A Study of Bevacizumab in Combination With Standard of Care Treatment in Participants With Advanced Non-squamous Non-small Cell Lung Cancer (NSCLC)

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ClinicalTrials.gov Identifier: NCT01351415

Recruitment Status : Completed

First Posted : May 10, 2011

Results First Posted : September 18, 2017

Last Update Posted : September 18, 2017

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Sponsor:

Information provided by (Responsible Party):

Hoffmann-La Roche

Study Type	Interventional
Study Design	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
Condition	Non-Squamous Non-Small Cell Lung Cancer
Interventions	Drug: Bevacizumab Drug: Docetaxel Drug: Erlotinib Drug: Pemetrexed
Enrollment	485

Participant Flow

Recruitment Details	This phase 3b study was conducted across 16 different countries and enrolled 485 participants. Participants were 18 years or older and had locally recurrent or metastatic non-squamous Non-Small Cell Lung Cancer (NSCLC)
Pre-assignment Details	A total of 485 participants were enrolled and randomized into the study. Of these, 475 participants were treated; 243 participants received bevacizumab plus standard of care (SoC) and 232 participants received SoC alone. The study was terminated 60 months after study start, as per protocol, but was not ended prematurely.


Arm/Group Title	Bevacizumab + Standard of Care	Standard of Care
Arm/Group Description	Participants received bevacizumab o...	Participants received investigator'...
Arm/Group Description	Participants received bevacizumab on Day 1 of every 21-days cycle along with standard of care, until the occurrence of an unacceptable toxicity or withdrawal of consent (whichever occurs first).	Participants received investigator's choice of standard of care (Erlotinib or Docetaxel or Pemetrexed) according to local practice until the occurrence of an unacceptable toxicity or withdrawal of consent (whichever occurs first).
Period Title: Overall Study
Started	245	240
Treated Participants	243	232
Completed	0	0
Not Completed	245	240
Reason Not Completed
Withdrawal by Subject	15	17
Trial termination by the Sponsor	28	19
Lost to Follow-up	5	7
Death	190	187
Physician Decision	2	3
Reason unknown	0	2
Never Started	5	5

Baseline Characteristics

Arm/Group Title		Bevacizumab + Standard of Care	Standard of Care	Total
Arm/Group Description		Participants received bevacizumab o...	Participants received investigator'...	Total of all reporting groups
Arm/Group Description		Participants received bevacizumab on Day 1 of every 21-days cycle along with standard of care, until the occurrence of an unacceptable toxicity or withdrawal of consent (whichever occurs first).	Participants received investigator's choice of standard of care (Erlotinib or Docetaxel or Pemetrexed) according to local practice until the occurrence of an unacceptable toxicity or withdrawal of consent (whichever occurs first).	Total of all reporting groups
Overall Number of Baseline Participants		245	240	485
Baseline Analysis Population Description		...
Baseline Analysis Population Description		Intent-to-treat population includes all randomized participants.
Age, Continuous Mean (Standard Deviation) Unit of measure: Years
	Number Analyzed	245 participants	240 participants	485 participants
		61.5 (9.61)	61.8 (9.29)	61.6 (9.44)
Sex: Female, Male Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	245 participants	240 participants	485 participants
	Female	90 36.7%	102 42.5%	192 39.6%
	Male	155 63.3%	138 57.5%	293 60.4%

Outcome Measures

1.Primary Outcome


Title	Overall Survival (OS)
Description	Overall survival (OS) was defined as the time from the date of randomi...
Description	Overall survival (OS) was defined as the time from the date of randomization at first progression of disease to the date of death, regardless of the cause of death.
Time Frame	Up to data cut-off date 24 June 2016 (approximately 5 years)

Outcome Measure Data

Analysis Population Description

Intent to treat population included all randomized participants.


Arm/Group Title	Bevacizumab + Standard of Care	Standard of Care
Arm/Group Description:	Participants received bevacizumab o...	Participants received investigator'...
Arm/Group Description:	Participants received bevacizumab on Day 1 of every 21-days cycle along with standard of care, until the occurrence of an unacceptable toxicity or withdrawal of consent (whichever occurs first).	Participants received investigator's choice of standard of care (Erlotinib or Docetaxel or Pemetrexed) according to local practice until the occurrence of an unacceptable toxicity or withdrawal of consent (whichever occurs first).
Overall Number of Participants Analyzed	245	240
Median (90% Confidence Interval) Unit of Measure: Months
	11.86 (10.22 to 13.67)	10.22 (8.61 to 11.93)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Bevacizumab + Standard of Care, Standard of Care
	Comments	The stratification factors for Log-Rank test and Hazard Ratio (HR) are the type of planned 2nd-line SoC treatment, the number of cycles of bevacizumab maintenance treatment prior to first PD and smoking status.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.1044
	Comments	[Not Specified]
	Method	Stratified Log-Rank test
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Stratified Hazard Ratio
	Estimated Value	0.84
	Confidence Interval	(2-Sided) 90% 0.71 to 1.00
	Estimation Comments	[Not Specified]

2.Secondary Outcome


Title	Progression-free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1)
Description	PFS was defined as the time from start of treatment to the first event...
Description	PFS was defined as the time from start of treatment to the first event of death or PD. Tumor response was assessed by the IRF according to RECIST v1.1. Disease progression or PD was defined as ≥20% increase in sum LD in reference to the smallest on-study sum LD, or the appearance of new lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. PFS2 is defined as the time between randomization at PD1 and the date of PD2 or death, whichever occurs first. PFS3 is defined as the time between PD2 and the date of PD3 or death, whichever occurs first.
Time Frame	Up to data cut-off date 24 June 2016 (approximately 5 years)

Outcome Measure Data

Analysis Population Description

Intent to treat population included all randomized participants.


