposed	0 / 169 (0.00%)	1 / 171 (0.58%)
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 / 169 (0.00%)	1 / 171 (0.58%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Seizure
subjects affected / exposed	5 / 169 (2.96%)	1 / 171 (0.58%)
occurrences causally related to treatment / all	1 / 5	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Blood and lymphatic system disorders
Lymphadenopathy mediastinal
subjects affected / exposed	0 / 169 (0.00%)	1 / 171 (0.58%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Anaemia
subjects affected / exposed	1 / 169 (0.59%)	0 / 171 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Febrile neutropenia
subjects affected / exposed	2 / 169 (1.18%)	0 / 171 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	0 / 169 (0.00%)	1 / 171 (0.58%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Constipation
subjects affected / exposed	1 / 169 (0.59%)	0 / 171 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	1 / 169 (0.59%)	2 / 171 (1.17%)
occurrences causally related to treatment / all	1 / 1	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Dysphagia
subjects affected / exposed	1 / 169 (0.59%)	0 / 171 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Haemorrhoids
subjects affected / exposed	0 / 169 (0.00%)	1 / 171 (0.58%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Intestinal obstruction
subjects affected / exposed	0 / 169 (0.00%)	2 / 171 (1.17%)
occurrences causally related to treatment / all	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Nausea
subjects affected / exposed	1 / 169 (0.59%)	4 / 171 (2.34%)
occurrences causally related to treatment / all	1 / 1	3 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Oesophageal ulcer
subjects affected / exposed	0 / 169 (0.00%)	1 / 171 (0.58%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Oesophagitis
subjects affected / exposed	0 / 169 (0.00%)	3 / 171 (1.75%)
occurrences causally related to treatment / all	0 / 0	3 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Vomiting
subjects affected / exposed	4 / 169 (2.37%)	3 / 171 (1.75%)
occurrences causally related to treatment / all	5 / 5	2 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Colitis
subjects affected / exposed	0 / 169 (0.00%)	1 / 171 (0.58%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatobiliary disorders
Drug-induced liver injury
subjects affected / exposed	0 / 169 (0.00%)	1 / 171 (0.58%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cholecystitis
subjects affected / exposed	0 / 169 (0.00%)	2 / 171 (1.17%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Cholecystitis acute
subjects affected / exposed	1 / 169 (0.59%)	0 / 171 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Bile duct obstruction
subjects affected / exposed	1 / 169 (0.59%)	0 / 171 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Renal and urinary disorders
Haematuria
subjects affected / exposed	1 / 169 (0.59%)	0 / 171 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Renal cyst
subjects affected / exposed	0 / 169 (0.00%)	3 / 171 (1.75%)
occurrences causally related to treatment / all	0 / 0	3 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary retention
subjects affected / exposed	0 / 169 (0.00%)	1 / 171 (0.58%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Dysuria
subjects affected / exposed	0 / 169 (0.00%)	1 / 171 (0.58%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Acute kidney injury
subjects affected / exposed	1 / 169 (0.59%)	0 / 171 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Arthritis
subjects affected / exposed	0 / 169 (0.00%)	2 / 171 (1.17%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Bone pain
subjects affected / exposed	0 / 169 (0.00%)	1 / 171 (0.58%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Muscle spasms
subjects affected / exposed	1 / 169 (0.59%)	0 / 171 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Muscular weakness
subjects affected / exposed	0 / 169 (0.00%)	2 / 171 (1.17%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Osteonecrosis
subjects affected / exposed	0 / 169 (0.00%)	1 / 171 (0.58%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Rotator cuff syndrome
subjects affected / exposed	1 / 169 (0.59%)	0 / 171 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Spinal column stenosis
subjects affected / exposed	0 / 169 (0.00%)	1 / 171 (0.58%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Flank pain
subjects affected / exposed	0 / 169 (0.00%)	1 / 171 (0.58%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Abdominal abscess
subjects affected / exposed	0 / 169 (0.00%)	1 / 171 (0.58%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	0 / 169 (0.00%)	2 / 171 (1.17%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatitis B
subjects affected / exposed	0 / 169 (0.00%)	1 / 171 (0.58%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Lower respiratory tract infection
subjects affected / exposed	0 / 169 (0.00%)	2 / 171 (1.17%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Periodontitis
subjects affected / exposed	0 / 169 (0.00%)	1 / 171 (0.58%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	1 / 169 (0.59%)	3 / 171 (1.75%)
occurrences causally related to treatment / all	0 / 1	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary sepsis
subjects affected / exposed	0 / 169 (0.00%)	1 / 171 (0.58%)
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 / 169 (0.59%)	2 / 171 (1.17%)
occurrences causally related to treatment / all	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Septic shock
subjects affected / exposed	0 / 169 (0.00%)	2 / 171 (1.17%)
occurrences causally related to treatment / all	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	2 / 2
Upper respiratory tract infection
subjects affected / exposed	0 / 169 (0.00%)	1 / 171 (0.58%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	0 / 169 (0.00%)	2 / 171 (1.17%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Bronchitis
subjects affected / exposed	1 / 169 (0.59%)	0 / 171 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Lung infection
subjects affected / exposed	0 / 169 (0.00%)	1 / 171 (0.58%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Sepsis
subjects affected / exposed	0 / 169 (0.00%)	2 / 171 (1.17%)
occurrences causally related to treatment / all	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Arthritis bacterial
subjects affected / exposed	0 / 169 (0.00%)	1 / 171 (0.58%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Influenza
subjects affected / exposed	0 / 169 (0.00%)	1 / 171 (0.58%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Neutropenic sepsis
subjects affected / exposed	0 / 169 (0.00%)	1 / 171 (0.58%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Peritonitis
subjects affected / exposed	0 / 169 (0.00%)	1 / 171 (0.58%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pyelonephritis
subjects affected / exposed	0 / 169 (0.00%)	1 / 171 (0.58%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory tract infection viral
subjects affected / exposed	0 / 169 (0.00%)	1 / 171 (0.58%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Skin infection
subjects affected / exposed	0 / 169 (0.00%)	1 / 171 (0.58%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Atypical pneumonia
subjects affected / exposed	0 / 169 (0.00%)	1 / 171 (0.58%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	0 / 169 (0.00%)	2 / 171 (1.17%)
occurrences causally related to treatment / all	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Dehydration
subjects affected / exposed	2 / 169 (1.18%)	0 / 171 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Diabetic ketoacidosis
subjects affected / exposed	0 / 169 (0.00%)	1 / 171 (0.58%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	1 / 1
Hypokalaemia
subjects affected / exposed	0 / 169 (0.00%)	1 / 171 (0.58%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hyponatraemia
subjects affected / exposed	1 / 169 (0.59%)	1 / 171 (0.58%)
occurrences causally related to treatment / all	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hypoproteinaemia
subjects affected / exposed	0 / 169 (0.00%)	1 / 171 (0.58%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0

