Trial Outcomes & Findings for A Study of Avastin (Bevacizumab) in Combination With Platinum-Containing Chemotherapy in Patients With Advanced or Recurrent Non-Squamous Cell Lung Cancer. (NCT NCT00451906)

NCT ID: NCT00451906

Last Updated: 2016-05-24

Results Overview

Participants with adverse events (AEs) of special interest (hypertension, proteinuria, wound healing complications, gastrointestinal perforation, arterial and venous thromboembolic events, hemoptysis, Central Nervous System (CNS) bleeding, other hemorrhage events and congestive heart failure) were reported.

• Recruitment status: COMPLETED
• Study phase: PHASE4
• Target enrollment: 2252 participants
• Primary outcome timeframe: Up to 3 years
• Results posted on: 2016-05-24

Participant Flow

This study was conducted at 384 sites in 39 countries from 21 August 2006 to 30 June 2009.

A total of 2252 participants were enrolled into the study, of which 2172 received the study drug. A total of 80 randomized participants did not receive study drug.

Participant milestones

Measure	Bevacizumab + Chemotherapy Eligible participants with advanced or recurrent non-squamous non-small cell lung cancer (NSCLC) were administered bevacizumab infusions at a dose of 7.5 milligram per kilogram (mg/kg) or 15 mg/kg (investigator's choice) on Day 1 and then every 3 weeks, intravenously (IV) for a maximum of 6 cycles in combination with the standard of care NSCLC first-line chemotherapy in line with the licensed national prescribing information, during the treatment period. The initial dose of bevacizumab was to be administered following chemotherapy; all subsequent doses could be given before or after chemotherapy. After the end of chemotherapy participants without disease progression could continue bevacizumab as maintenance therapy until confirmed disease progression, unacceptable toxicity or participant consent withdrawal. Participants were followed-up through a final-visit (28 days after last bevacizumab infusion) and then every 3 months until death.
Overall Study STARTED	2252
Overall Study COMPLETED	13
Overall Study NOT COMPLETED	2239

Reasons for withdrawal

Measure	Bevacizumab + Chemotherapy Eligible participants with advanced or recurrent non-squamous non-small cell lung cancer (NSCLC) were administered bevacizumab infusions at a dose of 7.5 milligram per kilogram (mg/kg) or 15 mg/kg (investigator's choice) on Day 1 and then every 3 weeks, intravenously (IV) for a maximum of 6 cycles in combination with the standard of care NSCLC first-line chemotherapy in line with the licensed national prescribing information, during the treatment period. The initial dose of bevacizumab was to be administered following chemotherapy; all subsequent doses could be given before or after chemotherapy. After the end of chemotherapy participants without disease progression could continue bevacizumab as maintenance therapy until confirmed disease progression, unacceptable toxicity or participant consent withdrawal. Participants were followed-up through a final-visit (28 days after last bevacizumab infusion) and then every 3 months until death.
Overall Study Adverse Event	515
Overall Study Lost to Follow-up	31
Overall Study Withdrawal by Subject	111
Overall Study Protocol Violation	21
Overall Study Progressive disease	1328
Overall Study Termination of the study	108
Overall Study Other Reasons	121
Overall Study Did not complete final visit	4

Baseline Characteristics

A Study of Avastin (Bevacizumab) in Combination With Platinum-Containing Chemotherapy in Patients With Advanced or Recurrent Non-Squamous Cell Lung Cancer.

Baseline characteristics by cohort

Measure	Bevacizumab + Chemotherapy n=2172 Participants Eligible participants with advanced or recurrent non-squamous non-small cell lung cancer (NSCLC) were administered bevacizumab infusions at a dose of 7.5 milligram per kilogram (mg/kg) or 15 mg/kg (investigator's choice) on Day 1 and then every 3 weeks, intravenously (IV) for a maximum of 6 cycles in combination with the standard of care NSCLC first-line chemotherapy in line with the licensed national prescribing information, during the treatment period. The initial dose of bevacizumab was to be administered following chemotherapy; all subsequent doses could be given before or after chemotherapy. After the end of chemotherapy participants without disease progression could continue bevacizumab as maintenance therapy until confirmed disease progression, unacceptable toxicity or participant consent withdrawal. Participants were followed-up through a final-visit (28 days after last bevacizumab infusion) and then every 3 months until death.
Age, Continuous	58.8 years STANDARD_DEVIATION 10.3 • n=5 Participants
Sex: Female, Male Female	866 Participants n=5 Participants
Sex: Female, Male Male	1306 Participants n=5 Participants

PRIMARY outcome

Timeframe: Up to 3 years

Population: The ITT population included all participants with at least one valid post-baseline (Day -28 to -1) assessment.