Arm/Group Title	Bevacizumab + Standard of Care	Standard of Care
Arm/Group Description:	Participants received bevacizumab o...	Participants received investigator'...
Arm/Group Description:	Participants received bevacizumab on Day 1 of every 21-days cycle along with standard of care, until the occurrence of an unacceptable toxicity or withdrawal of consent (whichever occurs first).	Participants received investigator's choice of standard of care (Erlotinib or Docetaxel or Pemetrexed) according to local practice until the occurrence of an unacceptable toxicity or withdrawal of consent (whichever occurs first).
Overall Number of Participants Analyzed	245	240
Median (90% Confidence Interval) Unit of Measure: Months
PFS 2	5.45 (4.21 to 5.68)	3.98 (3.38 to 4.30)
PFS 3	4.01 (2.86 to 4.47)	2.60 (2.33 to 2.92)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Bevacizumab + Standard of Care, Standard of Care
	Comments	PFS 2: The stratification factors for Log-Rank test are the type of planned 2nd-line SoC treatment, the number of cycles of bevacizumab maintenance treatment prior to PD1 and the smoking status.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.0573
	Comments	[Not Specified]
	Method	Stratified Log-Rank test
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Stratified Hazard Ratio
	Estimated Value	0.83
	Confidence Interval	(2-Sided) 90% 0.70 to 0.98
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Bevacizumab + Standard of Care, Standard of Care
	Comments	PFS 3: The stratification factors for Log-Rank test are the type of planned 2nd-line SoC treatment, the number of cycles of bevacizumab maintenance treatment prior to PD1 and the smoking status.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.0045
	Comments	[Not Specified]
	Method	Stratified Log-Rank test
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Stratified Hazard Ratio
	Estimated Value	0.63
	Confidence Interval	(2-Sided) 90% 0.49 to 0.83
	Estimation Comments	[Not Specified]

3.Secondary Outcome


Title	Percentage of Participants With Objective Response According to RECIST v1.1
Description	The objective response is defined as complete response (CR) or partial...
Description	The objective response is defined as complete response (CR) or partial response (PR) assessed according to the RECIST v.1.1 criteria with baseline tumour assessment as the reference. CR was defined as disappearance of all target and non-target lesions and (if applicable) normalization of tumor marker levels. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR was defined as greater than or equal to (≥) 30 percent (%) decrease in sum of longest diameter (LD) of target lesions in reference to Baseline sum LD. Response was to be confirmed ≥4 weeks after the initial assessment of CR or PR.
Time Frame	Up to data cut-off date 24 June 2016 (approximately 5 years)

Outcome Measure Data

Analysis Population Description

Intent to treat population included all randomized participants.


Arm/Group Title	Bevacizumab + Standard of Care	Standard of Care
Arm/Group Description:	Participants received bevacizumab o...	Participants received investigator'...
Arm/Group Description:	Participants received bevacizumab on Day 1 of every 21-days cycle along with standard of care, until the occurrence of an unacceptable toxicity or withdrawal of consent (whichever occurs first).	Participants received investigator's choice of standard of care (Erlotinib or Docetaxel or Pemetrexed) according to local practice until the occurrence of an unacceptable toxicity or withdrawal of consent (whichever occurs first).
Overall Number of Participants Analyzed	245	240
Measure Type: Number Number (90% Confidence Interval) Unit of Measure: Percentage of Participants
	8.6 (5.86 to 12.21)	6.3 (3.91 to 9.50)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Bevacizumab + Standard of Care, Standard of Care
	Comments	The stratification factors for Cochran-Mantel-Haenszel test are the type of planned 2nd-line SoC treatment, the number of cycles of Bevacizumab maintenance treatment prior to PD1 and the smoking status.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.0810
	Comments	[Not Specified]
	Method	Stratified Cochran-Mantel-Haenszel test
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Estimated difference in response rate
	Estimated Value	0.0237
	Confidence Interval	(2-Sided) 90% -0.0156 to 0.0630
	Estimation Comments	[Not Specified]

4.Secondary Outcome


Title	Percentage of Participants With Disease Control According to RECIST v1.1
Description	The disease control rate is defined as CR or PR or stable disease (SD)...
Description	The disease control rate is defined as CR or PR or stable disease (SD) assessed according to the RECIST v.1.1 criteria with baseline tumour assessment as the reference. SD was defined as neither sufficient shrinkage to qualify for a PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of the longest diameter since treatment started for target lesions and the persistence of 1 or more non-target lesions.
Time Frame	Up to data cut-off date 24 June 2016 (approximately 5 years)

Outcome Measure Data

Analysis Population Description

Intent to treat population included all randomized participants.


