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Clinical Trial Results:
MAVERICC (Marker Evaluation for Avastin Research in CRC): A Randomized Phase II Study of Bevacizumab+mFOLFOX6 Vs. Bevacizumab+FOLFIRI With Biomarker Stratification in Patients With Previously Untreated Metastatic Colorectal Cancer

Summary
EudraCT number	2011-004755-39
Trial protocol	IE EE PT
Global end of trial date	02 Jul 2015

Results information
Results version number	v1(current)
This version publication date	16 Jul 2016
First version publication date	16 Jul 2016
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

ML25710

ISRCTN number

US NCT number

NCT01374425

WHO universal trial number (UTN)

Sponsor organisation name

F. Hoffmann-La Roche AG

Sponsor organisation address

Grenzacherstrasse 124, Basel, Switzerland, CH-4070

Public contact

Roche Trial Information Hotline, F. Hoffmann-La Roche AG, +41 61 6878333, global.trial_information@roche.com

Scientific contact

Roche Trial Information Hotline, F. Hoffmann-La Roche AG, +41 61 6878333, global.trial_information@roche.com

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

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

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

Analysis stage

Final

Date of interim/final analysis

27 Jan 2016

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

02 Jul 2015

Was the trial ended prematurely?

Main objective of the trial

This was a randomized, open-label, multicenter, Phase II study with primary objectives to assess whether expression of select chemotherapy markers is associated with progression-free survival (PFS) in participants treated with bevacizumab plus leucovorin, 5-fluorouracil, and oxaliplatin (mFOLFOX6) or bevacizumab plus leucovorin, 5-fluorouracil, and irinotecan (FOLFIRI). The study population consisted of participants with first-line metastatic colorectal cancer (mCRC).

Protection of trial subjects

The Investigator has ensured that this study was conducted in full conformance with the principles of the Declaration of Helsinki or with the laws and regulations of the country in which the research was conducted, whichever affords the greater protection to the individual. The study must have fully adhered to the principles outlined in the Guideline for Good Clinical Practice International Council for Harmonisation (ICH) Tripartite Guideline (January 1997) or with local law if it affords greater protection to the participant. In other countries where the Guideline for Good Clinical Practice exists, Roche and the investigators have strictly ensured adherence to the stated provisions.

Background therapy

Evidence for comparator

Actual start date of recruitment

21 Aug 2011

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Norway: 2

Country: Number of subjects enrolled

Portugal: 18

Country: Number of subjects enrolled

Estonia: 8

Country: Number of subjects enrolled

Ireland: 11

Country: Number of subjects enrolled

Canada: 11

Country: Number of subjects enrolled

Switzerland: 8

Country: Number of subjects enrolled

United States: 318

Worldwide total number of subjects

376

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

236

From 65 to 84 years

139

85 years and over

Subject disposition

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Recruitment details

Screening details

The trial included a 21-day Screening period during which participants provided information for demographics, medical history and cancer/treatment history and completed urinalysis collection.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Bevacizumab + mFOLFOX6

Arm description

Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus mFOLFOX6 until disease progression or unacceptable toxicity. Bevacizumab was given as 5 milligrams per kilogram (mg/kg), leucovorin as 400 milligrams per meter-squared (mg/m^2), oxaliplatin as 85 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via intravenous (IV) infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to oxaliplatin and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles.

Arm type

Experimental

Investigational medicinal product name

Bevacizumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Bevacizumab was given as 5 mg/kg IV infusion on Day 1 of each 2-week cycle. For participants who discontinued from oxaliplatin or irinotecan due to unacceptable toxicity, bevacizumab was given in 3-week cycles with capecitabine.

Investigational medicinal product name

Leucovorin

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Leucovorin was given as 400 mg/m^2 via IV infusion on Day 1 of each 2-week cycle.

Investigational medicinal product name

5-Fluorouracil

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

5-Fluorouracil was given as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion started on Day 1 of each 2-week cycle.

Investigational medicinal product name

Oxaliplatin

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Oxaliplatin was given as 85 mg/m^2 via IV infusion on Day 1 of each 2-week cycle.

Investigational medicinal product name

Capecitabine

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Capecitabine was given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14 of each 3-week cycle.

Bevacizumab + FOLFIRI

Arm description

Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus FOLFIRI until disease progression or unacceptable toxicity. Bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, irinotecan as 180 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to irinotecan and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles.

Arm type

Experimental

Investigational medicinal product name

Bevacizumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Investigational medicinal product name

Leucovorin

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Leucovorin was given as 400 mg/m^2 via IV infusion on Day 1 of each 2-week cycle.

Investigational medicinal product name

5-Fluorouracil

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

5-Fluorouracil was given as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion started on Day 1 of each 2-week cycle.

Investigational medicinal product name

Irinotecan

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Irinotecan was given as 180 mg/m^2 via IV infusion on Day 1 of each 2-week cycle.

Investigational medicinal product name

Capecitabine

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Capecitabine was given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14 of each 3-week cycle.

Bevacizumab + mFOLFOX/FOLFIRI

Arm description

Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus mFOLFOX6 or bevacizumab plus FOLFIRI until disease progression or unacceptable toxicity. Depending on the regimen to which the participant was randomized, bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, oxaliplatin as 85 mg/m^2, irinotecan as 180 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to oxaliplatin or irinotecan and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles.

Arm type

Experimental

Investigational medicinal product name

Bevacizumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Investigational medicinal product name

Leucovorin

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Leucovorin was given as 400 mg/m^2 via IV infusion on Day 1 of each 2-week cycle.

Investigational medicinal product name

5-Fluorouracil

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

5-Fluorouracil was given as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion started on Day 1 of each 2-week cycle.

Investigational medicinal product name

Oxaliplatin

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Oxaliplatin was given as 85 mg/m^2 via IV infusion on Day 1 of each 2-week cycle.

Investigational medicinal product name

Irinotecan

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Irinotecan was given as 180 mg/m^2 via IV infusion on Day 1 of each 2-week cycle.

Investigational medicinal product name

Capecitabine

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Capecitabine was given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14 of each 3-week cycle.

Number of subjects in period 1	Bevacizumab + mFOLFOX6	Bevacizumab + FOLFIRI	Bevacizumab + mFOLFOX/FOLFIRI
Started	188	188	376
Completed	0	0	0
Not completed	188	188	376
Death (adverse event)	2	4	6
Consent withdrawn by subject	6	7	13
Radiographic disease progression	86	81	167
Protocol violation	2	3	5
Not specified	41	43	84
Death (progression of disease)	1	-	1
Refused treatment	10	24	34
Clinical disease progression	9	6	15
Adverse event	29	18	47
Lost to follow-up	2	1	3
Sponsor decision	-	1	1

Baseline characteristics

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Reporting group title

Bevacizumab + mFOLFOX6

Reporting group description

Reporting group title

Bevacizumab + FOLFIRI

Reporting group description

Reporting group title

Bevacizumab + mFOLFOX/FOLFIRI

Reporting group description

Reporting group values	Bevacizumab + mFOLFOX6	Bevacizumab + FOLFIRI	Bevacizumab + mFOLFOX/FOLFIRI	Total
Number of subjects	188	188	376
Age categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	59.2 ( 10.88 )	60.7 ( 10.66 )	59.9 ( 10.78 )	-
Gender categorical
Units: Subjects
Female	66	71	137	137
Male	122	117	239	239

End points

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Reporting group title

Bevacizumab + mFOLFOX6

Reporting group description

Reporting group title

Bevacizumab + FOLFIRI

Reporting group description

Reporting group title

Bevacizumab + mFOLFOX/FOLFIRI

Reporting group description

Subject analysis set title

Bevacizumab + mFOLFOX6 (ERCC-1 High)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus mFOLFOX6 until disease progression or unacceptable toxicity. Bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, oxaliplatin as 85 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to oxaliplatin and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. Participants with excision repair cross-complementing (ERCC)-1 level greater than (>) 1.7 × 10^-3 ERCC-1/B-actin messenger ribonucleic acid (mRNA) at Baseline were included in separate analyses.

Subject analysis set title

Bevacizumab + FOLFIRI (ERCC-1 High)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subject analysis set title

Bevacizumab + mFOLFOX6 (ERCC-1 Low)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus mFOLFOX6 until disease progression or unacceptable toxicity. Bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, oxaliplatin as 85 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to oxaliplatin and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. Participants with ERCC-1 level less than or equal to (≤) 1.7 × 10^-3 ERCC-1/B-actin mRNA at Baseline were included in separate analyses.

Subject analysis set title

Bevacizumab + FOLFIRI (ERCC-1 Low)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subject analysis set title

Bevacizumab + mFOLFOX/FOLFIRI (ERCC-1 High)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subject analysis set title

Bevacizumab + mFOLFOX/FOLFIRI (ERCC-1 Low)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subject analysis set title

Bevacizumab + mFOLFOX/FOLFIRI (VEGF-A High)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subject analysis set title

Bevacizumab + mFOLFOX/FOLFIRI (VEGF-A Low)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subject analysis set title

Bevacizumab + mFOLFOX6 (ERCC-1 High, VEGF-A Low)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus mFOLFOX6 until disease progression or unacceptable toxicity. Bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, oxaliplatin as 85 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle.Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to oxaliplatin and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. Participants with ERCC-1 level >1.7 × 10^-3 ERCC-1/B-actin mRNA and VEGF-A level ≤5 pg/mL at Baseline were included in separate analyses.

Subject analysis set title

Bevacizumab + FOLFIRI (ERCC-1 High, VEGF-A Low)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subject analysis set title

Bevacizumab + mFOLFOX6 (ERCC-1 High, VEGF-A High)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus mFOLFOX6 until disease progression or unacceptable toxicity. Bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, oxaliplatin as 85 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to oxaliplatin and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. Participants with ERCC-1 level >1.7 × 10^-3 ERCC-1/B-actin mRNA and VEGF-A level >5 pg/mL at Baseline were included in separate analyses.

Subject analysis set title

Bevacizumab + FOLFIRI (ERCC-1 High, VEGF-A High)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subject analysis set title

Bevacizumab + mFOLFOX6 (ERCC-1 Low, VEGF-A High)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus mFOLFOX6 until disease progression or unacceptable toxicity. Bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, oxaliplatin as 85 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to oxaliplatin and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. Participants with ERCC-1 level ≤1.7 × 10^-3 ERCC-1/B-actin mRNA and VEGF-A level >5 pg/mL at Baseline were included in separate analyses.

Subject analysis set title

Bevacizumab + FOLFIRI (ERCC-1 Low, VEGF-A High)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subject analysis set title

Bevacizumab + mFOLFOX6 (ERCC-1 Low, VEGF-A Low)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus mFOLFOX6 until disease progression or unacceptable toxicity. Bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, oxaliplatin as 85 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to oxaliplatin and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. Participants with ERCC-1 level ≤1.7 × 10^-3 ERCC-1/B-actin mRNA and VEGF-A level ≤5 pg/mL at Baseline were included in separate analyses.

Subject analysis set title

Bevacizumab + FOLFIRI (ERCC-1 Low, VEGF-A Low)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subject analysis set title

Bevacizumab + mFOLFOX/FOLFIRI (KRAS Wild-Type)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subject analysis set title

Bevacizumab + mFOLFOX/FOLFIRI (KRAS Mutant)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Primary: PFS According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1

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End point title

PFS According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 ^[1]

End point description

Tumor assessments were performed according to RECIST Version 1.1. Disease progression was defined as greater than or equal to (≥) 20 percent (%) increase in sum of largest diameters (LD) of target lesions in reference to the smallest sum of LD on study, in addition to an absolute increase ≥5 millimeters (mm). Disease progression was further defined as the last documented progression determined by the Investigator no later than 1 day before initiation of second-line therapy. Death on study included death from any cause occurring no later than 3 months after the last component of study treatment. PFS was defined as the time from randomization to death or disease progression, whichever occurred first. The median duration of PFS was estimated by Kaplan-Meier analysis and expressed in months. The 95% confidence interval (CI) was computed using the method of Brookmeyer and Crowley. Intent-to-Treat (ITT) Population: All randomized participants regardless of receiving any study drug.

End point type

Primary

End point timeframe

From Baseline until death or disease progression; assessed every 6 weeks (maximum up to 45 months overall)

Notes
[1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Analyses were planned and reported for the separate Bevacizumab + mFOLFOX6 and Bevacizumab + FOLFIRI arms, not for all participants combined.

End point values	Bevacizumab + mFOLFOX6	Bevacizumab + FOLFIRI
Number of subjects analysed	188	188
Units: months
median (confidence interval 95%)	10.09 (8.8 to 11.56)	12.55 (10.48 to 14.29)

Hazard Ratio

Statistical analysis description

Analysis stratified by high/low ERCC-1 level and region of enrollment. Hazard ratio (HR, relative to Bevacizumab + mFOLFOX6) was estimated by Cox regression.

Comparison groups

Bevacizumab + mFOLFOX6 v Bevacizumab + FOLFIRI

Number of subjects included in analysis

376

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.0555 ^[2]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.79

Confidence interval

level

95%

sides

2-sided

lower limit

0.61

upper limit

1.01

Notes
[2] - P-value (relative to Bevacizumab + mFOLFOX6) based on two-sided stratified log rank test and not adjusted for multiple comparisons.