Participants with adverse events (AEs) of special interest (hypertension, proteinuria, wound healing complications, gastrointestinal perforation, arterial and venous thromboembolic events, hemoptysis, Central Nervous System (CNS) bleeding, other hemorrhage events and congestive heart failure) were reported.

Outcome measures

Measure	Bevacizumab + Chemotherapy n=2172 Participants Eligible participants with advanced or recurrent non-squamous non-small cell lung cancer (NSCLC) were administered bevacizumab infusions at a dose of 7.5 milligram per kilogram (mg/kg) or 15 mg/kg (investigator's choice) on Day 1 and then every 3 weeks, intravenously (IV) for a maximum of 6 cycles in combination with the standard of care NSCLC first-line chemotherapy in line with the licensed national prescribing information, during the treatment period. The initial dose of bevacizumab was to be administered following chemotherapy; all subsequent doses could be given before or after chemotherapy. After the end of chemotherapy participants without disease progression could continue bevacizumab as maintenance therapy until confirmed disease progression, unacceptable toxicity or participant consent withdrawal. Participants were followed-up through a final-visit (28 days after last bevacizumab infusion) and then every 3 months until death.
Number of Participants With Adverse Events of Special Interest Hypertension	687 participants
Number of Participants With Adverse Events of Special Interest Proteinuria	672 participants
Number of Participants With Adverse Events of Special Interest Wound healing complication	26 participants
Number of Participants With Adverse Events of Special Interest Gastrointestinal perforation	30 participants
Number of Participants With Adverse Events of Special Interest Arterial/Venous thromboembolic events	274 participants
Number of Participants With Adverse Events of Special Interest Hemoptysis	176 participants
Number of Participants With Adverse Events of Special Interest CNS bleeding	7 participants
Number of Participants With Adverse Events of Special Interest Other hemorrhage events	744 participants
Number of Participants With Adverse Events of Special Interest Congestive heart failure	17 participants

PRIMARY outcome

Timeframe: Up to 3 years

Population: The ITT population included all participants with at least one valid post-baseline (Day -28 to -1) assessment.

Participants with serious adverse events (SAEs) related to bevacizumab were reported for the duration of the study.

Outcome measures

Measure

Bevacizumab + Chemotherapy n=2172 Participants Eligible participants with advanced or recurrent non-squamous non-small cell lung cancer (NSCLC) were administered bevacizumab infusions at a dose of 7.5 milligram per kilogram (mg/kg) or 15 mg/kg (investigator's choice) on Day 1 and then every 3 weeks, intravenously (IV) for a maximum of 6 cycles in combination with the standard of care NSCLC first-line chemotherapy in line with the licensed national prescribing information, during the treatment period. The initial dose of bevacizumab was to be administered following chemotherapy; all subsequent doses could be given before or after chemotherapy. After the end of chemotherapy participants without disease progression could continue bevacizumab as maintenance therapy until confirmed disease progression, unacceptable toxicity or participant consent withdrawal. Participants were followed-up through a final-visit (28 days after last bevacizumab infusion) and then every 3 months until death.

Number of Participants With Serious Adverse Events Related to Bevacizumab

283 participants

SECONDARY outcome

Timeframe: Up to 3 years

Population: The ITT population included all participants with at least one valid post-baseline (Day -28 to -1) assessment. Participants available at the time of assessment were included in the analysis.

Overall survival time was defined as time between first bevacizumab administration and date of death, irrespective of the cause of death. Participants for whom no death was captured on the clinical database were censored at the most recent date they were known to be alive.

Outcome measures

Measure

Bevacizumab + Chemotherapy n=1258 Participants Eligible participants with advanced or recurrent non-squamous non-small cell lung cancer (NSCLC) were administered bevacizumab infusions at a dose of 7.5 milligram per kilogram (mg/kg) or 15 mg/kg (investigator's choice) on Day 1 and then every 3 weeks, intravenously (IV) for a maximum of 6 cycles in combination with the standard of care NSCLC first-line chemotherapy in line with the licensed national prescribing information, during the treatment period. The initial dose of bevacizumab was to be administered following chemotherapy; all subsequent doses could be given before or after chemotherapy. After the end of chemotherapy participants without disease progression could continue bevacizumab as maintenance therapy until confirmed disease progression, unacceptable toxicity or participant consent withdrawal. Participants were followed-up through a final-visit (28 days after last bevacizumab infusion) and then every 3 months until death.