Arm/Group Title	Bevacizumab + Standard of Care	Standard of Care
Arm/Group Description:	Participants received bevacizumab o...	Participants received investigator'...
Arm/Group Description:	Participants received bevacizumab on Day 1 of every 21-days cycle along with standard of care, until the occurrence of an unacceptable toxicity or withdrawal of consent (whichever occurs first).	Participants received investigator's choice of standard of care (Erlotinib or Docetaxel or Pemetrexed) according to local practice until the occurrence of an unacceptable toxicity or withdrawal of consent (whichever occurs first).
Overall Number of Participants Analyzed	245	240
Measure Type: Number Number (90% Confidence Interval) Unit of Measure: Percentage of Participants
	80.2 (75.57 to 84.36)	77.0 (72.06 to 81.41)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Bevacizumab + Standard of Care, Standard of Care
	Comments	The stratification factors for Cochran-Mantel-Haenszel test are the type of planned 2nd-line SoC treatment, the number of cycles of Bevacizumab maintenance treatment prior to PD1 and the smoking status.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.0218
	Comments	[Not Specified]
	Method	Stratified Cochran-Mantel-Haenszel test
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Estimated difference in Disease Control
	Estimated Value	0.0326
	Confidence Interval	(2-Sided) 90% -0.0288 to 0.0940
	Estimation Comments	[Not Specified]

5.Secondary Outcome


Title	Duration of Response (DoR) According to RECIST v1.1
Description	Duration of response is defined as the time that measurement criteria ...
Description	Duration of response is defined as the time that measurement criteria are met for objective response (CR/PR) (whichever status is recorded first) until the first date of progression or death is documented. CR was defined as disappearance of all target and non-target lesions and (if applicable) normalization of tumor marker levels. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to less than < 10 mm. PR was defined as greater than or equal to ≥30 % decrease in sum of longest diameter of target lesions in reference to baseline sum longest diameter.
Time Frame	Up to data cut-off date 24 June 2016 (approximately 5 years)

Outcome Measure Data

Analysis Population Description

Intent to treat population included all randomized participants.


Arm/Group Title	Bevacizumab + Standard of Care	Standard of Care
Arm/Group Description:	Participants received bevacizumab o...	Participants received investigator'...
Arm/Group Description:	Participants received bevacizumab on Day 1 of every 21-days cycle along with standard of care, until the occurrence of an unacceptable toxicity or withdrawal of consent (whichever occurs first).	Participants received investigator's choice of standard of care (Erlotinib or Docetaxel or Pemetrexed) according to local practice until the occurrence of an unacceptable toxicity or withdrawal of consent (whichever occurs first).
Overall Number of Participants Analyzed	245	240
Median (90% Confidence Interval) Unit of Measure: Months
	7.46 (5.39 to 8.54)	6.24 (3.52 to 6.83)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Bevacizumab + Standard of Care, Standard of Care
	Comments	The stratification factors for Log-Rank test are the type of planned 2nd-line SoC treatment, the number of cycles of Bevacizumab maintenance treatment prior to PD1 and the smoking status.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.0600
	Comments	[Not Specified]
	Method	Stratified Log-Rank test
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Stratified Hazard Ratio
	Estimated Value	0.29
	Confidence Interval	(2-Sided) 90% 0.09 to 0.90
	Estimation Comments	[Not Specified]

6.Secondary Outcome


Title	Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
Description	An AE was considered any unfavorable and unintended sign, symptom, or ...
Description	An AE was considered any unfavorable and unintended sign, symptom, or disease associated with the use of the study drug, whether or not considered related to the study drug. Preexisting conditions that worsened during the study and laboratory or clinical tests that resulted in a change in treatment or discontinuation from study drug were reported as adverse events. A SAE was any experience that: resulted in death, was life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect or was medically significant.
Time Frame	Up to data cut-off date 24 June 2016 (approximately 5 years)

Outcome Measure Data

Analysis Population Description

The safety population included all participants who had received at least one dose of any study drug.


Arm/Group Title	Bevacizumab + Standard of Care	Standard of Care
Arm/Group Description:	Participants received bevacizumab o...	Participants received investigator'...
Arm/Group Description:	Participants received bevacizumab on Day 1 of every 21-days cycle along with standard of care, until the occurrence of an unacceptable toxicity or withdrawal of consent (whichever occurs first).	Participants received investigator's choice of standard of care (Erlotinib or Docetaxel or Pemetrexed) according to local practice until the occurrence of an unacceptable toxicity or withdrawal of consent (whichever occurs first).
Overall Number of Participants Analyzed	243	232
Measure Type: Number Unit of Measure: Percentage of Participants
AEs	97.5	96.1
SAEs	51.9	37.1

7.Secondary Outcome


Title	Time to Progression (TTP) According to RECIST v1.1
Description	The time to progression was defined as the time from baseline until di...
Description	The time to progression was defined as the time from baseline until disease progression as determined by the RECIST v1.1. TTP2 is defined as the interval between the day of randomization at PD1 and PD2. TTP3 is defined as the interval between the day of PD2 and PD3. PD was defined as ≥20% increase in sum LD in reference to the smallest on-study sum LD, or the appearance of new lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.
Time Frame	Up to data cut-off date 24 June 2016 (approximately 5 years)

Outcome Measure Data

Analysis Population Description

Intent to treat population included all randomized participants.