Primary: PFS According to RECIST Version 1.1 in Participants With High ERCC-1 Levels

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End point title

PFS According to RECIST Version 1.1 in Participants With High ERCC-1 Levels

End point description

Tumor assessments were performed according to RECIST Version 1.1. Disease progression was defined as ≥20% increase in sum of LD of target lesions in reference to the smallest sum of LD on study, in addition to an absolute increase ≥5 mm. Disease progression was further defined as the last documented progression determined by the Investigator no later than 1 day before initiation of second-line therapy. Death on study included death from any cause occurring no later than 3 months after the last component of study treatment. PFS was defined as the time from randomization to death or disease progression, whichever occurred first. The median duration of PFS was estimated by Kaplan-Meier analysis and expressed in months. The 95% CI was computed using the method of Brookmeyer and Crowley. ITT Population. "Number of subjects analysed" reflects the number of evaluable participants for the outcome measure.

End point type

Primary

End point timeframe

From Baseline until death or disease progression; assessed every 6 weeks (maximum up to 45 months overall)

End point values	Bevacizumab + mFOLFOX6 (ERCC-1 High)	Bevacizumab + FOLFIRI (ERCC-1 High)
Number of subjects analysed	64	67
Units: months
median (confidence interval 95%)	9.92 (8.51 to 12.48)	11.17 (9.1 to 17.84)

Hazard Ratio

Statistical analysis description

Analysis stratified by region of enrollment. HR (relative to Bevacizumab + mFOLFOX6) was estimated by Cox regression.

Comparison groups

Bevacizumab + mFOLFOX6 (ERCC-1 High) v Bevacizumab + FOLFIRI (ERCC-1 High)

Number of subjects included in analysis

131

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.3944 ^[3]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.84

Confidence interval

level

95%

sides

2-sided

lower limit

0.56

upper limit

1.26

Notes
[3] - P-value (relative to Bevacizumab + mFOLFOX6) based on two-sided stratified log rank test and not adjusted for multiple comparisons.

Primary: PFS According to RECIST Version 1.1 in Participants With Low ERCC-1 Levels

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End point title

PFS According to RECIST Version 1.1 in Participants With Low ERCC-1 Levels

End point description

End point type

Primary

End point timeframe

From Baseline until death or disease progression; assessed every 6 weeks (maximum up to 45 months overall)

End point values	Bevacizumab + mFOLFOX6 (ERCC-1 Low)	Bevacizumab + FOLFIRI (ERCC-1 Low)
Number of subjects analysed	124	120
Units: months
median (confidence interval 95%)	10.97 (8.54 to 12.29)	12.68 (10.48 to 14.49)

Hazard Ratio

Statistical analysis description

Analysis stratified by region of enrollment. HR (relative to Bevacizumab + mFOLFOX6) was estimated by Cox regression.

Comparison groups

Bevacizumab + mFOLFOX6 (ERCC-1 Low) v Bevacizumab + FOLFIRI (ERCC-1 Low)

Number of subjects included in analysis

244

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.0786 ^[4]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.76

Confidence interval

level

95%

sides

2-sided

lower limit

0.55

upper limit

1.03

Notes
[4] - P-value (relative to Bevacizumab + mFOLFOX6) based on two-sided stratified log rank test and not adjusted for multiple comparisons.

Primary: PFS According to RECIST Version 1.1 in Participants With High ERCC-1 Levels Versus Participants With Low ERCC-1 Levels

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End point title

PFS According to RECIST Version 1.1 in Participants With High ERCC-1 Levels Versus Participants With Low ERCC-1 Levels

End point description

End point type

Primary

End point timeframe

From Baseline until death or disease progression (maximum up to 45 months overall)

End point values	Bevacizumab + mFOLFOX/FOLFIRI (ERCC-1 High)	Bevacizumab + mFOLFOX/FOLFIRI (ERCC-1 Low)
Number of subjects analysed	131	244
Units: months
median (confidence interval 95%)	10.87 (9.1 to 12.68)	11.56 (9.95 to 12.98)

Hazard Ratio

Statistical analysis description

Analysis stratified by region of enrollment. HR (relative to ERCC-1 Low subgroup) was estimated by Cox regression.

Comparison groups

Bevacizumab + mFOLFOX/FOLFIRI (ERCC-1 High) v Bevacizumab + mFOLFOX/FOLFIRI (ERCC-1 Low)

Number of subjects included in analysis

375

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.9576 ^[5]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.99

Confidence interval

level

95%

sides

2-sided

lower limit

0.77

upper limit

1.28

Notes
[5] - P-value (relative to ERCC-1 Low subgroup) based on two-sided stratified log rank test and not adjusted for multiple comparisons.

Primary: PFS According to RECIST Version 1.1 in Participants With High VEGF-A Levels Versus Participants With Low VEGF-A Levels

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End point title

PFS According to RECIST Version 1.1 in Participants With High VEGF-A Levels Versus Participants With Low VEGF-A Levels

End point description

End point type

Primary

End point timeframe

From Baseline until death or disease progression; assessed every 6 weeks (maximum up to 45 months overall)

End point values	Bevacizumab + mFOLFOX/FOLFIRI (VEGF-A High)	Bevacizumab + mFOLFOX/FOLFIRI (VEGF-A Low)
Number of subjects analysed	185	185
Units: months
median (confidence interval 95%)	10.02 (8.8 to 11.17)	12.68 (10.9 to 14.26)

Hazard Ratio

Statistical analysis description

Analysis stratified by high/low ERCC-1 level and region of enrollment. HR (relative to VEGF-A Low subgroup) was estimated by Cox regression.

Comparison groups

Bevacizumab + mFOLFOX/FOLFIRI (VEGF-A High) v Bevacizumab + mFOLFOX/FOLFIRI (VEGF-A Low)

Number of subjects included in analysis

370

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.1658 ^[6]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

1.19

Confidence interval

level

95%

sides

2-sided

lower limit

0.93

upper limit

1.53

Notes
[6] - P-value (relative to VEGF-A Low subgroup) based on two-sided stratified log rank test and not adjusted for multiple comparisons.

Secondary: PFS According to RECIST Version 1.1 in Participants With High ERCC-1 and High VEGF-A Levels

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End point title

PFS According to RECIST Version 1.1 in Participants With High ERCC-1 and High VEGF-A Levels

End point description

End point type

Secondary

End point timeframe

From Baseline until death or disease progression; assessed every 6 weeks (maximum up to 45 months overall)

End point values	Bevacizumab + mFOLFOX6 (ERCC-1 High, VEGF-A High)	Bevacizumab + FOLFIRI (ERCC-1 High, VEGF-A High)
Number of subjects analysed	28	31
Units: months
median (confidence interval 95%)	8.8 (5.91 to 10.02)	11.17 (8.11 to 18.07)

Hazard Ratio Stratified

Statistical analysis description

Analysis stratified by region of enrollment. HR (relative to Bevacizumab + mFOLFOX6) was estimated by Cox regression.

Comparison groups

Bevacizumab + mFOLFOX6 (ERCC-1 High, VEGF-A High) v Bevacizumab + FOLFIRI (ERCC-1 High, VEGF-A High)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.3019 ^[7]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.73

Confidence interval

level

95%

sides

2-sided

lower limit

0.41

upper limit

1.32

Notes
[7] - P-value (relative to Bevacizumab + mFOLFOX6) based on two-sided stratified log rank test and not adjusted for multiple comparisons.

Hazard Ratio Unstratified

Statistical analysis description

Unstratified analysis. HR (relative to Bevacizumab + mFOLFOX6) was estimated by Cox regression.

Comparison groups

Bevacizumab + mFOLFOX6 (ERCC-1 High, VEGF-A High) v Bevacizumab + FOLFIRI (ERCC-1 High, VEGF-A High)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.5308 ^[8]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.83

Confidence interval

level

95%

sides

2-sided

lower limit

0.47

upper limit

1.47

Notes
[8] - P-value (relative to Bevacizumab + mFOLFOX6) based on two-sided unstratified log rank test and not adjusted for multiple comparisons.

Secondary: PFS According to RECIST Version 1.1 in Participants With High ERCC-1 and Low VEGF-A Levels

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End point title

PFS According to RECIST Version 1.1 in Participants With High ERCC-1 and Low VEGF-A Levels

End point description

End point type

Secondary

End point timeframe

From Baseline until death or disease progression; assessed every 6 weeks (maximum up to 45 months overall)

End point values	Bevacizumab + mFOLFOX6 (ERCC-1 High, VEGF-A Low)	Bevacizumab + FOLFIRI (ERCC-1 High, VEGF-A Low)
Number of subjects analysed	35	35
Units: months
median (confidence interval 95%)	12.52 (9.43 to 15.64)	12.68 (8.18 to 20.83)

Hazard Ratio Stratified

Statistical analysis description

Analysis stratified by region of enrollment. HR (relative to Bevacizumab + mFOLFOX6) was estimated by Cox regression.

Comparison groups

Bevacizumab + mFOLFOX6 (ERCC-1 High, VEGF-A Low) v Bevacizumab + FOLFIRI (ERCC-1 High, VEGF-A Low)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.6035 ^[9]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.86

Confidence interval

level

95%

sides

2-sided

lower limit

0.48

upper limit

1.53

Notes
[9] - P-value (relative to Bevacizumab + mFOLFOX6) based on two-sided stratified log rank test and not adjusted for multiple comparisons.

Hazard Ratio Unstratified

Statistical analysis description

Unstratified analysis. HR (relative to Bevacizumab + mFOLFOX6) was estimated by Cox regression.

Comparison groups

Bevacizumab + mFOLFOX6 (ERCC-1 High, VEGF-A Low) v Bevacizumab + FOLFIRI (ERCC-1 High, VEGF-A Low)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.5026 ^[10]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.82

Confidence interval

level

95%

sides

2-sided

lower limit

0.46

upper limit

1.46

Notes
[10] - P-value (relative to Bevacizumab + mFOLFOX6) based on two-sided unstratified log rank test and not adjusted for multiple comparisons.

Secondary: PFS According to RECIST Version 1.1 in Participants With Low ERCC-1 and High VEGF-A Levels

Top of page

End point title

PFS According to RECIST Version 1.1 in Participants With Low ERCC-1 and High VEGF-A Levels

End point description

End point type

Secondary

End point timeframe

From Baseline until death or disease progression; assessed every 6 weeks (maximum up to 45 months overall)

End point values	Bevacizumab + mFOLFOX6 (ERCC-1 Low, VEGF-A High)	Bevacizumab + FOLFIRI (ERCC-1 Low, VEGF-A High)
Number of subjects analysed	66	59
Units: months
median (confidence interval 95%)	9.76 (8.18 to 12.45)	11.07 (8.18 to 14.29)

Hazard Ratio Stratified

Statistical analysis description

Analysis stratified by region of enrollment. HR (relative to Bevacizumab + mFOLFOX6) was estimated by Cox regression.

Comparison groups

Bevacizumab + mFOLFOX6 (ERCC-1 Low, VEGF-A High) v Bevacizumab + FOLFIRI (ERCC-1 Low, VEGF-A High)

Number of subjects included in analysis

125

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.4032 ^[11]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.83

Confidence interval

level

95%

sides

2-sided

lower limit

0.54

upper limit

1.28

Notes
[11] - P-value (relative to Bevacizumab + mFOLFOX6) based on two-sided stratified log rank test and not adjusted for multiple comparisons.

Hazard Ratio Unstratified

Statistical analysis description

Unstratified analysis. HR (relative to Bevacizumab + mFOLFOX6) was estimated by Cox regression.

Comparison groups

Bevacizumab + mFOLFOX6 (ERCC-1 Low, VEGF-A High) v Bevacizumab + FOLFIRI (ERCC-1 Low, VEGF-A High)

Number of subjects included in analysis

125

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.235 ^[12]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.77

Confidence interval

level

95%

sides

2-sided

lower limit

0.51

upper limit

1.18

Notes
[12] - P-value (relative to Bevacizumab + mFOLFOX6) based on two-sided unstratified log rank test and not adjusted for multiple comparisons.

Secondary: PFS According to RECIST Version 1.1 in Participants With Low ERCC-1 and Low VEGF-A Levels

Top of page

End point title

PFS According to RECIST Version 1.1 in Participants With Low ERCC-1 and Low VEGF-A Levels

End point description

End point type

Secondary

End point timeframe

From Baseline until death or disease progression; assessed every 6 weeks (maximum up to 45 months overall)

End point values	Bevacizumab + mFOLFOX6 (ERCC-1 Low, VEGF-A Low)	Bevacizumab + FOLFIRI (ERCC-1 Low, VEGF-A Low)
Number of subjects analysed	55	60
Units: months
median (confidence interval 95%)	11.1 (8.54 to 13.08)	14.32 (11.56 to 14.98)

Hazard Ratio Stratified

Statistical analysis description

Analysis stratified by region of enrollment. HR (relative to Bevacizumab + mFOLFOX6) was estimated by Cox regression.

Comparison groups

Bevacizumab + mFOLFOX6 (ERCC-1 Low, VEGF-A Low) v Bevacizumab + FOLFIRI (ERCC-1 Low, VEGF-A Low)

Number of subjects included in analysis

115

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.0647 ^[13]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.65

Confidence interval

level

95%

sides

2-sided

lower limit

0.41

upper limit

1.03

Notes
[13] - P-value (relative to Bevacizumab + mFOLFOX6) based on two-sided stratified log rank test and not adjusted for multiple comparisons.