Duration of Overall Survival

14.6 Months Interval 13.8 to 15.3

SECONDARY outcome

Timeframe: Up to 3 years

Population: The ITT population was considered for analysis, which included all participants with at least one valid post-baseline (Day -28 to -1) assessment. Participants available at the time of assessment were included in the analysis.

Time to disease progression was defined as time between first bevacizumab administration and date of first occurrence of progressive disease. Participants who had not progressed at the time of study completion (including participants who died before progressive disease) or who were lost to follow-up were censored at the last bevacizumab administration date. Progressive disease is defined as at least a 20% increase in the sum of the longest diameter (LD) of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. Time to disease progression was assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0.

Outcome measures

Measure

Bevacizumab + Chemotherapy n=1501 Participants Eligible participants with advanced or recurrent non-squamous non-small cell lung cancer (NSCLC) were administered bevacizumab infusions at a dose of 7.5 milligram per kilogram (mg/kg) or 15 mg/kg (investigator's choice) on Day 1 and then every 3 weeks, intravenously (IV) for a maximum of 6 cycles in combination with the standard of care NSCLC first-line chemotherapy in line with the licensed national prescribing information, during the treatment period. The initial dose of bevacizumab was to be administered following chemotherapy; all subsequent doses could be given before or after chemotherapy. After the end of chemotherapy participants without disease progression could continue bevacizumab as maintenance therapy until confirmed disease progression, unacceptable toxicity or participant consent withdrawal. Participants were followed-up through a final-visit (28 days after last bevacizumab infusion) and then every 3 months until death.

Time to Disease Progression

7.8 Months Interval 7.5 to 8.1

SECONDARY outcome

Timeframe: Up to 3 years

Population: The ITT population was used for analysis, which included all participants with at least one valid post-baseline (Day -28 to -1) assessment. n = number of participants available at the time of assessment who were included in the analysis.

The incidence of central nervous system (CNS) bleeding was reported for participants who developed CNS metastases during the study period and who did not have Computed Tomography (CT) or magnetic resonance imaging (MRI) techniques of the head performed at baseline.

Outcome measures

Measure	Bevacizumab + Chemotherapy n=367 Participants Eligible participants with advanced or recurrent non-squamous non-small cell lung cancer (NSCLC) were administered bevacizumab infusions at a dose of 7.5 milligram per kilogram (mg/kg) or 15 mg/kg (investigator's choice) on Day 1 and then every 3 weeks, intravenously (IV) for a maximum of 6 cycles in combination with the standard of care NSCLC first-line chemotherapy in line with the licensed national prescribing information, during the treatment period. The initial dose of bevacizumab was to be administered following chemotherapy; all subsequent doses could be given before or after chemotherapy. After the end of chemotherapy participants without disease progression could continue bevacizumab as maintenance therapy until confirmed disease progression, unacceptable toxicity or participant consent withdrawal. Participants were followed-up through a final-visit (28 days after last bevacizumab infusion) and then every 3 months until death.
Number of Participants With Central Nervous System Bleeding With CNS metastases (n = 281)	12 participants
Number of Participants With Central Nervous System Bleeding Without CT/MRI scans (n = 367)	16 participants