Arm/Group Title	Bevacizumab + Standard of Care	Standard of Care
Arm/Group Description:	Participants received bevacizumab o...	Participants received investigator'...
Arm/Group Description:	Participants received bevacizumab on Day 1 of every 21-days cycle along with standard of care, until the occurrence of an unacceptable toxicity or withdrawal of consent (whichever occurs first).	Participants received investigator's choice of standard of care (Erlotinib or Docetaxel or Pemetrexed) according to local practice until the occurrence of an unacceptable toxicity or withdrawal of consent (whichever occurs first).
Overall Number of Participants Analyzed	245	240
Median (90% Confidence Interval) Unit of Measure: Months
TTP2	5.55 (4.86 to 6.18)	4.21 (3.75 to 5.06)
TTP3	4.07 (3.25 to 4.63)	2.73 (2.37 to 3.06)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Bevacizumab + Standard of Care, Standard of Care
	Comments	TTP2: The stratification factors for Log-Rank test are the type of planned 2nd-line SoC treatment, the number of cycles of Bevacizumab maintenance treatment prior to PD1 and the smoking status.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.0311
	Comments	[Not Specified]
	Method	Stratified Log-Rank test
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Stratified Hazard Ratio
	Estimated Value	0.79
	Confidence Interval	(2-Sided) 90% 0.65 to 0.95
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Bevacizumab + Standard of Care, Standard of Care
	Comments	TTP3: The stratification factors for Log-Rank test are the type of planned 2nd-line SoC treatment, the number of cycles of Bevacizumab maintenance treatment prior to PD1 and the smoking status.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.0326
	Comments	[Not Specified]
	Method	Stratified Log-Rank test
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Stratified Hazard Ratio
	Estimated Value	0.69
	Confidence Interval	(2-Sided) 90% 0.52 to 0.92
	Estimation Comments	[Not Specified]

8.Secondary Outcome


Title	Percentage of Participants Who Are Alive at Month 6, 12, and 18
Description	Percentage of participants who were alive at Month 6, 12 and 18 were r...
Description	Percentage of participants who were alive at Month 6, 12 and 18 were reported.
Time Frame	Month 6, 12, 18

Outcome Measure Data

Analysis Population Description

Intent to treat population included all randomized participants.


Arm/Group Title	Bevacizumab + Standard of Care	Standard of Care
Arm/Group Description:	Participants received bevacizumab o...	Participants received investigator'...
Arm/Group Description:	Participants received bevacizumab on Day 1 of every 21-days cycle along with standard of care, until the occurrence of an unacceptable toxicity or withdrawal of consent (whichever occurs first).	Participants received investigator's choice of standard of care (Erlotinib or Docetaxel or Pemetrexed) according to local practice until the occurrence of an unacceptable toxicity or withdrawal of consent (whichever occurs first).
Overall Number of Participants Analyzed	245	240
Measure Type: Number Number (90% Confidence Interval) Unit of Measure: Percentage of Participants
Month 6	0.8 (0.73 to 0.82)	0.7 (0.62 to 0.72)
Month 12	0.5 (0.44 to 0.54)	0.4 (0.39 to 0.50)
Month 18	0.4 (0.31 to 0.41)	0.3 (0.25 to 0.36)

Adverse Events

Time Frame	Up to data cut-off date 24 June 2016 (approximately 5 years)
Adverse Event Reporting Description	The safety population included all participants who had received at least one dose of any study drug.