Hazard Ratio Unstratified

Statistical analysis description

Unstratified analysis. HR (relative to Bevacizumab + mFOLFOX6) was estimated by Cox regression.

Comparison groups

Bevacizumab + mFOLFOX6 (ERCC-1 Low, VEGF-A Low) v Bevacizumab + FOLFIRI (ERCC-1 Low, VEGF-A Low)

Number of subjects included in analysis

115

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.0856 ^[14]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.67

Confidence interval

level

95%

sides

2-sided

lower limit

0.43

upper limit

1.06

Notes
[14] - P-value (relative to Bevacizumab + mFOLFOX6) based on two-sided unstratified log rank test and not adjusted for multiple comparisons.

Secondary: Overall Survival (OS)

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End point title

Overall Survival (OS) ^[15]

End point description

Death on study included death from any cause occurring no later than 3 months after the last component of study treatment. OS was defined as the time from randomization to death. The median duration of OS was estimated by Kaplan-Meier analysis and expressed in months. The 95% CI was computed using the method of Brookmeyer and Crowley. ITT Population.

End point type

Secondary

End point timeframe

From Baseline until death (maximum up to 45 months overall)

Notes
[15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Analyses were planned and reported for the separate Bevacizumab + mFOLFOX6 and Bevacizumab + FOLFIRI arms, not for all participants combined.

End point values	Bevacizumab + mFOLFOX6	Bevacizumab + FOLFIRI
Number of subjects analysed	188	188
Units: months
median (confidence interval 95%)	23.85 (20.4 to 26.05)	27.47 (24.64 to 36.73)

Hazard Ratio

Statistical analysis description

Analysis stratified by high/low ERCC-1 level and region of enrollment. HR (relative to Bevacizumab + mFOLFOX6)was estimated by Cox regression.

Comparison groups

Bevacizumab + mFOLFOX6 v Bevacizumab + FOLFIRI

Number of subjects included in analysis

376

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.0861 ^[16]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.76

Confidence interval

level

95%

sides

2-sided

lower limit

0.56

upper limit

1.04

Notes
[16] - P-value (relative to Bevacizumab + mFOLFOX6) based on two-sided stratified log rank test and not adjusted for multiple comparisons.

Secondary: OS in Participants With High ERCC-1 Levels

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End point title

OS in Participants With High ERCC-1 Levels

End point description

End point type

Secondary

End point timeframe

From Baseline until death (maximum up to 45 months overall)

End point values	Bevacizumab + mFOLFOX6 (ERCC-1 High)	Bevacizumab + FOLFIRI (ERCC-1 High)
Number of subjects analysed	64	67
Units: months
median (confidence interval 95%)	22.54 (17.02 to 26.05)	26.51 (19.09 to 36.73)

Hazard Ratio

Statistical analysis description

Analysis stratified by region of enrollment. HR (relative to Bevacizumab + mFOLFOX6) was estimated by Cox regression.

Comparison groups

Bevacizumab + FOLFIRI (ERCC-1 High) v Bevacizumab + mFOLFOX6 (ERCC-1 High)

Number of subjects included in analysis

131

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.3295 ^[17]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.8

Confidence interval

level

95%

sides

2-sided

lower limit

0.51

upper limit

1.26

Notes
[17] - P-value (relative to Bevacizumab + mFOLFOX6) based on two-sided stratified log rank test and not adjusted for multiple comparisons.

Secondary: OS in Participants With Low ERCC-1 Levels

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End point title

OS in Participants With Low ERCC-1 Levels

End point description

End point type

Secondary

End point timeframe

From Baseline until death (maximum up to 45 months overall)

End point values	Bevacizumab + mFOLFOX6 (ERCC-1 Low)	Bevacizumab + FOLFIRI (ERCC-1 Low)
Number of subjects analysed	124	120
Units: months
median (confidence interval 95%)	25.53 (20.4 to 28.75)	27.93 (24.97 to 38.44)

Hazard Ratio

Statistical analysis description

Analysis stratified by region of enrollment. HR (relative to Bevacizumab + mFOLFOX6) was estimated by Cox regression.

Comparison groups

Bevacizumab + mFOLFOX6 (ERCC-1 Low) v Bevacizumab + FOLFIRI (ERCC-1 Low)

Number of subjects included in analysis

244

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.1519 ^[18]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.74

Confidence interval

level

95%

sides

2-sided

lower limit

0.49

upper limit

1.12

Notes
[18] - P-value (relative to Bevacizumab + mFOLFOX6) based on two-sided stratified log rank test and not adjusted for multiple comparisons.

Secondary: OS in Participants With High ERCC-1 Levels Versus Participants With Low ERCC-1 Levels

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End point title

OS in Participants With High ERCC-1 Levels Versus Participants With Low ERCC-1 Levels

End point description

End point type

Secondary

End point timeframe

From Baseline until death (maximum up to 45 months overall)

End point values	Bevacizumab + mFOLFOX/FOLFIRI (ERCC-1 High)	Bevacizumab + mFOLFOX/FOLFIRI (ERCC-1 Low)
Number of subjects analysed	131	244
Units: months
median (confidence interval 95%)	23.23 (19.09 to 26.94)	27.27 (24.34 to 31.28)

Hazard Ratio

Statistical analysis description

Analysis stratified by region of enrollment. HR (relative to ERCC-1 Low subgroup) was estimated by Cox regression.

Comparison groups

Bevacizumab + mFOLFOX/FOLFIRI (ERCC-1 High) v Bevacizumab + mFOLFOX/FOLFIRI (ERCC-1 Low)

Number of subjects included in analysis

375

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.2774 ^[19]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

1.19

Confidence interval

level

95%

sides

2-sided

lower limit

0.87

upper limit

1.62

Notes
[19] - P-value (relative to ERCC-1 Low subgroup) based on two-sided stratified log rank test and not adjusted for multiple comparisons.

Secondary: Percentage of Participants With Objective Response According to RECIST Version 1.1

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End point title

Percentage of Participants With Objective Response According to RECIST Version 1.1 ^[20]

End point description

Objective response was defined as complete response (CR) or partial response (PR) according to RECIST Version 1.1. CR was defined as disappearance of all target lesions and short-axis reduction to less than (<) 10 mm of any pathological lymph nodes. PR was defined as ≥30% decrease in sum of LD of target lesions in reference to sum of LD at Baseline. Confirmation of response at a consecutive assessment was not required. The percentage of participants with CR or PR was reported. The 95% CI was computed using normal approximation to the binomial distribution. ITT Population.

End point type

Secondary

End point timeframe

From Baseline until disease progression; assessed every 6 weeks (maximum up to 45 months overall)

Notes
[20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Analyses were planned and reported for the separate Bevacizumab + mFOLFOX6 and Bevacizumab + FOLFIRI arms, not for all participants combined.

End point values	Bevacizumab + mFOLFOX6	Bevacizumab + FOLFIRI
Number of subjects analysed	188	188
Units: percentage of participants
number (confidence interval 95%)	61.2 (54.2 to 68.1)	65.4 (58.6 to 72.2)

Difference in Objective Response Rates

Statistical analysis description

The difference was calculated as the percentage of participants with objective response in the Bevacizumab + FOLFIRI arm minus the Bevacizumab + mFOLFOX6 arm. The 95% CI was computed using normal approximation to the binomial distribution.

Comparison groups

Bevacizumab + mFOLFOX6 v Bevacizumab + FOLFIRI

Number of subjects included in analysis

376

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Difference in objective response rates

Point estimate

4.3

Confidence interval

level

95%

sides

2-sided

lower limit

-5.5

upper limit

Secondary: Percentage of Participants With Objective Response According to RECIST Version 1.1 in Participants With High ERCC-1 Levels

Top of page

End point title

Percentage of Participants With Objective Response According to RECIST Version 1.1 in Participants With High ERCC-1 Levels

End point description

Objective response was defined as CR or PR according to RECIST Version 1.1. CR was defined as disappearance of all target lesions and short-axis reduction to <10 mm of any pathological lymph nodes. PR was defined as ≥30% decrease in sum of LD of target lesions in reference to sum of LD at Baseline. Confirmation of response at a consecutive assessment was not required. The percentage of participants with CR or PR was reported. The 95% CI was computed using normal approximation to the binomial distribution. ITT Population. "Number of subjects analysed" reflects the number of evaluable participants for the outcome measure.

End point type

Secondary

End point timeframe

From Baseline until disease progression; assessed every 6 weeks (maximum up to 45 months overall)

End point values	Bevacizumab + mFOLFOX6 (ERCC-1 High)	Bevacizumab + FOLFIRI (ERCC-1 High)
Number of subjects analysed	64	67
Units: percentage of participants
number (confidence interval 95%)	56.3 (44.1 to 68.4)	65.7 (54.3 to 77)

Difference in Objective Response Rates

Statistical analysis description

Comparison groups

Bevacizumab + mFOLFOX6 (ERCC-1 High) v Bevacizumab + FOLFIRI (ERCC-1 High)

Number of subjects included in analysis

131

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Difference in objective response rates

Point estimate

9.4

Confidence interval

level

95%

sides

2-sided

lower limit

7.2

upper limit

26.1

Secondary: Percentage of Participants With Objective Response According to RECIST Version 1.1 in Participants With Low ERCC-1 Levels

Top of page

End point title

Percentage of Participants With Objective Response According to RECIST Version 1.1 in Participants With Low ERCC-1 Levels

End point description

End point type

Secondary

End point timeframe

From Baseline until disease progression; assessed every 6 weeks (maximum up to 45 months overall)

End point values	Bevacizumab + mFOLFOX6 (ERCC-1 Low)	Bevacizumab + FOLFIRI (ERCC-1 Low)
Number of subjects analysed	124	120
Units: percentage of participants
number (confidence interval 95%)	63.7 (55.2 to 72.2)	65.8 (57.3 to 74.3)

Difference in Objective Response Rates

Statistical analysis description

Comparison groups

Bevacizumab + mFOLFOX6 (ERCC-1 Low) v Bevacizumab + FOLFIRI (ERCC-1 Low)

Number of subjects included in analysis

244

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Difference in objective response rates

Point estimate

2.1

Confidence interval

level

95%

sides

2-sided

lower limit

-9.9

upper limit

14.1

Secondary: Percentage of Participants With Objective Response According to RECIST Version 1.1 in Participants With High ERCC-1 Levels Versus Participants With Low ERCC-1 Levels

Top of page

End point title

Percentage of Participants With Objective Response According to RECIST Version 1.1 in Participants With High ERCC-1 Levels Versus Participants With Low ERCC-1 Levels

End point description

End point type

Secondary

End point timeframe

From Baseline until disease progression; assessed every 6 weeks (maximum up to 45 months overall)

End point values	Bevacizumab + mFOLFOX/FOLFIRI (ERCC-1 High)	Bevacizumab + mFOLFOX/FOLFIRI (ERCC-1 Low)
Number of subjects analysed	131	244
Units: percentage of participants
number (confidence interval 95%)	61.1 (52.7 to 69.4)	64.8 (58.8 to 70.7)

Difference in Objective Response Rates

Statistical analysis description

The difference was calculated as the percentage of participants with objective response in the ERCC-1 High subgroup minus the ERCC-1 Low subgroup. The 95% CI was computed using normal approximation to the binomial distribution.

Comparison groups

Bevacizumab + mFOLFOX/FOLFIRI (ERCC-1 High) v Bevacizumab + mFOLFOX/FOLFIRI (ERCC-1 Low)

Number of subjects included in analysis

375

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Difference in objective response rates

Point estimate

-3.7

Confidence interval

level

95%

sides

2-sided

lower limit

-14

upper limit

6.6

Secondary: Percentage of Participants With Disease Control According to RECIST Version 1.1

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End point title

Percentage of Participants With Disease Control According to RECIST Version 1.1 ^[21]

End point description

Disease control was defined as CR, PR, or stable disease (SD) according to RECIST Version 1.1. CR was defined as disappearance of all target lesions and short-axis reduction to <10 mm of any pathological lymph nodes. PR was defined as ≥30% decrease in sum of LD of target lesions in reference to sum of LD at Baseline. Confirmation of response at a consecutive assessment was not required. SD was defined as neither sufficient shrinkage to quality for PR nor sufficient increase to qualify for disease progression (≥20% increase in sum of LD of target lesions plus absolute increase ≥5 mm) in reference to the smallest sum of LD on study. The percentage of participants with CR, PR, or SD was reported. The 95% CI was computed using normal approximation to the binomial distribution. ITT Population.

End point type

Secondary

End point timeframe

From Baseline until disease progression; assessed every 6 weeks (maximum up to 45 months overall)

Notes
[21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Analyses were planned and reported for the separate Bevacizumab + mFOLFOX6 and Bevacizumab + FOLFIRI arms, not for all participants combined.

End point values	Bevacizumab + mFOLFOX6	Bevacizumab + FOLFIRI
Number of subjects analysed	188	188
Units: percentage of participants
number (confidence interval 95%)	93.1 (89.5 to 96.7)	91 (86.9 to 95.1)

Difference in Disease Control Rates

Statistical analysis description

The difference was calculated as the percentage of participants with disease control in the Bevacizumab + FOLFIRI arm minus the Bevacizumab + mFOLFOX6 arm. The 95% CI was computed using normal approximation to the binomial distribution.