Adverse Events

Bevacizumab + Chemotherapy

Serious events: 834 serious events

Other events: 1982 other events

Deaths: 0 deaths

Serious adverse events

Measure	Bevacizumab + Chemotherapy n=2212 participants at risk Eligible participants with advanced or recurrent non-squamous non-small cell lung cancer (NSCLC) were administered bevacizumab infusions at a dose of 7.5 milligram per kilogram (mg/kg) or 15 mg/kg (investigator's choice) on Day 1 and then every 3 weeks, intravenously (IV) for a maximum of 6 cycles in combination with the standard of care NSCLC first-line chemotherapy in line with the licensed national prescribing information, during the treatment period. The initial dose of bevacizumab was to be administered following chemotherapy; all subsequent doses could be given before or after chemotherapy. After the end of chemotherapy participants without disease progression could continue bevacizumab as maintenance therapy until confirmed disease progression, unacceptable toxicity or participant consent withdrawal. Participants were followed-up through a final-visit (28 days after last bevacizumab infusion) and then every 3 months until death.
Respiratory, thoracic and mediastinal disorders Lung infiltration	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Respiratory, thoracic and mediastinal disorders Pharyngolaryngeal pain	0.09% 2/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Respiratory, thoracic and mediastinal disorders Pleural effusion	0.23% 5/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Respiratory, thoracic and mediastinal disorders Pleuritic pain	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Respiratory, thoracic and mediastinal disorders Pneumonitis	0.09% 2/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Respiratory, thoracic and mediastinal disorders Pneumothorax	0.54% 12/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Respiratory, thoracic and mediastinal disorders Pulmonary congestion	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	2.5% 55/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Respiratory, thoracic and mediastinal disorders Pulmonary haemorrhage	0.18% 4/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Respiratory, thoracic and mediastinal disorders Pulmonary infarction	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Respiratory, thoracic and mediastinal disorders Pulmonary thrombosis	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Respiratory, thoracic and mediastinal disorders Pulmonary venous thrombosis	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Respiratory, thoracic and mediastinal disorders Respiratory distress	0.09% 2/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Respiratory, thoracic and mediastinal disorders Respiratory failure	0.23% 5/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Respiratory, thoracic and mediastinal disorders Thoracic haemorrhage	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Skin and subcutaneous tissue disorders Angioedema	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Skin and subcutaneous tissue disorders Drug eruption	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Skin and subcutaneous tissue disorders Leukocytoclastic vasculitis	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Skin and subcutaneous tissue disorders Rash	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Skin and subcutaneous tissue disorders Skin lesion	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Skin and subcutaneous tissue disorders Skin ulcer	0.09% 2/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Skin and subcutaneous tissue disorders Skin ulcer haemorrhage	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Skin and subcutaneous tissue disorders Stevens-johnson syndrome	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Surgical and medical procedures Astringent therapy	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Surgical and medical procedures Catheter placement	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Surgical and medical procedures Knee operation	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Surgical and medical procedures Lung lobectomy	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Surgical and medical procedures Pleurodesis	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Surgical and medical procedures Tumour excision	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Vascular disorders Aortic aneurysm	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Vascular disorders Capillary leak syndrome	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Vascular disorders Deep vein thrombosis	1.3% 29/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Vascular disorders Embolism	0.14% 3/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Vascular disorders Embolism venous	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Vascular disorders Haemorrhage	0.09% 2/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Vascular disorders Hypertension	0.41% 9/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Vascular disorders Hypertensive crisis	0.18% 4/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Vascular disorders Infarction	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Vascular disorders Jugular vein thrombosis	0.09% 2/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Vascular disorders Orthostatic hypotension	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Vascular disorders Peripheral arterial occlusive disease	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Vascular disorders Peripheral ischaemia	0.09% 2/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Vascular disorders Peripheral vascular disorder	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Vascular disorders Phlebitis superficial	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Vascular disorders Shock	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Vascular disorders Subclavian vein thrombosis	0.09% 2/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Vascular disorders Thrombosis	0.32% 7/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Vascular disorders Vena cava thrombosis	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Vascular disorders Venous insufficiency	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Vascular disorders Venous thrombosis	0.14% 3/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Vascular disorders Venous thrombosis limb	0.09% 2/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Infections and infestations Not Codable	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Blood and lymphatic system disorders Anaemia	1.6% 36/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Blood and lymphatic system disorders Anaemia haemolytic autoimmune	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Blood and lymphatic system disorders Febrile bone marrow aplasia	0.23% 5/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Blood and lymphatic system disorders Febrile neutropenia	2.4% 52/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Blood and lymphatic system disorders Leukopenia	0.45% 10/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Blood and lymphatic system disorders Neutropenia	3.8% 84/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Blood and lymphatic system disorders Pancytopenia	0.50% 11/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Blood and lymphatic system disorders Thrombocythaemia	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Blood and lymphatic system disorders Thrombocytopenia	2.0% 44/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Cardiac disorders Acute coronary syndrome	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Cardiac disorders Acute myocardial infarction	0.09% 2/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Cardiac disorders Angina unstable	0.09% 2/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Cardiac disorders Arrhythmia	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Cardiac disorders Atrial fibrillation	0.36% 8/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Cardiac disorders Atrial flutter	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Cardiac disorders Bradycardia	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Cardiac disorders Cardiac arrest	0.09% 2/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Cardiac disorders Cardiac disorder	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Cardiac disorders Cardiac failure	0.18% 4/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Cardiac disorders Cardiac failure congestive	0.18% 4/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Cardiac disorders Cardiac flutter	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Cardiac disorders Cardiac tamponade	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Cardiac disorders Cardio-respiratory arrest	0.14% 3/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Cardiac disorders Cardiogenic shock	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Cardiac disorders Cardiomyopathy	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Cardiac