Arm/Group Title	Bevacizumab + Standard of Care	Standard of Care
Arm/Group Description	Participants received bevacizumab o...	Participants received investigator'...
Arm/Group Description	Participants received bevacizumab on Day 1 of every 21-days cycle along with standard of care, until the occurrence of an unacceptable toxicity or withdrawal of consent (whichever occurs first).	Participants received investigator's choice of standard of care (Erlotinib or Docetaxel or Pemetrexed) according to local practice until the occurrence of an unacceptable toxicity or withdrawal of consent (whichever occurs first).
All-Cause Mortality
	Bevacizumab + Standard of Care	Standard of Care
	Affected / at Risk (%)	Affected / at Risk (%)
Total	--/--	--/--
Serious Adverse Events Serious Adverse Events
	Bevacizumab + Standard of Care	Standard of Care
	Affected / at Risk (%)	Affected / at Risk (%)
Total	126/243 (51.85%)	86/232 (37.07%)
Blood and lymphatic system disorders
Anaemia ^† 1	2/243 (0.82%)	6/232 (2.59%)
Bone Marrow Failure ^† 1	1/243 (0.41%)	0/232 (0.00%)
Febrile Bone Marrow Aplasia ^† 1	1/243 (0.41%)	0/232 (0.00%)
Febrile Neutropenia ^† 1	12/243 (4.94%)	9/232 (3.88%)
Leukopenia ^† 1	2/243 (0.82%)	0/232 (0.00%)
Neutropenia ^† 1	9/243 (3.70%)	6/232 (2.59%)
Pure White Cell Aplasia ^† 1	1/243 (0.41%)	0/232 (0.00%)
Thrombocytopenia ^† 1	2/243 (0.82%)	0/232 (0.00%)
Pancytopenia ^† 1	2/243 (0.82%)	2/232 (0.86%)
Cardiac disorders
Atrial Fibrillation ^† 1	4/243 (1.65%)	1/232 (0.43%)
Cardiac Failure ^† 1	1/243 (0.41%)	1/232 (0.43%)
Cyanosis ^† 1	0/243 (0.00%)	1/232 (0.43%)
Myocardial Infarction ^† 1	1/243 (0.41%)	1/232 (0.43%)
Myocardial Ischaemia ^† 1	1/243 (0.41%)	0/232 (0.00%)
Congenital, familial and genetic disorders
Aplasia ^† 1	0/243 (0.00%)	1/232 (0.43%)
Tracheo-oesophageal Fistula ^† 1	1/243 (0.41%)	0/232 (0.00%)
Endocrine disorders
Adrenal Insufficiency ^† 1	1/243 (0.41%)	0/232 (0.00%)
Gastrointestinal disorders
Abdominal Pain ^† 1	2/243 (0.82%)	2/232 (0.86%)
Abdominal Pain Upper ^† 1	0/243 (0.00%)	1/232 (0.43%)
Ascites ^† 1	1/243 (0.41%)	0/232 (0.00%)
Constipation ^† 1	0/243 (0.00%)	1/232 (0.43%)
Diarrhoea ^† 1	7/243 (2.88%)	2/232 (0.86%)
Duodenal Ulcer ^† 1	0/243 (0.00%)	1/232 (0.43%)
Gastrointestinal Obstruction ^† 1	0/243 (0.00%)	1/232 (0.43%)
Inguinal Hernia Strangulated ^† 1	1/243 (0.41%)	0/232 (0.00%)
Intestinal Obstruction ^† 1	0/243 (0.00%)	1/232 (0.43%)
Intestinal Perforation ^† 1	1/243 (0.41%)	0/232 (0.00%)
Large Intestine Perforation ^† 1	1/243 (0.41%)	1/232 (0.43%)
Mechanical Ileus ^† 1	0/243 (0.00%)	1/232 (0.43%)
Nausea ^† 1	1/243 (0.41%)	1/232 (0.43%)
Oesophageal Stenosis ^† 1	0/243 (0.00%)	1/232 (0.43%)
Pancreatitis Acute ^† 1	2/243 (0.82%)	0/232 (0.00%)
Pneumatosis Intestinalis ^† 1	1/243 (0.41%)	0/232 (0.00%)
Small Intestinal Obstruction ^† 1	0/243 (0.00%)	1/232 (0.43%)
Small Intestinal Perforation ^† 1	1/243 (0.41%)	0/232 (0.00%)
Subileus ^† 1	1/243 (0.41%)	0/232 (0.00%)
Umbilical Hernia ^† 1	0/243 (0.00%)	1/232 (0.43%)
Upper Gastrointestinal Haemorrhage ^† 1	1/243 (0.41%)	0/232 (0.00%)
Vomiting ^† 1	2/243 (0.82%)	0/232 (0.00%)
General disorders
Asthenia ^† 1	4/243 (1.65%)	0/232 (0.00%)
Death ^† 1	1/243 (0.41%)	2/232 (0.86%)
Fatigue ^† 1	2/243 (0.82%)	2/232 (0.86%)
General Physical Health Deterioration ^† 1	1/243 (0.41%)	2/232 (0.86%)
Malaise ^† 1	0/243 (0.00%)	1/232 (0.43%)
Mucosal Inflammation ^† 1	3/243 (1.23%)	1/232 (0.43%)
Non-Cardiac Chest Pain ^† 1	0/243 (0.00%)	1/232 (0.43%)
Pain ^† 1	0/243 (0.00%)	1/232 (0.43%)
Performance Status Decreased ^† 1	1/243 (0.41%)	0/232 (0.00%)
Pyrexia ^† 1	4/243 (1.65%)	1/232 (0.43%)
Sudden Death ^† 1	1/243 (0.41%)	0/232 (0.00%)
Hepatobiliary disorders
Bile Duct Obstruction ^† 1	1/243 (0.41%)	0/232 (0.00%)
Bile Duct Stone ^† 1	1/243 (0.41%)	0/232 (0.00%)
Liver Disorder ^† 1	1/243 (0.41%)	0/232 (0.00%)
Infections and infestations
Anal Abcess ^† 1	0/243 (0.00%)	1/232 (0.43%)
Appendicitis ^† 1	1/243 (0.41%)	0/232 (0.00%)
Appendicitis Perforated ^† 1	1/243 (0.41%)	0/232 (0.00%)
Bronchitis ^† 1	1/243 (0.41%)	1/232 (0.43%)
Bronchopulmonary Aspergillosis ^† 1	1/243 (0.41%)	0/232 (0.00%)
Device related Infection ^† 1	1/243 (0.41%)	1/232 (0.43%)
Diarrhoea Infectious ^† 1	1/243 (0.41%)	0/232 (0.00%)
Diverticulitis ^† 1	0/243 (0.00%)	1/232 (0.43%)
Empyema ^† 1	0/243 (0.00%)	1/232 (0.43%)
Endocarditis ^† 1	1/243 (0.41%)	0/232 (0.00%)
Febrile Infection ^† 1	1/243 (0.41%)	0/232 (0.00%)
Gastroenteritis ^† 1	1/243 (0.41%)	0/232 (0.00%)
Gastrointestinal Infection ^† 1	0/243 (0.00%)	1/232 (0.43%)