Comparison groups

Bevacizumab + mFOLFOX6 v Bevacizumab + FOLFIRI

Number of subjects included in analysis

376

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Difference in response rates

Point estimate

2.1

Confidence interval

level

95%

sides

2-sided

lower limit

-7.6

upper limit

3.3

Secondary: Percentage of Participants With Disease Control According to RECIST Version 1.1 in Participants With High ERCC-1 Levels

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End point title

Percentage of Participants With Disease Control According to RECIST Version 1.1 in Participants With High ERCC-1 Levels

End point description

Disease control was defined as CR, PR, or SD according to RECIST Version 1.1. CR was defined as disappearance of all target lesions and short-axis reduction to <10 mm of any pathological lymph nodes. PR was defined as ≥30% decrease in sum of LD of target lesions in reference to sum of LD at Baseline. Confirmation of response at a consecutive assessment was not required. SD was defined as neither sufficient shrinkage to quality for PR nor sufficient increase to qualify for disease progression (≥20% increase in sum of LD of target lesions plus absolute increase ≥5 mm) in reference to the smallest sum of LD on study. The percentage of participants with CR, PR, or SD was reported. The 95% CI was computed using normal approximation to the binomial distribution. ITT Population. "Number of subjects analysed" reflects the number of evaluable participants for the outcome measure.

End point type

Secondary

End point timeframe

From Baseline until disease progression; assessed every 6 weeks (maximum up to 45 months overall)

End point values	Bevacizumab + mFOLFOX6 (ERCC-1 High)	Bevacizumab + FOLFIRI (ERCC-1 High)
Number of subjects analysed	64	67
Units: percentage of participants
number (confidence interval 95%)	93.8 (87.8 to 99.7)	85.1 (76.5 to 93.6)

Difference in Disease Control Rates

Statistical analysis description

Comparison groups

Bevacizumab + mFOLFOX6 (ERCC-1 High) v Bevacizumab + FOLFIRI (ERCC-1 High)

Number of subjects included in analysis

131

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Difference in disease control rates

Point estimate

-8.7

Confidence interval

level

95%

sides

2-sided

lower limit

-19.1

upper limit

1.7

Secondary: Percentage of Participants With Disease Control According to RECIST Version 1.1 in Participants With Low ERCC-1 Levels

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End point title

Percentage of Participants With Disease Control According to RECIST Version 1.1 in Participants With Low ERCC-1 Levels

End point description

End point type

Secondary

End point timeframe

From Baseline until disease progression; assessed every 6 weeks (maximum up to 45 months overall)

End point values	Bevacizumab + mFOLFOX6 (ERCC-1 Low)	Bevacizumab + FOLFIRI (ERCC-1 Low)
Number of subjects analysed	124	120
Units: percentage of participants
number (confidence interval 95%)	92.7 (88.2 to 97.3)	95 (91.1 to 98.9)

Difference in Disease Control Rates

Statistical analysis description

Comparison groups

Bevacizumab + mFOLFOX6 (ERCC-1 Low) v Bevacizumab + FOLFIRI (ERCC-1 Low)

Number of subjects included in analysis

244

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Difference in disease control rates

Point estimate

2.3

Confidence interval

level

95%

sides

2-sided

lower limit

-3.7

upper limit

8.3

Secondary: Percentage of Participants With Disease Control According to RECIST Version 1.1 in Participants With High ERCC-1 Levels Versus Participants With Low ERCC-1 Levels

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End point title

Percentage of Participants With Disease Control According to RECIST Version 1.1 in Participants With High ERCC-1 Levels Versus Participants With Low ERCC-1 Levels

End point description

End point type

Secondary

End point timeframe

From Baseline until disease progression; assessed every 6 weeks (maximum up to 45 months overall)

End point values	Bevacizumab + mFOLFOX/FOLFIRI (ERCC-1 High)	Bevacizumab + mFOLFOX/FOLFIRI (ERCC-1 Low)
Number of subjects analysed	131	244
Units: percentage of participants
number (confidence interval 95%)	89.3 (84 to 94.6)	93.9 (90.8 to 96.9)

Difference in Disease Control Rates

Statistical analysis description

The difference was calculated as the percentage of participants with disease control in the ERCC-1 High subgroup minus the ERCC-1 Low subgroup. The 95% CI was computed using normal approximation to the binomial distribution.

Comparison groups

Bevacizumab + mFOLFOX/FOLFIRI (ERCC-1 High) v Bevacizumab + mFOLFOX/FOLFIRI (ERCC-1 Low)

Number of subjects included in analysis

375

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Difference in disease control rates

Point estimate

-4.5

Confidence interval

level

95%

sides

2-sided

lower limit

-10.6

upper limit

1.5

Secondary: Percentage of Participants With Liver Metastasis Resection

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End point title

Percentage of Participants With Liver Metastasis Resection ^[22]

End point description

The timing of resective surgery was not defined in the protocol and was left at the discretion of the Investigator. Resection was classified as R0, R1, or R2 following surgery. R0 was defined as complete resection with clear margins ≥1 mm. R1 was defined as the presence of exposed tumor or histologically detected tumor cells at the line of transection, or <1 mm microscopic margins. In the case of use of radiofrequency ablation or cryotherapy, the resection was considered as R1. R2 was defined as macroscopic positive margins or incomplete resection at time of surgery. The percentage of participants with resection of liver or liver plus lymph node metastases was reported. The 95% CI was computed using normal approximation to the binomial distribution. ITT Population; only those participants with liver or liver plus lymph node metastases were included in the analysis.

End point type

Secondary

End point timeframe

At time of resective surgery during study (maximum up to 45 months overall)

Notes
[22] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Analyses were planned and reported for the separate Bevacizumab + mFOLFOX6 and Bevacizumab + FOLFIRI arms, not for all participants combined.

End point values	Bevacizumab + mFOLFOX6	Bevacizumab + FOLFIRI
Number of subjects analysed	67	55
Units: percentage of participants
number (confidence interval 95%)	14.9 (6.4 to 23.5)	10.9 (2.7 to 19.1)

Difference in Resection Rates

Statistical analysis description

The difference was calculated as the percentage of participants with resection in the Bevacizumab + FOLFIRI arm minus the Bevacizumab + mFOLFOX6 arm. The 95% CI was computed using normal approximation to the binomial distribution.

Comparison groups

Bevacizumab + FOLFIRI v Bevacizumab + mFOLFOX6

Number of subjects included in analysis

122

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Difference in resection rates

Point estimate

-4

Confidence interval

level

95%

sides

2-sided

lower limit

-15.9

upper limit

7.8

Secondary: Percentage of Participants With Complete Liver Metastasis Resection

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End point title

Percentage of Participants With Complete Liver Metastasis Resection ^[23]

End point description

The timing of resective surgery was not defined in the protocol and was left at the discretion of the Investigator. Resection was classified as R0, R1, or R2 following surgery. R0 was defined as complete resection with clear margins ≥1 mm. The percentage of participants with R0 resection of liver or liver plus lymph node metastases was reported. The 95% CI was computed using normal approximation to the binomial distribution. ITT Population; only those participants with liver or liver plus lymph node metastases were included in the analysis.

End point type

Secondary

End point timeframe

At time of resective surgery during study (maximum up to 45 months overall)

Notes
[23] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Analyses were planned and reported for the separate Bevacizumab + mFOLFOX6 and Bevacizumab + FOLFIRI arms, not for all participants combined.

End point values	Bevacizumab + mFOLFOX6	Bevacizumab + FOLFIRI
Number of subjects analysed	67	55
Units: percentage of participants
number (confidence interval 95%)	11.9 (4.2 to 19.7)	5.5 (0 to 11.5)

Difference in Complete Resection Rates

Statistical analysis description

The difference was calculated as the percentage of participants with complete resection in the Bevacizumab + FOLFIRI arm minus the Bevacizumab + mFOLFOX6 arm. The 95% CI was computed using normal approximation to the binomial distribution.

Comparison groups

Bevacizumab + mFOLFOX6 v Bevacizumab + FOLFIRI

Number of subjects included in analysis

122

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Difference in complete resection rates

Point estimate

-6.5

Confidence interval

level

95%

sides

2-sided

lower limit

-16.3

upper limit

3.3

Secondary: Percentage of Participants With Liver Metastasis Resection in Participants With High ERCC-1 Levels

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End point title

Percentage of Participants With Liver Metastasis Resection in Participants With High ERCC-1 Levels

End point description

End point type

Secondary

End point timeframe

At time of resective surgery during study (maximum up to 45 months overall)

End point values	Bevacizumab + mFOLFOX6 (ERCC-1 High)	Bevacizumab + FOLFIRI (ERCC-1 High)
Number of subjects analysed	17	15
Units: percentage of participants
number (confidence interval 95%)	17.6 (0 to 35.8)	6.7 (0 to 19.3)

Difference in Resection Rates

Statistical analysis description

Comparison groups

Bevacizumab + mFOLFOX6 (ERCC-1 High) v Bevacizumab + FOLFIRI (ERCC-1 High)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Difference in resection rates

Point estimate

-11

Confidence interval

level

95%

sides

2-sided

lower limit

-33.1

upper limit

11.1

Secondary: Percentage of Participants With Complete Liver Metastasis Resection in Participants With High ERCC-1 Levels

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End point title

Percentage of Participants With Complete Liver Metastasis Resection in Participants With High ERCC-1 Levels

End point description

The timing of resective surgery was not defined in the protocol and was left at the discretion of the Investigator. Resection was classified as R0, R1, or R2 following surgery. R0 was defined as complete resection with clear margins ≥1 mm. The percentage of participants with R0 resection of liver or liver plus lymph node metastases was reported. The 95% CI was computed using normal approximation to the binomial distribution. ITT Population; only those participants with liver or liver plus lymph node metastases were included in the analysis. "Number of subjects analysed" reflects the number of evaluable participants for the outcome measure.

End point type

Secondary

End point timeframe

At time of resective surgery during study (maximum up to 45 months overall)

End point values	Bevacizumab + mFOLFOX6 (ERCC-1 High)	Bevacizumab + FOLFIRI (ERCC-1 High)
Number of subjects analysed	17	15
Units: percentage of participants
number (confidence interval 95%)	17.6 (0 to 35.8)	6.7 (0 to 19.3)

Difference in Complete Resection Rates

Statistical analysis description

Comparison groups

Bevacizumab + mFOLFOX6 (ERCC-1 High) v Bevacizumab + FOLFIRI (ERCC-1 High)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Difference in complete resection rates

Point estimate

-11

Confidence interval

level

95%

sides

2-sided

lower limit

-33.1

upper limit

11.1

Secondary: Percentage of Participants With Liver Metastasis Resection in Participants With Low ERCC-1 Levels

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End point title

Percentage of Participants With Liver Metastasis Resection in Participants With Low ERCC-1 Levels

End point description

End point type

Secondary

End point timeframe

At time of resective surgery during study (maximum up to 45 months overall)

End point values	Bevacizumab + mFOLFOX6 (ERCC-1 Low)	Bevacizumab + FOLFIRI (ERCC-1 Low)
Number of subjects analysed	124	120
Units: percentage of participants
number (confidence interval 95%)	10.5 (5.1 to 15.9)	7.5 (2.8 to 12.2)

Difference in Resection Rates

Statistical analysis description

Comparison groups

Bevacizumab + mFOLFOX6 (ERCC-1 Low) v Bevacizumab + FOLFIRI (ERCC-1 Low)

Number of subjects included in analysis

244

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Difference in resection rates

Point estimate

-3

Confidence interval

level

95%

sides

2-sided

lower limit

-10.1

upper limit

4.2

Secondary: Percentage of Participants With Complete Liver Metastasis Resection in Participants With Low ERCC-1 Levels

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End point title

Percentage of Participants With Complete Liver Metastasis Resection in Participants With Low ERCC-1 Levels

End point description

The timing of resective surgery was not defined in the protocol and was left at the discretion of the Investigator. Resection was classified as R0, R1, or R2 following surgery. R0 was defined as complete resection with clear margins ≥1 mm. The percentage of participants with R0 resection of liver or liver plus lymph node metastases was reported. The 95% CI was computed using normal approximation to the binomial distribution. ITT Population; only those participants with liver or liver plus lymph node metastases were included in the analysis. "Number of subjects analysed" reflects the number of evaluable participants for the outcome measure.

End point type

Secondary

End point timeframe

At time of resective surgery during study (maximum up to 45 months overall)

End point values	Bevacizumab + mFOLFOX6 (ERCC-1 Low)	Bevacizumab + FOLFIRI (ERCC-1 Low)
Number of subjects analysed	124	120
Units: percentage of participants
number (confidence interval 95%)	8.9 (3.9 to 13.9)	3.3 (0.1 to 6.5)

Difference in Complete Resection Rates

Statistical analysis description

Comparison groups

Bevacizumab + mFOLFOX6 (ERCC-1 Low) v Bevacizumab + FOLFIRI (ERCC-1 Low)

Number of subjects included in analysis

244

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Difference in complete resection rates

Point estimate

-5.5

Confidence interval

level

95%

sides

2-sided

lower limit

-11.5

upper limit

0.4

Secondary: Percentage of Participants With Liver Metastasis Resection in Participants With High ERCC-1 Levels Versus Participants With Low ERCC-1 Levels

Top of page

End point title

Percentage of Participants With Liver Metastasis Resection in Participants With High ERCC-1 Levels Versus Participants With Low ERCC-1 Levels

End point description

End point type

Secondary

End point timeframe

At time of resective surgery during study (maximum up to 45 months overall)

End point values	Bevacizumab + mFOLFOX/FOLFIRI (ERCC-1 High)	Bevacizumab + mFOLFOX/FOLFIRI (ERCC-1 Low)
Number of subjects analysed	131	244
Units: percentage of participants
number (confidence interval 95%)	4.6 (1 to 8.2)	9 (5.4 to 12.6)

Difference in Resection Rates

Statistical analysis description

The difference was calculated as the percentage of participants with resection in the ERCC-1 High subgroup minus the ERCC-1 Low subgroup. The 95% CI was computed using normal approximation to the binomial distribution.