disorders Cardiopulmonary failure	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Cardiac disorders Coronary artery disease	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Cardiac disorders Left ventricular failure	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Cardiac disorders Myocardial infarction	0.77% 17/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Cardiac disorders Myocardial ischaemia	0.18% 4/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Cardiac disorders Pericardial effusion	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Cardiac disorders Pericarditis	0.09% 2/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Cardiac disorders Tachyarrhythmia	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Cardiac disorders Tachycardia	0.09% 2/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Ear and labyrinth disorders Tympanic membrane disorder	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Eye disorders Angle closure glaucoma	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Eye disorders Optic ischaemic neuropathy	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Eye disorders Retinal vein thrombosis	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Eye disorders Visual acuity reduced	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Eye disorders Visual disturbance	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Gastrointestinal disorders Abdominal pain	0.59% 13/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Gastrointestinal disorders Abdominal pain upper	0.14% 3/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Gastrointestinal disorders Anal fistula	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Gastrointestinal disorders Anal stenosis	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Gastrointestinal disorders Anal ulcer	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Gastrointestinal disorders Appendicitis perforated	0.09% 2/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Gastrointestinal disorders Colitis	0.14% 3/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Gastrointestinal disorders Colitis ischaemic	0.09% 2/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Gastrointestinal disorders Constipation	0.54% 12/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Gastrointestinal disorders Diarrhoea	0.81% 18/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Gastrointestinal disorders Diverticular perforation	0.14% 3/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Gastrointestinal disorders Duodenal ulcer	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Gastrointestinal disorders Duodenal ulcer haemorrhage	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Gastrointestinal disorders Dysphagia	0.09% 2/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Gastrointestinal disorders Enteritis	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Gastrointestinal disorders Faeces discoloured	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Gastrointestinal disorders Gastric haemorrhage	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Gastrointestinal disorders Gastric ulcer	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Gastrointestinal disorders Gastric ulcer haemorrhage	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Gastrointestinal disorders Gastritis	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Gastrointestinal disorders Gastrointestinal disorder	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Gastrointestinal disorders Gastrointestinal haemorrhage	0.36% 8/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Gastrointestinal disorders Gastrointestinal perforation	0.41% 9/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Gastrointestinal disorders Gingival disorder	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Gastrointestinal disorders Glossodynia	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Gastrointestinal disorders Haematemesis	0.14% 3/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Gastrointestinal disorders Haemorrhoids	0.09% 2/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Gastrointestinal disorders Ileus	0.18% 4/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Gastrointestinal disorders Ileus paralytic	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Gastrointestinal disorders Intestinal obstruction	0.09% 2/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Gastrointestinal disorders Intestinal perforation	0.09% 2/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Gastrointestinal disorders Jejunal perforation	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Gastrointestinal disorders Large intestine perforation	0.32% 7/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Gastrointestinal disorders Lower gastrointestinal haemorrhage	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Gastrointestinal disorders Mechanical ileus	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Gastrointestinal disorders Nausea	1.1% 25/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Gastrointestinal disorders Oesophagitis	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Gastrointestinal disorders Pancreatitis acute	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Gastrointestinal disorders Peptic ulcer perforation	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Gastrointestinal disorders Peritonitis	0.14% 3/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Gastrointestinal disorders Rectal haemorrhage	0.32% 7/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Gastrointestinal disorders Small intestinal perforation	0.14% 3/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Gastrointestinal disorders Stomatitis	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Gastrointestinal disorders Subileus	0.14% 3/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Gastrointestinal disorders Upper gastrointestinal haemorrhage	0.09% 2/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Gastrointestinal disorders Vomiting	1.2% 26/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
General disorders Aplasia	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
General disorders Asthenia	0.09% 2/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
General disorders Catheter thrombosis	0.18% 4/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
General disorders Chest pain	0.86% 19/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
General disorders Chills	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
General disorders Cyst rupture	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
General disorders Death	0.63% 14/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
General disorders Extravasation	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
General disorders Fatigue	0.86% 19/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
General disorders Feeling abnormal	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
General disorders Gait disturbance	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
General disorders General physical health deterioration	0.59% 13/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
General disorders Hyperpyrexia	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
General disorders Ill-defined disorder	0.09% 2/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
General disorders Impaired healing	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
General disorders Infusion related reaction	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
General disorders Mucosal inflammation	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
General disorders Multi-organ failure	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
General disorders Pain	0.14% 3/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
General disorders Performance status decreased	0.09% 2/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
General disorders Pyrexia	1.7% 37/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