Notes
[1] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: As this adverse event is gender specific, so the number of subjects at risk is equal to the number of female subjects in the study.
[2] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: As this adverse event is gender specific, so the number of subjects at risk is equal to the number of female subjects in the study.

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

Non-serious adverse events	Chemotherapy	Crizotinib
Total subjects affected by non serious adverse events
subjects affected / exposed	165 / 169 (97.63%)	168 / 171 (98.25%)
General disorders and administration site conditions
Asthenia
subjects affected / exposed	40 / 169 (23.67%)	28 / 171 (16.37%)
occurrences all number	71	47
Chest pain
subjects affected / exposed	14 / 169 (8.28%)	21 / 171 (12.28%)
occurrences all number	18	26
Fatigue
subjects affected / exposed	66 / 169 (39.05%)	54 / 171 (31.58%)
occurrences all number	105	99
Mucosal inflammation
subjects affected / exposed	9 / 169 (5.33%)	2 / 171 (1.17%)
occurrences all number	11	2
Oedema peripheral
subjects affected / exposed	12 / 169 (7.10%)	89 / 171 (52.05%)
occurrences all number	18	189
Pyrexia
subjects affected / exposed	17 / 169 (10.06%)	40 / 171 (23.39%)
occurrences all number	24	61
Influenza like illness
subjects affected / exposed	1 / 169 (0.59%)	10 / 171 (5.85%)
occurrences all number	1	14
Pain
subjects affected / exposed	5 / 169 (2.96%)	9 / 171 (5.26%)
occurrences all number	9	13
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	28 / 169 (16.57%)	44 / 171 (25.73%)
occurrences all number	35	75
Haemoptysis
subjects affected / exposed	6 / 169 (3.55%)	11 / 171 (6.43%)
occurrences all number	7	13
Dyspnoea
subjects affected / exposed	23 / 169 (13.61%)	31 / 171 (18.13%)
occurrences all number	32	45
Oropharyngeal pain
subjects affected / exposed	8 / 169 (4.73%)	14 / 171 (8.19%)
occurrences all number	8	18
Productive cough
subjects affected / exposed	8 / 169 (4.73%)	15 / 171 (8.77%)
occurrences all number	9	18
Psychiatric disorders
Anxiety
subjects affected / exposed	9 / 169 (5.33%)	10 / 171 (5.85%)
occurrences all number	10	14
Insomnia
subjects affected / exposed	15 / 169 (8.88%)	23 / 171 (13.45%)
occurrences all number	21	26
Investigations
Alanine aminotransferase increased
subjects affected / exposed	21 / 169 (12.43%)	59 / 171 (34.50%)
occurrences all number	48	184
Aspartate aminotransferase increased
subjects affected / exposed	16 / 169 (9.47%)	47 / 171 (27.49%)
occurrences all number	30	120
Electrocardiogram QT prolonged
subjects affected / exposed	2 / 169 (1.18%)	11 / 171 (6.43%)
occurrences all number	2	21
Neutrophil count decreased
subjects affected / exposed	17 / 169 (10.06%)	14 / 171 (8.19%)
occurrences all number	44	58
Platelet count decreased
subjects affected / exposed	19 / 169 (11.24%)	1 / 171 (0.58%)
occurrences all number	33	1
Weight decreased
subjects affected / exposed	5 / 169 (2.96%)	12 / 171 (7.02%)
occurrences all number	7	31
Weight increased
subjects affected / exposed	4 / 169 (2.37%)	16 / 171 (9.36%)
occurrences all number	9	34