Comparison groups

Bevacizumab + mFOLFOX/FOLFIRI (ERCC-1 High) v Bevacizumab + mFOLFOX/FOLFIRI (ERCC-1 Low)

Number of subjects included in analysis

375

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Difference in resection rates

Point estimate

-4.4

Confidence interval

level

95%

sides

2-sided

lower limit

-9.5

upper limit

0.6

Secondary: Percentage of Participants With Complete Liver Metastasis Resection in Participants With High ERCC-1 Levels Versus Participants With Low ERCC-1 Levels

Top of page

End point title

Percentage of Participants With Complete Liver Metastasis Resection in Participants With High ERCC-1 Levels Versus Participants With Low ERCC-1 Levels

End point description

The timing of resective surgery was not defined in the protocol and was left at the discretion of the Investigator. Resection was classified as R0, R1, or R2 following surgery. R0 was defined as complete resection with clear margins ≥1 mm. The percentage of participants with R0 resection of liver or liver plus lymph node metastases was reported. The 95% CI was computed using normal approximation to the binomial distribution. ITT Population; only those participants with liver or liver plus lymph node metastases were included in the analysis. "Number of subjects analysed" reflects the number of evaluable participants for the outcome measure.

End point type

Secondary

End point timeframe

At time of resective surgery during study (maximum up to 45 months overall)

End point values	Bevacizumab + mFOLFOX/FOLFIRI (ERCC-1 High)	Bevacizumab + mFOLFOX/FOLFIRI (ERCC-1 Low)
Number of subjects analysed	131	244
Units: percentage of participants
number (confidence interval 95%)	4.6 (1 to 8.2)	6.1 (3.1 to 9.2)

Difference in Complete Resection Rates

Statistical analysis description

The difference was calculated as the percentage of participants with complete resection in the ERCC-1 High subgroup minus the ERCC-1 Low subgroup. The 95% CI was computed using normal approximation to the binomial distribution.

Comparison groups

Bevacizumab + mFOLFOX/FOLFIRI (ERCC-1 High) v Bevacizumab + mFOLFOX/FOLFIRI (ERCC-1 Low)

Number of subjects included in analysis

375

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Difference in complete resection rates

Point estimate

-1.6

Confidence interval

level

95%

sides

2-sided

lower limit

-6.2

upper limit

3.1

Secondary: PFS According to RECIST Version 1.1 in Participants With Wild-Type KRAS Versus Participants With Mutant KRAS

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End point title

PFS According to RECIST Version 1.1 in Participants With Wild-Type KRAS Versus Participants With Mutant KRAS

End point description

End point type

Secondary

End point timeframe

From Baseline until death or disease progression; assessed every 6 weeks (maximum up to 45 months overall)

End point values	Bevacizumab + mFOLFOX/FOLFIRI (KRAS Wild-Type)	Bevacizumab + mFOLFOX/FOLFIRI (KRAS Mutant)
Number of subjects analysed	208	128
Units: months
median (confidence interval 95%)	12.45 (10.48 to 14.06)	10.94 (8.77 to 12.35)

Hazard Ratio

Comparison groups

Bevacizumab + mFOLFOX/FOLFIRI (KRAS Mutant) v Bevacizumab + mFOLFOX/FOLFIRI (KRAS Wild-Type)

Number of subjects included in analysis

336

Analysis specification

Pre-specified

Analysis type

other ^[24]

P-value

= 0.0593 ^[25]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

1.29

Confidence interval

level

95%

sides

2-sided

lower limit

0.99

upper limit

1.69

Notes
[24] - Analysis stratified by high/low ERCC-1 level and region of enrollment. HR (relative to KRAS Wild-Type subgroup) was estimated by Cox regression.
[25] - P-value (relative to KRAS Wild-Type subgroup) based on two-sided stratified log rank test and not adjusted for multiple comparisons.

Secondary: OS in Participants With High VEGF-A Levels Versus Participants With Low VEGF-A Levels

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End point title

OS in Participants With High VEGF-A Levels Versus Participants With Low VEGF-A Levels

End point description

End point type

Secondary

End point timeframe

From Baseline until death (maximum up to 45 months overall)

End point values	Bevacizumab + mFOLFOX/FOLFIRI (VEGF-A High)	Bevacizumab + mFOLFOX/FOLFIRI (VEGF-A Low)
Number of subjects analysed	185	185
Units: months
median (confidence interval 95%)	22.83 (18.76 to 27.27)	27.93 (24.97 to 36.01)

Hazard Ratio

Statistical analysis description

Analysis stratified by high/low ERCC-1 level and region of enrollment. HR (relative to VEGF-A Low subgroup) was estimated by Cox regression.

Comparison groups

Bevacizumab + mFOLFOX/FOLFIRI (VEGF-A High) v Bevacizumab + mFOLFOX/FOLFIRI (VEGF-A Low)

Number of subjects included in analysis

370

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.002 ^[26]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

1.64

Confidence interval

level

95%

sides

2-sided

lower limit

1.2

upper limit

2.24

Notes
[26] - P-value (relative to VEGF-A Low subgroup) based on two-sided stratified log rank test and not adjusted for multiple comparisons.

Secondary: OS in Participants With Wild-Type KRAS Versus Participants With Mutant KRAS

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End point title

OS in Participants With Wild-Type KRAS Versus Participants With Mutant KRAS

End point description

End point type

Secondary

End point timeframe

From Baseline until death (maximum up to 45 months overall)

End point values	Bevacizumab + mFOLFOX/FOLFIRI (KRAS Wild-Type)	Bevacizumab + mFOLFOX/FOLFIRI (KRAS Mutant)
Number of subjects analysed	208	128
Units: months
median (confidence interval 95%)	28.75 (24.77 to 36.73)	24.64 (19.98 to 26.94)

Hazard Ratio

Statistical analysis description

Analysis stratified by high/low ERCC-1 level and region of enrollment. HR (relative to KRAS Wild-Type subgroup) was estimated by Cox regression.

Comparison groups

Bevacizumab + mFOLFOX/FOLFIRI (KRAS Wild-Type) v Bevacizumab + mFOLFOX/FOLFIRI (KRAS Mutant)

Number of subjects included in analysis

336

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.0955 ^[27]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

1.34

Confidence interval

level

95%

sides

2-sided

lower limit

0.95

upper limit

1.88

Notes
[27] - P-value (relative to KRAS Wild-Type subgroup) based on two-sided stratified log rank test and not adjusted for multiple comparisons.

Secondary: Percentage of Participants With Objective Response According to RECIST Version 1.1 in Participants With High VEGF-A Levels Versus Participants With Low VEGF-A Levels

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End point title

Percentage of Participants With Objective Response According to RECIST Version 1.1 in Participants With High VEGF-A Levels Versus Participants With Low VEGF-A Levels

End point description

End point type

Secondary

End point timeframe

From Baseline until disease progression; assessed every 6 weeks (maximum up to 45 months overall)

End point values	Bevacizumab + mFOLFOX/FOLFIRI (VEGF-A High)	Bevacizumab + mFOLFOX/FOLFIRI (VEGF-A Low)
Number of subjects analysed	185	185
Units: percentage of participants
number (confidence interval 95%)	60.5 (53.5 to 67.6)	66.5 (59.7 to 73.3)

Difference in Objective Response Rates

Statistical analysis description

The difference was calculated as the percentage of participants with objective response in the VEGF-A High subgroup minus the VEGF-A Low subgroup. The 95% CI was computed using normal approximation to the binomial distribution.

Comparison groups

Bevacizumab + mFOLFOX/FOLFIRI (VEGF-A High) v Bevacizumab + mFOLFOX/FOLFIRI (VEGF-A Low)

Number of subjects included in analysis

370

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Difference in objective response rates

Point estimate

-5.9

Confidence interval

level

95%

sides

2-sided

lower limit

-15.7

upper limit

3.8

Secondary: Percentage of Participants With Objective Response According to RECIST Version 1.1 in Participants With Wild-Type KRAS Versus Participants With Mutant KRAS

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End point title

Percentage of Participants With Objective Response According to RECIST Version 1.1 in Participants With Wild-Type KRAS Versus Participants With Mutant KRAS

End point description

End point type

Secondary

End point timeframe

From Baseline until disease progression; assessed every 6 weeks (maximum up to 45 months overall)

End point values	Bevacizumab + mFOLFOX/FOLFIRI (KRAS Wild-Type)	Bevacizumab + mFOLFOX/FOLFIRI (KRAS Mutant)
Number of subjects analysed	208	128
Units: percentage of participants
number (confidence interval 95%)	66.3 (59.9 to 72.8)	60.9 (52.5 to 69.4)

Difference in Objective Response Rates

Statistical analysis description

The difference was calculated as the percentage of participants with objective response in the KRAS Mutant subgroup minus the KRAS Wild-Type subgroup. The 95% CI was computed using normal approximation to the binomial distribution.

Comparison groups

Bevacizumab + mFOLFOX/FOLFIRI (KRAS Wild-Type) v Bevacizumab + mFOLFOX/FOLFIRI (KRAS Mutant)

Number of subjects included in analysis

336

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Difference in objective response rates

Point estimate

-5.4

Confidence interval

level

95%

sides

2-sided

lower limit

-16

upper limit

5.2

Secondary: Percentage of Participants With Disease Control According to RECIST Version 1.1 in Participants With High VEGF-A Levels Versus Participants With Low VEGF-A Levels

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End point title

Percentage of Participants With Disease Control According to RECIST Version 1.1 in Participants With High VEGF-A Levels Versus Participants With Low VEGF-A Levels

End point description

End point type

Secondary

End point timeframe

From Baseline until disease progression; assessed every 6 weeks (maximum up to 45 months overall)

End point values	Bevacizumab + mFOLFOX/FOLFIRI (VEGF-A High)	Bevacizumab + mFOLFOX/FOLFIRI (VEGF-A Low)
Number of subjects analysed	185	185
Units: percentage of participants
number (confidence interval 95%)	91.9 (88 to 95.8)	93 (89.3 to 96.7)

Difference in Disease Control Rates

Statistical analysis description

The difference was calculated as the percentage of participants with disease control in the VEGF-A High subgroup minus the VEGF-A Low subgroup. The 95% CI was computed using normal approximation to the binomial distribution.

Comparison groups

Bevacizumab + mFOLFOX/FOLFIRI (VEGF-A High) v Bevacizumab + mFOLFOX/FOLFIRI (VEGF-A Low)

Number of subjects included in analysis

370

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Difference in disease control rates

Point estimate

-1.1

Confidence interval

level

95%

sides

2-sided

lower limit

-6.5

upper limit

4.3

Secondary: Percentage of Participants With Liver Metastasis Resection in Participants With High VEGF-A Levels Versus Participants With Low VEGF-A Levels

Top of page

End point title

Percentage of Participants With Liver Metastasis Resection in Participants With High VEGF-A Levels Versus Participants With Low VEGF-A Levels

End point description

End point type

Secondary

End point timeframe

At time of resective surgery during study (maximum up to 45 months overall)

End point values	Bevacizumab + mFOLFOX/FOLFIRI (VEGF-A High)	Bevacizumab + mFOLFOX/FOLFIRI (VEGF-A Low)
Number of subjects analysed	185	185
Units: percentage of participants
number (confidence interval 95%)	5.9 (2.5 to 9.4)	9.2 (5 to 13.4)

Difference in Resection Rates

Statistical analysis description

The difference was calculated as the percentage of participants with resection in the VEGF-A High subgroup minus the VEGF-A Low subgroup. The 95% CI was computed using normal approximation to the binomial distribution.

Comparison groups

Bevacizumab + mFOLFOX/FOLFIRI (VEGF-A High) v Bevacizumab + mFOLFOX/FOLFIRI (VEGF-A Low)

Number of subjects included in analysis

370

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Difference in resection rates

Point estimate

-3.2

Confidence interval

level

95%

sides

2-sided

lower limit

-8.6

upper limit

2.1

Secondary: Percentage of Participants With Complete Liver Metastasis Resection in Participants With High VEGF-A Levels Versus Participants With Low VEGF-A Levels

Top of page

End point title

Percentage of Participants With Complete Liver Metastasis Resection in Participants With High VEGF-A Levels Versus Participants With Low VEGF-A Levels

End point description

The timing of resective surgery was not defined in the protocol and was left at the discretion of the Investigator. Resection was classified as R0, R1, or R2 following surgery. R0 was defined as complete resection with clear margins ≥1 mm. The percentage of participants with R0 resection of liver or liver plus lymph node metastases was reported. The 95% CI was computed using normal approximation to the binomial distribution. ITT Population; only those participants with liver or liver plus lymph node metastases were included in the analysis. "Number of subjects analysed" reflects the number of evaluable participants for the outcome measure.