General disorders Sudden death	0.18% 4/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Hepatobiliary disorders Alcoholic liver disease	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Hepatobiliary disorders Bile duct stone	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Hepatobiliary disorders Cholecystitis	0.09% 2/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Hepatobiliary disorders Cholecystitis acute	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Hepatobiliary disorders Cholelithiasis	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Hepatobiliary disorders Cholestasis	0.14% 3/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Hepatobiliary disorders Hepatic failure	0.09% 2/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Hepatobiliary disorders Hepatitis acute	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Hepatobiliary disorders Hepatorenal syndrome	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Hepatobiliary disorders Jaundice	0.09% 2/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Immune system disorders Drug hypersensitivity	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Immune system disorders Hypersensitivity	0.09% 2/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Infections and infestations Abscess	0.14% 3/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Infections and infestations Abscess bacterial	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Infections and infestations Anal abscess	0.18% 4/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Infections and infestations Anal infection	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Infections and infestations Appendicitis	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Infections and infestations Bronchitis	0.09% 2/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Infections and infestations Bronchopneumonia	0.09% 2/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Infections and infestations Candidiasis	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Infections and infestations Catheter related infection	0.09% 2/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Infections and infestations Catheter site infection	0.09% 2/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Infections and infestations Cellulitis	0.09% 2/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Infections and infestations Central line infection	0.14% 3/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Infections and infestations Clostridial infection	0.09% 2/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Infections and infestations Device related infection	0.09% 2/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Infections and infestations Diverticulitis	0.09% 2/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Infections and infestations Empyema	0.27% 6/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Infections and infestations Enterocolitis infectious	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Infections and infestations Erysipelas	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Infections and infestations Febrile infection	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Infections and infestations Gastroenteritis	0.27% 6/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Infections and infestations Herpes zoster	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Infections and infestations Infection	0.32% 7/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Infections and infestations Lobar pneumonia	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Infections and infestations Lower respiratory tract infection	0.09% 2/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Infections and infestations Lung abscess	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Infections and infestations Lung infection	0.23% 5/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Infections and infestations Mumps	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Infections and infestations Nasopharyngitis	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Infections and infestations Neutropenic infection	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Infections and infestations Neutropenic sepsis	0.09% 2/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Infections and infestations Penile abscess	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Infections and infestations Peridiverticular abscess	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Infections and infestations Perirectal abscess	0.09% 2/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Infections and infestations Pneumonia	2.4% 52/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Infections and infestations Pneumonia necrotising	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Infections and infestations Pneumonia primary atypical	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Infections and infestations Psoas abscess	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Infections and infestations Pyopneumothorax	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Infections and infestations Respiratory tract infection	0.45% 10/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Infections and infestations Sepsis	0.36% 8/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Infections and infestations Septic shock	0.18% 4/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Infections and infestations Sinusitis	0.09% 2/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Infections and infestations Staphylococcal infection	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Infections and infestations Superinfection	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Infections and infestations Tonsillitis	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Infections and infestations Upper respiratory tract infection	0.18% 4/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Infections and infestations Urinary tract infection	0.18% 4/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Infections and infestations Urosepsis	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Infections and infestations Viral infection	0.09% 2/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Infections and infestations Viral skin infection	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Injury, poisoning and procedural complications Accidental overdose	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Injury, poisoning and procedural complications Alcohol poisoning	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Injury, poisoning and procedural complications Allergic transfusion reaction	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Injury, poisoning and procedural complications Ankle fracture	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Injury, poisoning and procedural complications Bone fissure	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Injury, poisoning and procedural complications Femur fracture	0.09% 2/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Injury, poisoning and procedural complications Incision site haemorrhage	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Injury, poisoning and procedural complications Overdose	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Injury, poisoning and procedural complications Post procedural haemorrhage	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Injury, poisoning and procedural complications Postoperative thoracic procedure complication	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Injury, poisoning and procedural complications Radiation oesophagitis	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Injury, poisoning and procedural complications Rib fracture	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Injury, poisoning and procedural complications Wound	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Injury, poisoning and procedural complications Wound dehiscence	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Investigations Activated partial thromboplastin time prolonged	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Investigations Aspiration bronchial	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Investigations Blood bilirubin increased	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Investigations Blood creatinine increased	0.41% 9/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Investigations Blood potassium decreased	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Investigations C-reactive protein increased	0.14% 3/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Investigations Creatinine renal clearance decreased	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Investigations Gamma-glutamyltransferase increased	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Investigations Haematology test abnormal	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Investigations Haemoglobin decreased	0.23% 5/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Investigations Neutrophil count decreased	0.41% 9/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Investigations Platelet count decreased	0.50% 11/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Investigations Transaminases abnormal	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Investigations Weight decreased	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Investigations White blood cell count decreased	0.36% 8/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Metabolism and nutrition disorders Anorexia	0.18% 4/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Metabolism and nutrition disorders Cachexia	0.14% 3/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Metabolism and nutrition disorders Dehydration	0.41% 9/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Metabolism and nutrition disorders Electrolyte imbalance	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Metabolism and nutrition disorders Hypercalcaemia	0.23% 5/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Metabolism and nutrition disorders Hypercreatininaemia	0.09% 2/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Metabolism and nutrition