Genital Herpes Simplex ^† 1	0/243 (0.00%)	1/232 (0.43%)
Herpes Zoster ^† 1	0/243 (0.00%)	1/232 (0.43%)
Influenza ^† 1	1/243 (0.41%)	0/232 (0.00%)
Lung Abcess ^† 1	0/243 (0.00%)	1/232 (0.43%)
Lung Infection ^† 1	3/243 (1.23%)	1/232 (0.43%)
Periorbital Abcess ^† 1	1/243 (0.41%)	0/232 (0.00%)
Pneumonia ^† 1	13/243 (5.35%)	19/232 (8.19%)
Post Procedural Infection ^† 1	1/243 (0.41%)	0/232 (0.00%)
Psoas Abcess ^† 1	1/243 (0.41%)	0/232 (0.00%)
Respiratory Tract Infection ^† 1	6/243 (2.47%)	1/232 (0.43%)
Respiratory tract Infection Bacterial ^† 1	0/243 (0.00%)	1/232 (0.43%)
Sepsis ^† 1	3/243 (1.23%)	0/232 (0.00%)
Septic Shock ^† 1	0/243 (0.00%)	1/232 (0.43%)
Subcutaneous Abcess ^† 1	1/243 (0.41%)	0/232 (0.00%)
Tracheitis ^† 1	1/243 (0.41%)	0/232 (0.00%)
Upper Respiratory Tract Infection ^† 1	1/243 (0.41%)	0/232 (0.00%)
Urinary Tract Infection ^† 1	1/243 (0.41%)	1/232 (0.43%)
Injury, poisoning and procedural complications
Alcohol Poisoning ^† 1	1/243 (0.41%)	0/232 (0.00%)
Arterial Injury ^† 1	0/243 (0.00%)	1/232 (0.43%)
Lumbar Vertebral Fracture ^† 1	1/243 (0.41%)	0/232 (0.00%)
Spinal Compression Fracture ^† 1	1/243 (0.41%)	1/232 (0.43%)
Upper Limb Fracture ^† 1	1/243 (0.41%)	0/232 (0.00%)
Investigations
Blood Bilirubin Increased ^† 1	0/243 (0.00%)	1/232 (0.43%)
Blood Creatinine Increased ^† 1	3/243 (1.23%)	0/232 (0.00%)
Liver Function Test Increased ^† 1	0/243 (0.00%)	1/232 (0.43%)
Lymphocyte Count Decreased ^† 1	1/243 (0.41%)	0/232 (0.00%)
White Blood Cell Count Decreased ^† 1	1/243 (0.41%)	0/232 (0.00%)
Metabolism and nutrition disorders
Decreased Appetite ^† 1	2/243 (0.82%)	2/232 (0.86%)
Dehydration ^† 1	3/243 (1.23%)	1/232 (0.43%)
Hyperglycaemia ^† 1	1/243 (0.41%)	0/232 (0.00%)
Hyperkalaemia ^† 1	0/243 (0.00%)	1/232 (0.43%)
Hyponatraemia ^† 1	2/243 (0.82%)	2/232 (0.86%)
Tetany ^† 1	1/243 (0.41%)	0/232 (0.00%)
Musculoskeletal and connective tissue disorders
Back Pain ^† 1	1/243 (0.41%)	0/232 (0.00%)
Bone Pain ^† 1	0/243 (0.00%)	2/232 (0.86%)
Flank Pain ^† 1	0/243 (0.00%)	1/232 (0.43%)
Intervetebral Disc Protrusion ^† 1	1/243 (0.41%)	0/232 (0.00%)
Musculoskeletal Chest Pain ^† 1	0/243 (0.00%)	2/232 (0.86%)
Musculoskeletal Pain ^† 1	1/243 (0.41%)	2/232 (0.86%)
Pathological Fracture ^† 1	1/243 (0.41%)	0/232 (0.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Lymphoma ^† 1	1/243 (0.41%)	0/232 (0.00%)
Metastases to Adrenals ^† 1	0/243 (0.00%)	1/232 (0.43%)
Nervous system disorders
Cerebral Infarction ^† 1	1/243 (0.41%)	0/232 (0.00%)
Cerebral Ischaemia ^† 1	0/243 (0.00%)	1/232 (0.43%)
Cerebrovascular Accident ^† 1	0/243 (0.00%)	1/232 (0.43%)
Dizziness ^† 1	2/243 (0.82%)	1/232 (0.43%)
Epilepsy ^† 1	1/243 (0.41%)	0/232 (0.00%)
Ischaemic Stroke ^† 1	0/243 (0.00%)	1/232 (0.43%)
Neuralgia ^† 1	1/243 (0.41%)	0/232 (0.00%)
Neuropathy Peripheral ^† 1	1/243 (0.41%)	0/232 (0.00%)
Parapalegia ^† 1	0/243 (0.00%)	1/232 (0.43%)
Peripheral Motor Neuropathy ^† 1	1/243 (0.41%)	0/232 (0.00%)
Posterior Reversible Encephalopathy Syndrome ^† 1	1/243 (0.41%)	0/232 (0.00%)
Seizure ^† 1	0/243 (0.00%)	1/232 (0.43%)
Subarachnoid Haemorrhage ^† 1	1/243 (0.41%)	0/232 (0.00%)
Syncope ^† 1	1/243 (0.41%)	0/232 (0.00%)
Transient Ischaemic Attack ^† 1	1/243 (0.41%)	0/232 (0.00%)
Psychiatric disorders
Apathy ^† 1	0/243 (0.00%)	1/232 (0.43%)
Confusional State ^† 1	1/243 (0.41%)	2/232 (0.86%)
Delirium ^† 1	0/243 (0.00%)	1/232 (0.43%)
Depression ^† 1	1/243 (0.41%)	0/232 (0.00%)
Disorientation ^† 1	0/243 (0.00%)	1/232 (0.43%)
Suicide Attempt ^† 1	2/243 (0.82%)	0/232 (0.00%)
Renal and urinary disorders
Acute Kidney Injury ^† 1	1/243 (0.41%)	0/232 (0.00%)
Nephrotic Syndrome ^† 1	1/243 (0.41%)	0/232 (0.00%)
Prerenal Failure ^† 1	1/243 (0.41%)	0/232 (0.00%)
Renal Failure ^† 1	1/243 (0.41%)	0/232 (0.00%)
Renal Tubular Disorder ^† 1	1/243 (0.41%)	0/232 (0.00%)
Reproductive system and breast disorders
Uterine Haemorrhage ^† 1	0/243 (0.00%)	1/232 (0.43%)
Respiratory, thoracic and mediastinal disorders
Acute Respiratory Failure ^† 1	1/243 (0.41%)	1/232 (0.43%)
Aspiration ^† 1	1/243 (0.41%)	0/232 (0.00%)
Bronchial Disorder ^† 1	1/243 (0.41%)	0/232 (0.00%)
Chronic Obstructive Pulmonary Disease ^† 1	3/243 (1.23%)	0/232 (0.00%)
Cough ^† 1	0/243 (0.00%)	1/232 (0.43%)
Dyspnoea ^† 1	4/243 (1.65%)	3/232 (1.29%)
Epistaxis ^† 1	1/243 (0.41%)	0/232 (0.00%)
Haemoptysis ^† 1	0/243 (0.00%)	2/232 (0.86%)
Hypoxia ^† 1	0/243 (0.00%)	2/232 (0.86%)
Interstitial Lung Disease ^† 1	2/243 (0.82%)	3/232 (1.29%)
Lung Disorder ^† 1	0/243 (0.00%)	1/232 (0.43%)