End point type

Secondary

End point timeframe

At time of resective surgery during study (maximum up to 45 months overall)

End point values	Bevacizumab + mFOLFOX/FOLFIRI (VEGF-A High)	Bevacizumab + mFOLFOX/FOLFIRI (VEGF-A Low)
Number of subjects analysed	185	185
Units: percentage of participants
number (confidence interval 95%)	3.2 (0.7 to 5.8)	8.1 (4.2 to 12)

Difference in Complete Resection Rates

Statistical analysis description

The difference was calculated as the percentage of participants with complete resection in the VEGF-A High subgroup minus the VEGF-A Low subgroup. The 95% CI was computed using normal approximation to the binomial distribution.

Comparison groups

Bevacizumab + mFOLFOX/FOLFIRI (VEGF-A High) v Bevacizumab + mFOLFOX/FOLFIRI (VEGF-A Low)

Number of subjects included in analysis

370

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Difference in complete resection rates

Point estimate

-4.9

Confidence interval

level

95%

sides

2-sided

lower limit

-9.6

upper limit

-0.2

Adverse events

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Timeframe for reporting adverse events

Serious Adverse Events (AEs): Baseline until 3 months after last dose or study discontinuation/termination (up to 45 months overall); Non-Serious AEs: Baseline until 28 days after last dose or study discontinuation/termination (up to 45 months overall).

Adverse event reporting additional description

Safety Population: All randomized participants who received at least one partial or complete dose of study drug.

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

18.1

Reporting group title

Bevacizumab + mFOLFOX6

Reporting group description

Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus mFOLFOX6 until disease progression or unacceptable toxicity. Bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, oxaliplatin as 85 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to oxaliplatin and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles.

Reporting group title

Bevacizumab + FOLFIRI

Reporting group description

Serious adverse events	Bevacizumab + mFOLFOX6	Bevacizumab + FOLFIRI
Total subjects affected by serious adverse events
subjects affected / exposed	79 / 185 (42.70%)	87 / 183 (47.54%)
number of deaths (all causes)	96	73
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Meningioma
subjects affected / exposed	0 / 185 (0.00%)	1 / 183 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular disorders
Hypotension
subjects affected / exposed	5 / 185 (2.70%)	1 / 183 (0.55%)
occurrences causally related to treatment / all	1 / 5	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hypertension
subjects affected / exposed	3 / 185 (1.62%)	6 / 183 (3.28%)
occurrences causally related to treatment / all	3 / 3	9 / 9
deaths causally related to treatment / all	0 / 0	0 / 0
Arterial thrombosis
subjects affected / exposed	1 / 185 (0.54%)	0 / 183 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Deep vein thrombosis
subjects affected / exposed	1 / 185 (0.54%)	4 / 183 (2.19%)
occurrences causally related to treatment / all	1 / 1	2 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Embolism venous
subjects affected / exposed	1 / 185 (0.54%)	1 / 183 (0.55%)
occurrences causally related to treatment / all	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Venous thrombosis
subjects affected / exposed	1 / 185 (0.54%)	1 / 183 (0.55%)
occurrences causally related to treatment / all	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Jugular vein thrombosis
subjects affected / exposed	0 / 185 (0.00%)	1 / 183 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Thrombosis
subjects affected / exposed	0 / 185 (0.00%)	1 / 183 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Surgical and medical procedures
Colostomy
subjects affected / exposed	0 / 185 (0.00%)	1 / 183 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
General disorders and administration site conditions
Chest pain
subjects affected / exposed	3 / 185 (1.62%)	4 / 183 (2.19%)
occurrences causally related to treatment / all	1 / 3	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	3 / 185 (1.62%)	4 / 183 (2.19%)
occurrences causally related to treatment / all	2 / 3	1 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Device dislocation
subjects affected / exposed	2 / 185 (1.08%)	1 / 183 (0.55%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Asthenia
subjects affected / exposed	1 / 185 (0.54%)	1 / 183 (0.55%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Chills
subjects affected / exposed	1 / 185 (0.54%)	0 / 183 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Mucosal inflammation
subjects affected / exposed	1 / 185 (0.54%)	0 / 183 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Multi-organ failure
subjects affected / exposed	1 / 185 (0.54%)	0 / 183 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Peripheral swelling
subjects affected / exposed	1 / 185 (0.54%)	0 / 183 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Systemic inflammatory response syndrome
subjects affected / exposed	1 / 185 (0.54%)	0 / 183 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Device malfunction
subjects affected / exposed	0 / 185 (0.00%)	1 / 183 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Fatigue
subjects affected / exposed	0 / 185 (0.00%)	3 / 183 (1.64%)
occurrences causally related to treatment / all	0 / 0	3 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Gait disturbance
subjects affected / exposed	0 / 185 (0.00%)	1 / 183 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Localised oedema
subjects affected / exposed	0 / 185 (0.00%)	1 / 183 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Pulmonary embolism
subjects affected / exposed	9 / 185 (4.86%)	9 / 183 (4.92%)
occurrences causally related to treatment / all	8 / 10	7 / 9
deaths causally related to treatment / all	1 / 1	0 / 0
Acute respiratory failure
subjects affected / exposed	2 / 185 (1.08%)	1 / 183 (0.55%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Respiratory distress
subjects affected / exposed	2 / 185 (1.08%)	0 / 183 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Chronic obstructive pulmonary disease
subjects affected / exposed	1 / 185 (0.54%)	0 / 183 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	1 / 185 (0.54%)	1 / 183 (0.55%)
occurrences causally related to treatment / all	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Epistaxis
subjects affected / exposed	1 / 185 (0.54%)	1 / 183 (0.55%)
occurrences causally related to treatment / all	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hiccups
subjects affected / exposed	1 / 185 (0.54%)	0 / 183 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary thrombosis
subjects affected / exposed	1 / 185 (0.54%)	0 / 183 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Asthma
subjects affected / exposed	0 / 185 (0.00%)	1 / 183 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cough
subjects affected / exposed	0 / 185 (0.00%)	1 / 183 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Interstitial lung disease
subjects affected / exposed	0 / 185 (0.00%)	1 / 183 (0.55%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary artery thrombosis
subjects affected / exposed	0 / 185 (0.00%)	1 / 183 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Psychiatric disorders
Confusional state
subjects affected / exposed	1 / 185 (0.54%)	1 / 183 (0.55%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Mental status changes
subjects affected / exposed	0 / 185 (0.00%)	2 / 183 (1.09%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Investigations
Platelet count decreased
subjects affected / exposed	2 / 185 (1.08%)	0 / 183 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Weight decreased
subjects affected / exposed	1 / 185 (0.54%)	0 / 183 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Blood bilirubin increased
subjects affected / exposed	0 / 185 (0.00%)	2 / 183 (1.09%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Injury, poisoning and procedural complications
Infusion related reaction
subjects affected / exposed	1 / 185 (0.54%)	0 / 183 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Laceration
subjects affected / exposed	1 / 185 (0.54%)	0 / 183 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Stoma site haemorrhage
subjects affected / exposed	1 / 185 (0.54%)	0 / 183 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Toxicity to various agents
subjects affected / exposed	1 / 185 (0.54%)	0 / 183 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Wound dehiscence
subjects affected / exposed	1 / 185 (0.54%)	0 / 183 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Abdominal wound dehiscence
subjects affected / exposed	0 / 185 (0.00%)	1 / 183 (0.55%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Intestinal anastomosis complication
subjects affected / exposed	0 / 185 (0.00%)	1 / 183 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Spinal compression fracture
subjects affected / exposed	0 / 185 (0.00%)	1 / 183 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders
Atrial flutter
subjects affected / exposed	1 / 185 (0.54%)	0 / 183 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardio-respiratory arrest
subjects affected / exposed	1 / 185 (0.54%)	0 / 183 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Left ventricular dysfunction
subjects affected / exposed	1 / 185 (0.54%)	0 / 183 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Myocardial infarction
subjects affected / exposed	1 / 185 (0.54%)	1 / 183 (0.55%)
occurrences causally related to treatment / all	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Supraventricular tachycardia
subjects affected / exposed	1 / 185 (0.54%)	0 / 183 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Atrial fibrillation
subjects affected / exposed	0 / 185 (0.00%)	3 / 183 (1.64%)
occurrences causally related to treatment / all	0 / 0	1 / 6
deaths causally related to treatment / all	0 / 0	0 / 0
Atrial thrombosis
subjects affected / exposed	0 / 185 (0.00%)	1 / 183 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorders
Aphonia
subjects affected / exposed	1 / 185 (0.54%)	0 / 183 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Ataxia
subjects affected / exposed	1 / 185 (0.54%)	0 / 183 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cerebrovascular accident
subjects affected / exposed	1 / 185 (0.54%)	1 / 183 (0.55%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Seizure
subjects affected / exposed	1 / 185 (0.54%)	0 / 183 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Syncope
subjects affected / exposed	1 / 185 (0.54%)	2 / 183 (1.09%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Haemorrhage intracranial
subjects affected / exposed	0 / 185 (0.00%)	1 / 183 (0.55%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Ischaemic stroke
subjects affected / exposed	0 / 185 (0.00%)	1 / 183 (0.55%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Thrombotic stroke
subjects affected / exposed	0 / 185 (0.00%)	1 / 183 (0.55%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	1 / 1
Blood and lymphatic system disorders
Thrombocytopenia
subjects affected / exposed	3 / 185 (1.62%)	0 / 183 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Febrile neutropenia
subjects affected / exposed	2 / 185 (1.08%)	4 / 183 (2.19%)
occurrences causally related to treatment / all	1 / 2	4 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Anaemia
subjects affected / exposed	1 / 185 (0.54%)	1 / 183 (0.55%)
occurrences causally related to treatment / all	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Immune thrombocytopenic purpura
subjects affected / exposed	1 / 185 (0.54%)	0 / 183 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Neutropenia
subjects affected / exposed	1 / 185 (0.54%)	2 / 183 (1.09%)
occurrences causally related to treatment / all	1 / 1	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Pancytopenia
subjects affected / exposed	1 / 185 (0.54%)	1 / 183 (0.55%)
occurrences causally related to treatment / all	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	6 / 185 (3.24%)	2 / 183 (1.09%)
occurrences causally related to treatment / all	4 / 6	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Small intestinal obstruction
subjects affected / exposed	5 / 185 (2.70%)	6 / 183 (3.28%)
occurrences causally related to treatment / all	2 / 5	0 / 7
deaths causally related to treatment / all	0 / 0	0 / 0
Rectal haemorrhage
subjects affected / exposed	4 / 185 (2.16%)	0 / 183 (0.00%)
occurrences causally related to treatment / all	2 / 5	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Abdominal pain
subjects affected / exposed	3 / 185 (1.62%)	7 / 183 (3.83%)
occurrences causally related to treatment / all	0 / 3	0 / 8
deaths causally related to treatment / all	0 / 0	0 / 0
Intestinal obstruction
subjects affected / exposed	3 / 185 (1.62%)	3 / 183 (1.64%)
occurrences causally related to treatment / all	1 / 3	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Vomiting
subjects affected / exposed	3 / 185 (1.62%)	4 / 183 (2.19%)
occurrences causally related to treatment / all	0 / 6	2 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
Constipation
subjects affected / exposed	2 / 185 (1.08%)	0 / 183 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Dysphagia
subjects affected / exposed	2 / 185 (1.08%)	0 / 183 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Large intestine perforation
subjects affected / exposed	2 / 185 (1.08%)	1 / 183 (0.55%)
occurrences causally related to treatment / all	2 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Nausea
subjects affected / exposed	2 / 185 (1.08%)	1 / 183 (0.55%)
occurrences causally related to treatment / all	0 / 4	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Oesophagitis
subjects affected / exposed	2 / 185 (1.08%)	0 / 183 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Upper gastrointestinal haemorrhage
subjects affected / exposed	2 / 185 (1.08%)	0 / 183 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Abdominal pain lower
subjects affected / exposed	1 / 185 (0.54%)	0 / 183 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Ascites
subjects affected / exposed	1 / 185 (0.54%)	0 / 183 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Duodenal ulcer haemorrhage
subjects affected / exposed	1 / 185 (0.54%)	0 / 183 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Enteritis
subjects affected / exposed	1 / 185 (0.54%)	0 / 183 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrooesophageal reflux disease
subjects affected / exposed	1 / 185 (0.54%)	0 / 183 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Ileal perforation
subjects affected / exposed	1 / 185 (0.54%)	0 / 183 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0
Large intestinal haemorrhage
subjects affected / exposed	1 / 185 (0.54%)	0 / 183 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Neutropenic colitis
subjects affected / exposed	1 / 185 (0.54%)	0 / 183 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Oesophageal motility disorder
subjects affected / exposed	1 / 185 (0.54%)	0 / 183 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Oesophageal varices haemorrhage
subjects affected / exposed	1 / 185 (0.54%)	0 / 183 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumoperitoneum
subjects affected / exposed	1 / 185 (0.54%)	0 / 183 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0
Small intestinal perforation
subjects affected / exposed	1 / 185 (0.54%)	0 / 183 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Abdominal distension
subjects affected / exposed	0 / 185 (0.00%)	1 / 183 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Abdominal pain upper
subjects affected / exposed	0 / 185 (0.00%)	2 / 183 (1.09%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Anal fistula
subjects affected / exposed	0 / 185 (0.00%)	1 / 183 (0.55%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Colitis
subjects affected / exposed	0 / 185 (0.00%)	2 / 183 (1.09%)
occurrences causally related to treatment / all	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Duodenitis
subjects affected / exposed	0 / 185 (0.00%)	1 / 183 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Enterovesical fistula
subjects affected / exposed	0 / 185 (0.00%)	1 / 183 (0.55%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastric haemorrhage
subjects affected / exposed	0 / 185 (0.00%)	1 / 183 (0.55%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal haemorrhage
subjects affected / exposed	0 / 185 (0.00%)	1 / 183 (0.55%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Haemorrhoidal haemorrhage
subjects affected / exposed	0 / 185 (0.00%)	1 / 183 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Ileus
subjects affected / exposed	0 / 185 (0.00%)	2 / 183 (1.09%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Large intestinal obstruction
subjects affected / exposed	0 / 185 (0.00%)	2 / 183 (1.09%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 1
Pancreatitis
subjects affected / exposed	0 / 185 (0.00%)	1 / 183 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Reflux gastritis
subjects affected / exposed	0 / 185 (0.00%)	1 / 183 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatobiliary disorders
Cholecystitis
subjects affected / exposed	1 / 185 (0.54%)	1 / 183 (0.55%)
occurrences causally related to treatment / all	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cholecystitis acute
subjects affected / exposed	1 / 185 (0.54%)	0 / 183 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hyperbilirubinaemia
subjects affected / exposed	1 / 185 (0.54%)	0 / 183 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Ischaemic hepatitis
subjects affected / exposed	1 / 185 (0.54%)	0 / 183 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0
Biloma
subjects affected / exposed	0 / 185 (0.00%)	1 / 183 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cholangitis
subjects affected / exposed	0 / 185 (0.00%)	1 / 183 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cholecystitis chronic
subjects affected / exposed	0 / 185 (0.00%)	1 / 183 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cholelithiasis
subjects affected / exposed	0 / 185 (0.00%)	1 / 183 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatic steatosis
subjects affected / exposed	0 / 185 (0.00%)	1 / 183 (0.55%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatitis
subjects affected / exposed	0 / 185 (0.00%)	1 / 183 (0.55%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Jaundice
subjects affected / exposed	0 / 185 (0.00%)	1 / 183 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	1 / 185 (0.54%)	2 / 183 (1.09%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 1
Proteinuria
subjects affected / exposed	1 / 185 (0.54%)	1 / 183 (0.55%)
occurrences causally related to treatment / all	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Renal failure
subjects affected / exposed	0 / 185 (0.00%)	1 / 183 (0.55%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Muscular weakness
subjects affected / exposed	1 / 185 (0.54%)	1 / 183 (0.55%)
occurrences causally related to treatment / all	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Polyarthritis
subjects affected / exposed	1 / 185 (0.54%)	0 / 183 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Rhabdomyolysis
subjects affected / exposed	1 / 185 (0.54%)	0 / 183 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Sepsis
subjects affected / exposed	4 / 185 (2.16%)	3 / 183 (1.64%)
occurrences causally related to treatment / all	1 / 6	1 / 3
deaths causally related to treatment / all	0 / 0	1 / 2
Pneumonia
subjects affected / exposed	3 / 185 (1.62%)	7 / 183 (3.83%)
occurrences causally related to treatment / all	0 / 3	1 / 7
deaths causally related to treatment / all	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	2 / 185 (1.08%)	0 / 183 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Septic shock
subjects affected / exposed	2 / 185 (1.08%)	1 / 183 (0.55%)
occurrences causally related to treatment / all	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0
Upper respiratory tract infection
subjects affected / exposed	2 / 185 (1.08%)	0 / 183 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Abdominal abscess
subjects affected / exposed	1 / 185 (0.54%)	0 / 183 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Abdominal infection
subjects affected / exposed	1 / 185 (0.54%)	0 / 183 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Appendicitis
subjects affected / exposed	1 / 185 (0.54%)	0 / 183 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Bronchitis
subjects affected / exposed	1 / 185 (0.54%)	0 / 183 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Candida sepsis
subjects affected / exposed	1 / 185 (0.54%)	0 / 183 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Diverticulitis
subjects affected / exposed	1 / 185 (0.54%)	0 / 183 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Endocarditis
subjects affected / exposed	1 / 185 (0.54%)	0 / 183 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Infection
subjects affected / exposed	1 / 185 (0.54%)	1 / 183 (0.55%)
occurrences causally related to treatment / all	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Lung infection
subjects affected / exposed	1 / 185 (0.54%)	0 / 183 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory tract infection
subjects affected / exposed	1 / 185 (0.54%)	0 / 183 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Subcutaneous abscess
subjects affected / exposed	1 / 185 (0.54%)	0 / 183 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	1 / 185 (0.54%)	0 / 183 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Urosepsis
subjects affected / exposed	1 / 185 (0.54%)	1 / 183 (0.55%)
occurrences causally related to treatment / all	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Device related infection
subjects affected / exposed	0 / 185 (0.00%)	2 / 183 (1.09%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	0 / 185 (0.00%)	1 / 183 (0.55%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastroenteritis viral
subjects affected / exposed	0 / 185 (0.00%)	1 / 183 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Kidney infection
subjects affected / exposed	0 / 185 (0.00%)	1 / 183 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Lower respiratory tract infection
subjects affected / exposed	0 / 185 (0.00%)	1 / 183 (0.55%)
occurrences causally related to treatment / all	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Neutropenic sepsis
subjects affected / exposed	0 / 185 (0.00%)	1 / 183 (0.55%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Perineal abscess
subjects affected / exposed	0 / 185 (0.00%)	1 / 183 (0.55%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia bacterial
subjects affected / exposed	0 / 185 (0.00%)	1 / 183 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia parainfluenzae viral
subjects affected / exposed	0 / 185 (0.00%)	1 / 183 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	8 / 185 (4.32%)	5 / 183 (2.73%)
occurrences causally related to treatment / all	2 / 10	3 / 6
deaths causally related to treatment / all	0 / 0	0 / 0
Decreased appetite
subjects affected / exposed	1 / 185 (0.54%)	0 / 183 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Diabetes mellitus
subjects affected / exposed	1 / 185 (0.54%)	0 / 183 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Failure to thrive
subjects affected / exposed	1 / 185 (0.54%)	1 / 183 (0.55%)
occurrences causally related to treatment / all	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hyperglycaemia
subjects affected / exposed	1 / 185 (0.54%)	0 / 183 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hypokalaemia
subjects affected / exposed	1 / 185 (0.54%)	1 / 183 (0.55%)
occurrences causally related to treatment / all	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hyponatraemia
subjects affected / exposed	1 / 185 (0.54%)	2 / 183 (1.09%)
occurrences causally related to treatment / all	0 / 1	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Malnutrition
subjects affected / exposed	1 / 185 (0.54%)	0 / 183 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hypoalbuminaemia
subjects affected / exposed	0 / 185 (0.00%)	1 / 183 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hypophosphataemia
subjects affected / exposed	0 / 185 (0.00%)	1 / 183 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Metabolic alkalosis
subjects affected / exposed	0 / 185 (0.00%)	1 / 183 (0.55%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0