White blood cell count decreased
subjects affected / exposed	12 / 169 (7.10%)	11 / 171 (6.43%)
occurrences all number	25	84
Blood bilirubin increased
subjects affected / exposed	2 / 169 (1.18%)	9 / 171 (5.26%)
occurrences all number	4	21
Blood creatinine increased
subjects affected / exposed	5 / 169 (2.96%)	9 / 171 (5.26%)
occurrences all number	5	9
Cardiac disorders
Bradycardia
subjects affected / exposed	0 / 169 (0.00%)	22 / 171 (12.87%)
occurrences all number	0	33
Sinus bradycardia
subjects affected / exposed	1 / 169 (0.59%)	10 / 171 (5.85%)
occurrences all number	1	11
Nervous system disorders
Dizziness
subjects affected / exposed	15 / 169 (8.88%)	35 / 171 (20.47%)
occurrences all number	25	54
Dysgeusia
subjects affected / exposed	9 / 169 (5.33%)	45 / 171 (26.32%)
occurrences all number	9	64
Headache
subjects affected / exposed	25 / 169 (14.79%)	48 / 171 (28.07%)
occurrences all number	30	74
Neuropathy peripheral
subjects affected / exposed	12 / 169 (7.10%)	4 / 171 (2.34%)
occurrences all number	12	4
Paraesthesia
subjects affected / exposed	8 / 169 (4.73%)	29 / 171 (16.96%)
occurrences all number	11	36
Peripheral sensory neuropathy
subjects affected / exposed	10 / 169 (5.92%)	6 / 171 (3.51%)
occurrences all number	14	7
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	53 / 169 (31.36%)	18 / 171 (10.53%)
occurrences all number	101	27
Leukopenia
subjects affected / exposed	16 / 169 (9.47%)	8 / 171 (4.68%)
occurrences all number	47	21
Thrombocytopenia
subjects affected / exposed	14 / 169 (8.28%)	1 / 171 (0.58%)
occurrences all number	36	1
Neutropenia
subjects affected / exposed	36 / 169 (21.30%)	32 / 171 (18.71%)
occurrences all number	107	203
Ear and labyrinth disorders
Tinnitus
subjects affected / exposed	10 / 169 (5.92%)	4 / 171 (2.34%)
occurrences all number	10	4
Eye disorders
Photopsia
subjects affected / exposed	2 / 169 (1.18%)	18 / 171 (10.53%)
occurrences all number	2	30
Vision blurred
subjects affected / exposed	5 / 169 (2.96%)	13 / 171 (7.60%)
occurrences all number	5	16
Visual impairment
subjects affected / exposed	5 / 169 (2.96%)	98 / 171 (57.31%)
occurrences all number	5	123
Vitreous floaters
subjects affected / exposed	1 / 169 (0.59%)	11 / 171 (6.43%)
occurrences all number	1	12
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	8 / 169 (4.73%)	25 / 171 (14.62%)
occurrences all number	8	37
Abdominal pain upper
subjects affected / exposed	10 / 169 (5.92%)	27 / 171 (15.79%)
occurrences all number	17	34
Constipation
subjects affected / exposed	51 / 169 (30.18%)	78 / 171 (45.61%)
occurrences all number	68	135
Diarrhoea
subjects affected / exposed	22 / 169 (13.02%)	111 / 171 (64.91%)
occurrences all number	25	269
Dyspepsia
subjects affected / exposed	5 / 169 (2.96%)	27 / 171 (15.79%)
occurrences all number	7	41
Dysphagia
subjects affected / exposed	3 / 169 (1.78%)	19 / 171 (11.11%)
occurrences all number	4	25
Gastrooesophageal reflux disease
subjects affected / exposed	6 / 169 (3.55%)	14 / 171 (8.19%)
occurrences all number	7	18
Nausea
subjects affected / exposed	98 / 169 (57.99%)	100 / 171 (58.48%)
occurrences all number	206	246
Stomatitis