disorders Hyperglycaemia	0.09% 2/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Metabolism and nutrition disorders Hypoalbuminaemia	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Metabolism and nutrition disorders Hypokalaemia	0.14% 3/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Metabolism and nutrition disorders Hyponatraemia	0.14% 3/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Metabolism and nutrition disorders Hypoproteinaemia	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Metabolism and nutrition disorders Starvation	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Musculoskeletal and connective tissue disorders Arthralgia	0.14% 3/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Musculoskeletal and connective tissue disorders Arthritis	0.09% 2/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Musculoskeletal and connective tissue disorders Back pain	0.23% 5/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Musculoskeletal and connective tissue disorders Bone pain	0.23% 5/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Musculoskeletal and connective tissue disorders Fistula	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Musculoskeletal and connective tissue disorders Muscle haemorrhage	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Musculoskeletal and connective tissue disorders Muscular weakness	0.09% 2/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Musculoskeletal and connective tissue disorders Musculoskeletal chest pain	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Musculoskeletal and connective tissue disorders Musculoskeletal pain	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Musculoskeletal and connective tissue disorders Osteolysis	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Musculoskeletal and connective tissue disorders Pain in extremity	0.09% 2/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Musculoskeletal and connective tissue disorders Pathological fracture	0.09% 2/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Bladder cancer	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Bladder neoplasm	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Colon cancer	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Infected neoplasm	0.09% 2/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Lung neoplasm	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Metastases to bone	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Metastases to meninges	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Metastatic pain	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Paraneoplastic syndrome	0.14% 3/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Tumour haemorrhage	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Nervous system disorders Aphonia	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Nervous system disorders Autonomic nervous system imbalance	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Nervous system disorders Brain stem infarction	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Nervous system disorders Cerebral haematoma	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Nervous system disorders Cerebral haemorrhage	0.09% 2/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Nervous system disorders Cerebral infarction	0.18% 4/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Nervous system disorders Cerebral ischaemia	0.18% 4/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Nervous system disorders Cerebral microangiopathy	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Nervous system disorders Cerebrovascular accident	0.32% 7/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Nervous system disorders Coma	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Nervous system disorders Convulsion	0.27% 6/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Nervous system disorders Dizziness	0.09% 2/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Nervous system disorders Encephalopathy	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Nervous system disorders Epilepsy	0.09% 2/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Nervous system disorders Headache	0.36% 8/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Nervous system disorders Hemiparesis	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Nervous system disorders Hydrocephalus	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Nervous system disorders Hypertensive encephalopathy	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Nervous system disorders Intracranial aneurysm	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Nervous system disorders Ischaemic stroke	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Nervous system disorders Lacunar infarction	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Nervous system disorders Leukoencephalopathy	0.09% 2/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Nervous system disorders Nervous system disorder	0.09% 2/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Nervous system disorders Neuralgia	0.09% 2/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Nervous system disorders Neuropathy peripheral	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Nervous system disorders Optic neuritis	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Nervous system disorders Peroneal nerve palsy	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Nervous system disorders Polyneuropathy	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Nervous system disorders Presyncope	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Nervous system disorders Sciatica	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Nervous system disorders Status epilepticus	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Nervous system disorders Syncope	0.50% 11/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Nervous system disorders Toxic encephalopathy	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Nervous system disorders Transient ischaemic attack	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Psychiatric disorders Confusional state	0.32% 7/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Psychiatric disorders Emotional disorder	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Renal and urinary disorders Haematuria	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Renal and urinary disorders Nephritic syndrome	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Renal and urinary disorders Nephrolithiasis	0.09% 2/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Renal and urinary disorders Nephrotic syndrome	0.14% 3/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Renal and urinary disorders Proteinuria	0.14% 3/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Renal and urinary disorders Renal failure	0.50% 11/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Renal and urinary disorders Renal failure acute	0.36% 8/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Renal and urinary disorders Renal haemorrhage	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Renal and urinary disorders Renal impairment	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Renal and urinary disorders Urinary retention	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Reproductive system and breast disorders Benign prostatic hyperplasia	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Reproductive system and breast disorders Pelvic pain	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Respiratory, thoracic and mediastinal disorders Acute pulmonary oedema	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Respiratory, thoracic and mediastinal disorders Acute respiratory failure	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Respiratory, thoracic and mediastinal disorders Alveolitis	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Respiratory, thoracic and mediastinal disorders Bronchopleural fistula	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Respiratory, thoracic and mediastinal disorders Bronchospasm	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Respiratory, thoracic and mediastinal disorders Dysphonia	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Respiratory, thoracic and mediastinal disorders Dyspnoea	1.4% 32/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Respiratory, thoracic and mediastinal disorders Epistaxis	0.95% 21/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Respiratory, thoracic and mediastinal disorders Haemoptysis	0.81% 18/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Respiratory, thoracic and mediastinal disorders Haemothorax	0.09% 2/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Respiratory, thoracic and mediastinal disorders Hydropneumothorax	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Respiratory, thoracic and mediastinal disorders Interstitial lung disease	0.05% 1/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Respiratory, thoracic and mediastinal disorders Lung disorder	0.18% 4/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.