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

Non-serious adverse events	Bevacizumab + mFOLFOX6	Bevacizumab + FOLFIRI
Total subjects affected by non serious adverse events
subjects affected / exposed	185 / 185 (100.00%)	181 / 183 (98.91%)
Vascular disorders
Hypertension
subjects affected / exposed	61 / 185 (32.97%)	54 / 183 (29.51%)
occurrences all number	110	96
General disorders and administration site conditions
Fatigue
subjects affected / exposed	105 / 185 (56.76%)	104 / 183 (56.83%)
occurrences all number	145	177
Mucosal inflammation
subjects affected / exposed	37 / 185 (20.00%)	51 / 183 (27.87%)
occurrences all number	50	82
Pyrexia
subjects affected / exposed	18 / 185 (9.73%)	29 / 183 (15.85%)
occurrences all number	23	38
Asthenia
subjects affected / exposed	21 / 185 (11.35%)	18 / 183 (9.84%)
occurrences all number	24	28
Oedema peripheral
subjects affected / exposed	18 / 185 (9.73%)	18 / 183 (9.84%)
occurrences all number	22	20
Temperature intolerance
subjects affected / exposed	34 / 185 (18.38%)	1 / 183 (0.55%)
occurrences all number	39	1
Chest pain
subjects affected / exposed	15 / 185 (8.11%)	10 / 183 (5.46%)
occurrences all number	19	12
Chills
subjects affected / exposed	10 / 185 (5.41%)	10 / 183 (5.46%)
occurrences all number	12	13
Influenza like illness
subjects affected / exposed	10 / 185 (5.41%)	6 / 183 (3.28%)
occurrences all number	13	6
Immune system disorders
Hypersensitivity
subjects affected / exposed	10 / 185 (5.41%)	0 / 183 (0.00%)
occurrences all number	11	0
Respiratory, thoracic and mediastinal disorders
Epistaxis
subjects affected / exposed	41 / 185 (22.16%)	59 / 183 (32.24%)
occurrences all number	51	82
Cough
subjects affected / exposed	31 / 185 (16.76%)	29 / 183 (15.85%)
occurrences all number	37	43
Dyspnoea
subjects affected / exposed	28 / 185 (15.14%)	26 / 183 (14.21%)
occurrences all number	39	38
Rhinorrhoea
subjects affected / exposed	12 / 185 (6.49%)	21 / 183 (11.48%)
occurrences all number	16	23
Dysphonia
subjects affected / exposed	14 / 185 (7.57%)	18 / 183 (9.84%)
occurrences all number	17	39
Hiccups
subjects affected / exposed	8 / 185 (4.32%)	14 / 183 (7.65%)
occurrences all number	11	16
Oropharyngeal pain
subjects affected / exposed	11 / 185 (5.95%)	8 / 183 (4.37%)
occurrences all number	11	12
Psychiatric disorders
Insomnia
subjects affected / exposed	29 / 185 (15.68%)	35 / 183 (19.13%)
occurrences all number	31	44
Depression
subjects affected / exposed	24 / 185 (12.97%)	18 / 183 (9.84%)
occurrences all number	26	24
Anxiety
subjects affected / exposed	19 / 185 (10.27%)	20 / 183 (10.93%)
occurrences all number	20	23
Investigations
Weight decreased
subjects affected / exposed	33 / 185 (17.84%)	29 / 183 (15.85%)
occurrences all number	40	32
Neutrophil count decreased
subjects affected / exposed	33 / 185 (17.84%)	23 / 183 (12.57%)
occurrences all number	55	33
Platelet count decreased
subjects affected / exposed	24 / 185 (12.97%)	3 / 183 (1.64%)
occurrences all number	64	6
White blood cell count decreased
subjects affected / exposed	15 / 185 (8.11%)	9 / 183 (4.92%)
occurrences all number	25	25
Injury, poisoning and procedural complications
Infusion related reaction
subjects affected / exposed	15 / 185 (8.11%)	8 / 183 (4.37%)
occurrences all number	27	13
Nervous system disorders
Neuropathy peripheral
subjects affected / exposed	85 / 185 (45.95%)	23 / 183 (12.57%)
occurrences all number	134	30
Headache
subjects affected / exposed	31 / 185 (16.76%)	38 / 183 (20.77%)
occurrences all number	40	51
Dysgeusia
subjects affected / exposed	33 / 185 (17.84%)	31 / 183 (16.94%)
occurrences all number	38	38
Paraesthesia
subjects affected / exposed	35 / 185 (18.92%)	15 / 183 (8.20%)
occurrences all number	66	18
Peripheral sensory neuropathy
subjects affected / exposed	35 / 185 (18.92%)	12 / 183 (6.56%)
occurrences all number	50	12
Dizziness
subjects affected / exposed	15 / 185 (8.11%)	28 / 183 (15.30%)
occurrences all number	15	36
Blood and lymphatic system disorders
Neutropenia
subjects affected / exposed	65 / 185 (35.14%)	86 / 183 (46.99%)
occurrences all number	103	158
Anaemia
subjects affected / exposed	25 / 185 (13.51%)	34 / 183 (18.58%)
occurrences all number	31	45
Thrombocytopenia
subjects affected / exposed	44 / 185 (23.78%)	13 / 183 (7.10%)
occurrences all number	134	22
Eye disorders
Vision blurred
subjects affected / exposed	13 / 185 (7.03%)	12 / 183 (6.56%)
occurrences all number	16	13
Lacrimation increased
subjects affected / exposed	4 / 185 (2.16%)	10 / 183 (5.46%)
occurrences all number	4	13
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	99 / 185 (53.51%)	123 / 183 (67.21%)
occurrences all number	189	242
Nausea
subjects affected / exposed	106 / 185 (57.30%)	109 / 183 (59.56%)
occurrences all number	201	203
Constipation
subjects affected / exposed	63 / 185 (34.05%)	65 / 183 (35.52%)
occurrences all number	86	115
Vomiting
subjects affected / exposed	58 / 185 (31.35%)	57 / 183 (31.15%)
occurrences all number	80	89
Abdominal pain
subjects affected / exposed	39 / 185 (21.08%)	54 / 183 (29.51%)
occurrences all number	47	82
Stomatitis
subjects affected / exposed	35 / 185 (18.92%)	38 / 183 (20.77%)
occurrences all number	50	56
Gastrooesophageal reflux disease
subjects affected / exposed	17 / 185 (9.19%)	18 / 183 (9.84%)
occurrences all number	19	20
Dyspepsia
subjects affected / exposed	19 / 185 (10.27%)	14 / 183 (7.65%)
occurrences all number	22	15
Rectal haemorrhage
subjects affected / exposed	11 / 185 (5.95%)	18 / 183 (9.84%)
occurrences all number	16	31
Abdominal pain upper
subjects affected / exposed	8 / 185 (4.32%)	15 / 183 (8.20%)
occurrences all number	8	22
Oral pain
subjects affected / exposed	8 / 185 (4.32%)	14 / 183 (7.65%)
occurrences all number	9	14
Haemorrhoids
subjects affected / exposed	6 / 185 (3.24%)	16 / 183 (8.74%)
occurrences all number	6	17
Proctalgia
subjects affected / exposed	7 / 185 (3.78%)	13 / 183 (7.10%)
occurrences all number	7	13
Dry mouth
subjects affected / exposed	7 / 185 (3.78%)	11 / 183 (6.01%)
occurrences all number	8	12
Abdominal distension
subjects affected / exposed	5 / 185 (2.70%)	12 / 183 (6.56%)
occurrences all number	5	14
Dysphagia
subjects affected / exposed	10 / 185 (5.41%)	2 / 183 (1.09%)
occurrences all number	10	2
Skin and subcutaneous tissue disorders
Alopecia
subjects affected / exposed	26 / 185 (14.05%)	61 / 183 (33.33%)
occurrences all number	30	69
Dry skin
subjects affected / exposed	27 / 185 (14.59%)	26 / 183 (14.21%)
occurrences all number	36	38
Rash
subjects affected / exposed	19 / 185 (10.27%)	26 / 183 (14.21%)
occurrences all number	25	31
Palmar-plantar erythrodysaesthesia syndrome
subjects affected / exposed	24 / 185 (12.97%)	18 / 183 (9.84%)
occurrences all number	37	22
Skin hyperpigmentation
subjects affected / exposed	18 / 185 (9.73%)	13 / 183 (7.10%)
occurrences all number	19	17
Pruritus
subjects affected / exposed	11 / 185 (5.95%)	9 / 183 (4.92%)
occurrences all number	17	14
Hyperhidrosis
subjects affected / exposed	2 / 185 (1.08%)	10 / 183 (5.46%)
occurrences all number	2	14
Renal and urinary disorders
Proteinuria
subjects affected / exposed	38 / 185 (20.54%)	39 / 183 (21.31%)
occurrences all number	58	52
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	22 / 185 (11.89%)	25 / 183 (13.66%)
occurrences all number	24	36
Back pain
subjects affected / exposed	21 / 185 (11.35%)	23 / 183 (12.57%)
occurrences all number	25	31
Pain in extremity
subjects affected / exposed	22 / 185 (11.89%)	19 / 183 (10.38%)
occurrences all number	23	25
Musculoskeletal pain
subjects affected / exposed	17 / 185 (9.19%)	11 / 183 (6.01%)
occurrences all number	17	12
Muscle spasms
subjects affected / exposed	7 / 185 (3.78%)	11 / 183 (6.01%)
occurrences all number	8	14
Infections and infestations
Urinary tract infection
subjects affected / exposed	18 / 185 (9.73%)	20 / 183 (10.93%)
occurrences all number	19	21
Upper respiratory tract infection
subjects affected / exposed	15 / 185 (8.11%)	18 / 183 (9.84%)
occurrences all number	18	18
Sinusitis
subjects affected / exposed	9 / 185 (4.86%)	13 / 183 (7.10%)
occurrences all number	10	13
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	56 / 185 (30.27%)	55 / 183 (30.05%)
occurrences all number	93	76
Hypokalaemia
subjects affected / exposed	36 / 185 (19.46%)	33 / 183 (18.03%)
occurrences all number	44	39
Dehydration
subjects affected / exposed	28 / 185 (15.14%)	27 / 183 (14.75%)
occurrences all number	51	36
Hyperglycaemia
subjects affected / exposed	9 / 185 (4.86%)	23 / 183 (12.57%)
occurrences all number	15	26
Hyponatraemia
subjects affected / exposed	8 / 185 (4.32%)	15 / 183 (8.20%)
occurrences all number	10	18