subjects affected / exposed	17 / 169 (10.06%)	13 / 171 (7.60%)
occurrences all number	28	23
Vomiting
subjects affected / exposed	57 / 169 (33.73%)	87 / 171 (50.88%)
occurrences all number	89	223
Abdominal distension
subjects affected / exposed	1 / 169 (0.59%)	11 / 171 (6.43%)
occurrences all number	1	11
Skin and subcutaneous tissue disorders
Alopecia
subjects affected / exposed	17 / 169 (10.06%)	16 / 171 (9.36%)
occurrences all number	18	17
Rash
subjects affected / exposed	20 / 169 (11.83%)	22 / 171 (12.87%)
occurrences all number	23	27
Pruritus
subjects affected / exposed	10 / 169 (5.92%)	9 / 171 (5.26%)
occurrences all number	11	13
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	11 / 169 (6.51%)	25 / 171 (14.62%)
occurrences all number	12	42
Back pain
subjects affected / exposed	20 / 169 (11.83%)	35 / 171 (20.47%)
occurrences all number	25	58
Muscle spasms
subjects affected / exposed	2 / 169 (1.18%)	17 / 171 (9.94%)
occurrences all number	2	21
Bone pain
subjects affected / exposed	4 / 169 (2.37%)	12 / 171 (7.02%)
occurrences all number	4	24
Musculoskeletal pain
subjects affected / exposed	8 / 169 (4.73%)	21 / 171 (12.28%)
occurrences all number	12	26
Pain in extremity
subjects affected / exposed	14 / 169 (8.28%)	44 / 171 (25.73%)
occurrences all number	17	61
Flank pain
subjects affected / exposed	2 / 169 (1.18%)	9 / 171 (5.26%)
occurrences all number	2	11
Muscular weakness
subjects affected / exposed	4 / 169 (2.37%)	9 / 171 (5.26%)
occurrences all number	4	14
Musculoskeletal chest pain
subjects affected / exposed	5 / 169 (2.96%)	10 / 171 (5.85%)
occurrences all number	7	12
Myalgia
subjects affected / exposed	6 / 169 (3.55%)	14 / 171 (8.19%)
occurrences all number	8	16
Neck pain
subjects affected / exposed	2 / 169 (1.18%)	11 / 171 (6.43%)
occurrences all number	2	12
Infections and infestations
Nasopharyngitis
subjects affected / exposed	5 / 169 (2.96%)	30 / 171 (17.54%)
occurrences all number	6	63
Upper respiratory tract infection
subjects affected / exposed	13 / 169 (7.69%)	41 / 171 (23.98%)
occurrences all number	15	99
Conjunctivitis
subjects affected / exposed	10 / 169 (5.92%)	3 / 171 (1.75%)
occurrences all number	11	4
Bronchitis
subjects affected / exposed	2 / 169 (1.18%)	11 / 171 (6.43%)
occurrences all number	4	15
Rhinitis
subjects affected / exposed	2 / 169 (1.18%)	9 / 171 (5.26%)
occurrences all number	2	11
Urinary tract infection
subjects affected / exposed	2 / 169 (1.18%)	10 / 171 (5.85%)
occurrences all number	2	13
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	58 / 169 (34.32%)	59 / 171 (34.50%)
occurrences all number	108	99
Hypoalbuminaemia
subjects affected / exposed	2 / 169 (1.18%)	19 / 171 (11.11%)
occurrences all number	5	31
Hypomagnesaemia
subjects affected / exposed	13 / 169 (7.69%)	3 / 171 (1.75%)
occurrences all number	17	3
Hypocalcaemia
subjects affected / exposed	1 / 169 (0.59%)	10 / 171 (5.85%)
occurrences all number	1	14
Hypophosphataemia
subjects affected / exposed	2 / 169 (1.18%)	10 / 171 (5.85%)
occurrences all number	2	13
Hypoproteinaemia
subjects affected / exposed	0 / 169 (0.00%)	10 / 171 (5.85%)
occurrences all number	0	28