Other adverse events

Measure	Bevacizumab + Chemotherapy n=2212 participants at risk Eligible participants with advanced or recurrent non-squamous non-small cell lung cancer (NSCLC) were administered bevacizumab infusions at a dose of 7.5 milligram per kilogram (mg/kg) or 15 mg/kg (investigator's choice) on Day 1 and then every 3 weeks, intravenously (IV) for a maximum of 6 cycles in combination with the standard of care NSCLC first-line chemotherapy in line with the licensed national prescribing information, during the treatment period. The initial dose of bevacizumab was to be administered following chemotherapy; all subsequent doses could be given before or after chemotherapy. After the end of chemotherapy participants without disease progression could continue bevacizumab as maintenance therapy until confirmed disease progression, unacceptable toxicity or participant consent withdrawal. Participants were followed-up through a final-visit (28 days after last bevacizumab infusion) and then every 3 months until death.
Gastrointestinal disorders Constipation	19.1% 423/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Gastrointestinal disorders Diarrhoea	15.7% 347/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Gastrointestinal disorders Nausea	37.4% 827/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Gastrointestinal disorders Stomatitis	11.8% 260/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Gastrointestinal disorders Vomiting	23.3% 516/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
General disorders Chest pain	10.1% 224/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
General disorders Fatigue	40.4% 893/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
General disorders Pyrexia	11.9% 263/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Investigations Alanine aminotransferase increased	7.2% 159/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Investigations Aspartate aminotransferase increased	6.4% 141/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Investigations Blood creatinine increased	8.4% 186/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Investigations Gamma-glutamyltransferase increased	5.5% 121/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Investigations Haemoglobin decreased	35.6% 788/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Investigations Neutrophil count decreased	31.5% 696/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Investigations Platelet count decreased	25.9% 573/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Investigations Protein urine present	5.0% 111/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Investigations White blood cell count decreased	28.2% 623/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Metabolism and nutrition disorders Anorexia	20.9% 462/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Metabolism and nutrition disorders Hyperglycaemia	5.5% 122/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Musculoskeletal and connective tissue disorders Arthralgia	8.2% 182/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Musculoskeletal and connective tissue disorders Back pain	9.9% 219/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Musculoskeletal and connective tissue disorders Musculoskeletal pain	6.1% 134/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Musculoskeletal and connective tissue disorders Myalgia	6.1% 135/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Musculoskeletal and connective tissue disorders Pain in extremity	8.5% 189/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Nervous system disorders Dizziness	5.8% 128/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Nervous system disorders Headache	14.0% 309/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Nervous system disorders Neuropathy	8.1% 179/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Psychiatric disorders Insomnia	5.1% 112/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Renal and urinary disorders Proteinuria	25.7% 568/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Respiratory, thoracic and mediastinal disorders Cough	14.8% 328/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Respiratory, thoracic and mediastinal disorders Dysphonia	5.9% 130/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Respiratory, thoracic and mediastinal disorders Dyspnoea	12.6% 279/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Respiratory, thoracic and mediastinal disorders Epistaxis	26.6% 589/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Respiratory, thoracic and mediastinal disorders Haemoptysis	7.5% 167/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Skin and subcutaneous tissue disorders Alopecia	23.8% 526/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Skin and subcutaneous tissue disorders Rash	7.5% 167/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.
Vascular disorders Hypertension	30.7% 680/2212 • Up to 3 years The ITT population was used for the safety analysis, which included all participants who had been treated with bevacizumab and chemotherapy at least once.

Additional Information

Roche Trial Information Hotline

F. Hoffmann-La Roche AG

Phone: +41 616878333

Email: global.trial_information@roche.com

Results disclosure agreements

• Principal investigator is a sponsor employee 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.
• Publication restrictions are in place

Restriction type: OTHER