More information

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Were there any global substantial amendments to the protocol? Yes

03 Jul 2012

The protocol was modified to include geographic region (United States or non-United States) as a stratification factor for enrollment. The start of Screening was also changed to the date that biopsy tissue became available, and biomarker samplings were updated.

26 Oct 2012

The protocol was amended primarily to modify the requirement for follow-up after study discontinuation. Participants who discontinued bevacizumab or other study drug were to continue with the rest of the treatment regimen until progression or unacceptable toxicity, and the end of treatment was re-defined as the time at which all study drugs were discontinued or the participant progressed. Thereafter, participants could enter the survival follow-up phase.

Were there any global interruptions to the trial? No

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

None reported

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Clinical trials

Clinical Trial Results: MAVERICC (Marker Evaluation for Avastin Research in CRC): A Randomized Phase II Study of Bevacizumab+mFOLFOX6 Vs. Bevacizumab+FOLFIRI With Biomarker Stratification in Patients With Previously Untreated Metastatic Colorectal Cancer

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: PFS According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1

Primary: PFS According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1

Primary: PFS According to RECIST Version 1.1 in Participants With High ERCC-1 Levels

Primary: PFS According to RECIST Version 1.1 in Participants With High ERCC-1 Levels

Primary: PFS According to RECIST Version 1.1 in Participants With Low ERCC-1 Levels

Primary: PFS According to RECIST Version 1.1 in Participants With Low ERCC-1 Levels

Primary: PFS According to RECIST Version 1.1 in Participants With High ERCC-1 Levels Versus Participants With Low ERCC-1 Levels

Primary: PFS According to RECIST Version 1.1 in Participants With High ERCC-1 Levels Versus Participants With Low ERCC-1 Levels

Primary: PFS According to RECIST Version 1.1 in Participants With High VEGF-A Levels Versus Participants With Low VEGF-A Levels

Primary: PFS According to RECIST Version 1.1 in Participants With High VEGF-A Levels Versus Participants With Low VEGF-A Levels

Secondary: PFS According to RECIST Version 1.1 in Participants With High ERCC-1 and High VEGF-A Levels

Secondary: PFS According to RECIST Version 1.1 in Participants With High ERCC-1 and High VEGF-A Levels

Secondary: PFS According to RECIST Version 1.1 in Participants With High ERCC-1 and Low VEGF-A Levels

Secondary: PFS According to RECIST Version 1.1 in Participants With High ERCC-1 and Low VEGF-A Levels

Secondary: PFS According to RECIST Version 1.1 in Participants With Low ERCC-1 and High VEGF-A Levels

Secondary: PFS According to RECIST Version 1.1 in Participants With Low ERCC-1 and High VEGF-A Levels

Secondary: PFS According to RECIST Version 1.1 in Participants With Low ERCC-1 and Low VEGF-A Levels

Secondary: PFS According to RECIST Version 1.1 in Participants With Low ERCC-1 and Low VEGF-A Levels

Secondary: Overall Survival (OS)

Secondary: Overall Survival (OS)

Secondary: OS in Participants With High ERCC-1 Levels

Secondary: OS in Participants With High ERCC-1 Levels

Secondary: OS in Participants With Low ERCC-1 Levels

Secondary: OS in Participants With Low ERCC-1 Levels

Secondary: OS in Participants With High ERCC-1 Levels Versus Participants With Low ERCC-1 Levels

Secondary: OS in Participants With High ERCC-1 Levels Versus Participants With Low ERCC-1 Levels

Secondary: Percentage of Participants With Objective Response According to RECIST Version 1.1

Secondary: Percentage of Participants With Objective Response According to RECIST Version 1.1

Secondary: Percentage of Participants With Objective Response According to RECIST Version 1.1 in Participants With High ERCC-1 Levels

Secondary: Percentage of Participants With Objective Response According to RECIST Version 1.1 in Participants With High ERCC-1 Levels

Secondary: Percentage of Participants With Objective Response According to RECIST Version 1.1 in Participants With Low ERCC-1 Levels

Secondary: Percentage of Participants With Objective Response According to RECIST Version 1.1 in Participants With Low ERCC-1 Levels

Secondary: Percentage of Participants With Objective Response According to RECIST Version 1.1 in Participants With High ERCC-1 Levels Versus Participants With Low ERCC-1 Levels

Secondary: Percentage of Participants With Objective Response According to RECIST Version 1.1 in Participants With High ERCC-1 Levels Versus Participants With Low ERCC-1 Levels

Secondary: Percentage of Participants With Disease Control According to RECIST Version 1.1

Secondary: Percentage of Participants With Disease Control According to RECIST Version 1.1

Secondary: Percentage of Participants With Disease Control According to RECIST Version 1.1 in Participants With High ERCC-1 Levels

Secondary: Percentage of Participants With Disease Control According to RECIST Version 1.1 in Participants With High ERCC-1 Levels

Secondary: Percentage of Participants With Disease Control According to RECIST Version 1.1 in Participants With Low ERCC-1 Levels

Secondary: Percentage of Participants With Disease Control According to RECIST Version 1.1 in Participants With Low ERCC-1 Levels

Secondary: Percentage of Participants With Disease Control According to RECIST Version 1.1 in Participants With High ERCC-1 Levels Versus Participants With Low ERCC-1 Levels

Secondary: Percentage of Participants With Disease Control According to RECIST Version 1.1 in Participants With High ERCC-1 Levels Versus Participants With Low ERCC-1 Levels

Secondary: Percentage of Participants With Liver Metastasis Resection

Secondary: Percentage of Participants With Liver Metastasis Resection

Secondary: Percentage of Participants With Complete Liver Metastasis Resection

Secondary: Percentage of Participants With Complete Liver Metastasis Resection

Secondary: Percentage of Participants With Liver Metastasis Resection in Participants With High ERCC-1 Levels

Secondary: Percentage of Participants With Liver Metastasis Resection in Participants With High ERCC-1 Levels

Secondary: Percentage of Participants With Complete Liver Metastasis Resection in Participants With High ERCC-1 Levels

Secondary: Percentage of Participants With Complete Liver Metastasis Resection in Participants With High ERCC-1 Levels

Secondary: Percentage of Participants With Liver Metastasis Resection in Participants With Low ERCC-1 Levels

Secondary: Percentage of Participants With Liver Metastasis Resection in Participants With Low ERCC-1 Levels

Secondary: Percentage of Participants With Complete Liver Metastasis Resection in Participants With Low ERCC-1 Levels

Secondary: Percentage of Participants With Complete Liver Metastasis Resection in Participants With Low ERCC-1 Levels

Secondary: Percentage of Participants With Liver Metastasis Resection in Participants With High ERCC-1 Levels Versus Participants With Low ERCC-1 Levels

Secondary: Percentage of Participants With Liver Metastasis Resection in Participants With High ERCC-1 Levels Versus Participants With Low ERCC-1 Levels

Secondary: Percentage of Participants With Complete Liver Metastasis Resection in Participants With High ERCC-1 Levels Versus Participants With Low ERCC-1 Levels

Secondary: Percentage of Participants With Complete Liver Metastasis Resection in Participants With High ERCC-1 Levels Versus Participants With Low ERCC-1 Levels

Secondary: PFS According to RECIST Version 1.1 in Participants With Wild-Type KRAS Versus Participants With Mutant KRAS

Secondary: PFS According to RECIST Version 1.1 in Participants With Wild-Type KRAS Versus Participants With Mutant KRAS

Secondary: OS in Participants With High VEGF-A Levels Versus Participants With Low VEGF-A Levels

Secondary: OS in Participants With High VEGF-A Levels Versus Participants With Low VEGF-A Levels

Secondary: OS in Participants With Wild-Type KRAS Versus Participants With Mutant KRAS

Secondary: OS in Participants With Wild-Type KRAS Versus Participants With Mutant KRAS

Secondary: Percentage of Participants With Objective Response According to RECIST Version 1.1 in Participants With High VEGF-A Levels Versus Participants With Low VEGF-A Levels

Secondary: Percentage of Participants With Objective Response According to RECIST Version 1.1 in Participants With High VEGF-A Levels Versus Participants With Low VEGF-A Levels

Secondary: Percentage of Participants With Objective Response According to RECIST Version 1.1 in Participants With Wild-Type KRAS Versus Participants With Mutant KRAS

Secondary: Percentage of Participants With Objective Response According to RECIST Version 1.1 in Participants With Wild-Type KRAS Versus Participants With Mutant KRAS

Secondary: Percentage of Participants With Disease Control According to RECIST Version 1.1 in Participants With High VEGF-A Levels Versus Participants With Low VEGF-A Levels

Secondary: Percentage of Participants With Disease Control According to RECIST Version 1.1 in Participants With High VEGF-A Levels Versus Participants With Low VEGF-A Levels

Clinical Trial Results:
MAVERICC (Marker Evaluation for Avastin Research in CRC): A Randomized Phase II Study of Bevacizumab+mFOLFOX6 Vs. Bevacizumab+FOLFIRI With Biomarker Stratification in Patients With Previously Untreated Metastatic Colorectal Cancer