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Were there any global substantial amendments to the protocol? Yes

20 Jul 2015

Extended survival followup period to 36 months after the randomization of the last subject, to enhance the likelihood to obtain an estimate of the median overall survival.

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

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Progression-Free Survival (PFS) Based on IRR

Primary: Progression-Free Survival (PFS) Based on IRR

Secondary: Overall Survival (OS)

Secondary: Overall Survival (OS)

Secondary: Overall Survival Probability at Month 12 and 18

Secondary: Overall Survival Probability at Month 12 and 18

Secondary: Objective Response Rate (ORR): Percentage of Subjects With Objective Response as Assessed by IRR

Secondary: Objective Response Rate (ORR): Percentage of Subjects With Objective Response as Assessed by IRR

Secondary: Duration of Response (DR) Based on IRR

Secondary: Duration of Response (DR) Based on IRR

Secondary: Time to tumor response (TTR) Based on IRR

Secondary: Time to tumor response (TTR) Based on IRR

Secondary: Percentage of Subjects With Disease Control at Week 12 Based on IRR

Secondary: Percentage of Subjects With Disease Control at Week 12 Based on IRR

Secondary: Time to progression (TTP) Based on IRR

Secondary: Time to progression (TTP) Based on IRR

Secondary: Time to Intracranial Progression (IC-TTP) Based on IRR

Secondary: Time to Intracranial Progression (IC-TTP) Based on IRR

Secondary: Time to Extracranial Progression (EC-TTP) Based on IRR

Secondary: Time to Extracranial Progression (EC-TTP) Based on IRR

Secondary: Percentage of Subjects With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)