Organizing Pneumonia ^† 1	0/243 (0.00%)	1/232 (0.43%)
Pleural Effusion ^† 1	3/243 (1.23%)	4/232 (1.72%)
Pneumonia Aspiration ^† 1	1/243 (0.41%)	0/232 (0.00%)
Pneumonitis ^† 1	0/243 (0.00%)	1/232 (0.43%)
Pneumothorax ^† 1	2/243 (0.82%)	0/232 (0.00%)
Pulmonary Embolism ^† 1	5/243 (2.06%)	6/232 (2.59%)
Pulmonary Haemorrhage ^† 1	1/243 (0.41%)	0/232 (0.00%)
Pulmonary Thrombosis ^† 1	1/243 (0.41%)	0/232 (0.00%)
Respiratory Distress ^† 1	2/243 (0.82%)	0/232 (0.00%)
Respiratory Failure ^† 1	2/243 (0.82%)	0/232 (0.00%)
Skin and subcutaneous tissue disorders
Acne ^† 1	1/243 (0.41%)	0/232 (0.00%)
Erythema Multiforme ^† 1	1/243 (0.41%)	0/232 (0.00%)
Rash ^† 1	0/243 (0.00%)	1/232 (0.43%)
Skin Toxicity ^† 1	1/243 (0.41%)	0/232 (0.00%)
Surgical and medical procedures
Osteosynthesis ^† 1	1/243 (0.41%)	0/232 (0.00%)
Vascular disorders
Deep Vein Thrombosis ^† 1	0/243 (0.00%)	1/232 (0.43%)
Hypertension ^† 1	1/243 (0.41%)	1/232 (0.43%)
Peripheral Embolism ^† 1	0/243 (0.00%)	1/232 (0.43%)
† Indicates events were collected by systematic assessment 1 Term from vocabulary, MedDRA 19.0
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Bevacizumab + Standard of Care	Standard of Care
	Affected / at Risk (%)	Affected / at Risk (%)
Total	226/243 (93.00%)	215/232 (92.67%)
Blood and lymphatic system disorders
Anaemia ^† 1	54/243 (22.22%)	69/232 (29.74%)
Leukopenia ^† 1	16/243 (6.58%)	10/232 (4.31%)
Neutropenia ^† 1	39/243 (16.05%)	20/232 (8.62%)
Thrombocytopenia ^† 1	15/243 (6.17%)	9/232 (3.88%)
Eye disorders
Lacrimation Increased ^† 1	18/243 (7.41%)	12/232 (5.17%)
Gastrointestinal disorders
Abdominal Pain ^† 1	16/243 (6.58%)	13/232 (5.60%)
Abdominal Pain Upper ^† 1	25/243 (10.29%)	14/232 (6.03%)
Constipation ^† 1	64/243 (26.34%)	49/232 (21.12%)
Diarrhoea ^† 1	90/243 (37.04%)	72/232 (31.03%)
Nausea ^† 1	84/243 (34.57%)	61/232 (26.29%)
Stomatitis ^† 1	39/243 (16.05%)	26/232 (11.21%)
Vomiting ^† 1	51/243 (20.99%)	40/232 (17.24%)
General disorders
Asthenia ^† 1	68/243 (27.98%)	61/232 (26.29%)
Chest Pain ^† 1	26/243 (10.70%)	16/232 (6.90%)
Fatigue ^† 1	71/243 (29.22%)	73/232 (31.47%)
Malaise ^† 1	24/243 (9.88%)	14/232 (6.03%)
Mucosal Inflammation ^† 1	49/243 (20.16%)	22/232 (9.48%)
Oedema Peripheral ^† 1	34/243 (13.99%)	32/232 (13.79%)
Pain ^† 1	10/243 (4.12%)	13/232 (5.60%)
Pyrexia ^† 1	46/243 (18.93%)	35/232 (15.09%)
Infections and infestations
Bronchitis ^† 1	23/243 (9.47%)	12/232 (5.17%)
Conjunctivitis ^† 1	16/243 (6.58%)	13/232 (5.60%)
Pneumonia ^† 1	9/243 (3.70%)	12/232 (5.17%)
Respiratory Tract Infection ^† 1	13/243 (5.35%)	9/232 (3.88%)
Urinary Tract Infection ^† 1	16/243 (6.58%)	10/232 (4.31%)
Investigations
Blood Creatinine Increased ^† 1	13/243 (5.35%)	4/232 (1.72%)
Weight Decreased ^† 1	42/243 (17.28%)	24/232 (10.34%)
Metabolism and nutrition disorders
Decreased Appetite ^† 1	83/243 (34.16%)	59/232 (25.43%)
Dehydration ^† 1	13/243 (5.35%)	2/232 (0.86%)
Musculoskeletal and connective tissue disorders
Arthralgia ^† 1	21/243 (8.64%)	21/232 (9.05%)
Back Pain ^† 1	28/243 (11.52%)	31/232 (13.36%)
Musculoskeletal Chest Pain ^† 1	13/243 (5.35%)	8/232 (3.45%)
Musculoskeletal Pain ^† 1	22/243 (9.05%)	18/232 (7.76%)
Myalgia ^† 1	18/243 (7.41%)	18/232 (7.76%)
Pain in Extremity ^† 1	17/243 (7.00%)	16/232 (6.90%)
Nervous system disorders
Dizziness ^† 1	20/243 (8.23%)	13/232 (5.60%)
Dysgeusia ^† 1	29/243 (11.93%)	16/232 (6.90%)
Headache ^† 1	39/243 (16.05%)	23/232 (9.91%)
Neuropathy Peripheral ^† 1	20/243 (8.23%)	16/232 (6.90%)
Paraesthesia ^† 1	15/243 (6.17%)	8/232 (3.45%)
Psychiatric disorders
Anxiety ^† 1	11/243 (4.53%)	12/232 (5.17%)
Insomnia ^† 1	14/243 (5.76%)	15/232 (6.47%)
Renal and urinary disorders
Proteinuria ^† 1	51/243 (20.99%)	23/232 (9.91%)
Respiratory, thoracic and mediastinal disorders
Cough ^† 1	39/243 (16.05%)	40/232 (17.24%)
Dysphonia ^† 1	13/243 (5.35%)	13/232 (5.60%)
Dyspnoea ^† 1	56/243 (23.05%)	56/232 (24.14%)
Epistaxis ^† 1	53/243 (21.81%)	20/232 (8.62%)
Haemoptysis ^† 1	17/243 (7.00%)	11/232 (4.74%)
Pleural Effusion ^† 1	13/243 (5.35%)	15/232 (6.47%)
Skin and subcutaneous tissue disorders
Alopecia ^† 1	55/243 (22.63%)	41/232 (17.67%)
Dermatitis Acneiform ^† 1	15/243 (6.17%)	8/232 (3.45%)
Dry Skin ^† 1	29/243 (11.93%)	22/232 (9.48%)
Erythema ^† 1	11/243 (4.53%)	17/232 (7.33%)
Pruritus ^† 1	17/243 (7.00%)	14/232 (6.03%)
Rash ^† 1	49/243 (20.16%)	46/232 (19.83%)
Vascular disorders
Hypertension ^† 1	52/243 (21.40%)	25/232 (10.78%)
† Indicates events were collected by systematic assessment 1 Term from vocabulary, MedDRA 19.0