Secondary: Percentage of Subjects With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)

Secondary: Percentage of Subjects With Treatment Emergent Treatment-Related Adverse Events (AEs) and Serious Adverse Events (SAEs)

Secondary: Percentage of Subjects With Treatment Emergent Treatment-Related Adverse Events (AEs) and Serious Adverse Events (SAEs)

Secondary: Percentage of Subjects With Adverse Events (AEs) According to Maximum Severity

Secondary: Percentage of Subjects With Adverse Events (AEs) According to Maximum Severity

Secondary: Plasma Predose Concentration (Ctrough) of Crizotinib and its Metabolite PF-06260182

Secondary: Plasma Predose Concentration (Ctrough) of Crizotinib and its Metabolite PF-06260182

Secondary: Percentage of Subjects For Each Anaplastic Lymphoma Kinase (ALK) Gene Fusion Variants

Secondary: Percentage of Subjects For Each Anaplastic Lymphoma Kinase (ALK) Gene Fusion Variants

Secondary: Objective Response Rate (ORR) of Anaplastic Lymphoma Kinase (ALK) Variant Groups Based on IRR

Secondary: Objective Response Rate (ORR) of Anaplastic Lymphoma Kinase (ALK) Variant Groups Based on IRR

Secondary: Time to Deterioration (TTD) in Chest Pain, Dyspnea or Cough

Secondary: Time to Deterioration (TTD) in Chest Pain, Dyspnea or Cough

Secondary: Change From Baseline in Functioning and Global Quality of Life (QOL) as Assessed by the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC-QLQ-C30)

Secondary: Change From Baseline in Functioning and Global Quality of Life (QOL) as Assessed by the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC-QLQ-C30)

Secondary: Change From Baseline Scores in QLQ-C30 Symptoms as Assessed by the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC-QLQ-C30)

Secondary: Change From Baseline Scores in QLQ-C30 Symptoms as Assessed by the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC-QLQ-C30)

Secondary: Change From Baseline in Lung Cancer Symptom Scores as Assessed by the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire-Lung Cancer 13 (QLQ- LC13)

Secondary: Change From Baseline in Lung Cancer Symptom Scores as Assessed by the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire-Lung Cancer 13 (QLQ- LC13)

Secondary: Change From Baseline in General Health Status as Assessed by EuroQol 5D (EQ-5D)- Visual Analog Scale (VAS)

Secondary: Change From Baseline in General Health Status as Assessed by EuroQol 5D (EQ-5D)- Visual Analog Scale (VAS)

Secondary: Percentage of Subjects with Hospital Admissions-Healthcare Resource Utilization (HCRU)

Secondary: Percentage of Subjects with Hospital Admissions-Healthcare Resource Utilization (HCRU)

Secondary: Percentage of Subjects With Laboratory Test Abnormalities By Maximum Severity: National Cancer Institute Common Terminology Criteria for Adverse Event (Version 4.0) Grade 1 to 4 Hematological Test Abnormalities

Secondary: Percentage of Subjects With Laboratory Test Abnormalities By Maximum Severity: National Cancer Institute Common Terminology Criteria for Adverse Event (Version 4.0) Grade 1 to 4 Hematological Test Abnormalities

Secondary: Percentage of Subjects With Laboratory Test Abnormalities By Maximum Severity: National Cancer Institute Common Terminology Criteria for Adverse Event (Version 4.0) Grade 1 to 4 Chemistry Test Abnormalities

Secondary: Percentage of Subjects With Laboratory Test Abnormalities By Maximum Severity: National Cancer Institute Common Terminology Criteria for Adverse Event (Version 4.0) Grade 1 to 4 Chemistry Test Abnormalities

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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