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.

Results Point of Contact

Layout table for Results Point of Contact information

Name/Title:	Medical Communications
Organization:	Hoffmann-La Roche
Phone:	888-6821-8590
EMail:	genentech@druginfo.com

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Gridelli C, de Castro Carpeno J, Dingemans AC, Griesinger F, Grossi F, Langer C, Ohe Y, Syrigos K, Thatcher N, Das-Gupta A, Truman M, Donica M, Smoljanovic V, Bennouna J. Safety and Efficacy of Bevacizumab Plus Standard-of-Care Treatment Beyond Disease Progression in Patients With Advanced Non-Small Cell Lung Cancer: The AvaALL Randomized Clinical Trial. JAMA Oncol. 2018 Dec 1;4(12):e183486. doi: 10.1001/jamaoncol.2018.3486. Epub 2018 Dec 13. Erratum In: JAMA Oncol. 2018 Dec 1;4(12):1792.

Takeda M, Yamanaka T, Seto T, Hayashi H, Azuma K, Okada M, Sugawara S, Daga H, Hirashima T, Yonesaka K, Urata Y, Murakami H, Saito H, Kubo A, Sawa T, Miyahara E, Nogami N, Nakagawa K, Nakanishi Y, Okamoto I. Bevacizumab beyond disease progression after first-line treatment with bevacizumab plus chemotherapy in advanced nonsquamous non-small cell lung cancer (West Japan Oncology Group 5910L): An open-label, randomized, phase 2 trial. Cancer. 2016 Apr 1;122(7):1050-9. doi: 10.1002/cncr.29893. Epub 2016 Feb 1.

Gridelli C, Bennouna J, de Castro J, Dingemans AM, Griesinger F, Grossi F, Rossi A, Thatcher N, Wong EK, Langer C. Randomized phase IIIb trial evaluating the continuation of bevacizumab beyond disease progression in patients with advanced non-squamous non-small-cell lung cancer after first-line treatment with bevacizumab plus platinum-based chemotherapy: treatment rationale and protocol dynamics of the AvaALL (MO22097) trial. Clin Lung Cancer. 2011 Nov;12(6):407-11. doi: 10.1016/j.cllc.2011.05.002. Epub 2011 Jun 25.

Layout table for additonal information

Responsible Party:	Hoffmann-La Roche
ClinicalTrials.gov Identifier:	NCT01351415
Other Study ID Numbers:	MO22097 2010-022645-14 ( EudraCT Number )
First Submitted:	May 9, 2011
First Posted:	May 10, 2011
Results First Submitted:	June 20, 2017
Results First Posted:	September 18, 2017
Last Update Posted:	September 18, 2017

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