Colorectal Cancer
Conditions
Brief summary
This will be 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 will consist of participants with first-line mCRC.
Interventions
DRUG5-Fluorouracil
5-Fluorouracil 400 milligrams per meter-squared (mg/m\^2) by IV bolus and subsequent 2400 mg/m\^2 by IV infusion over 46 hours will be administered every 2 weeks until disease progression or unacceptable toxicity.
DRUGBevacizumab
Bevacizumab 5 milligrams per kilogram (mg/kg) of body weight via IV infusion will be administered every 2 weeks until disease progression or unacceptable toxicity. If participants are discontinued from oxaliplatin or irinotecan due to unacceptable toxicity, bevacizumab may be given in 3-week cycles with capecitabine.
DRUGIrinotecan
Irinotecan 180 mg/m\^2 via IV infusion over 2 hours will be administered every 2 weeks until disease progression or unacceptable toxicity.
DRUGLeucovorin
Leucovorin 400 mg/m\^2 or dose deemed appropriate by Investigator via IV infusion over 2 hours will be administered every 2 weeks until disease progression or unacceptable toxicity.
DRUGOxaliplatin
Oxaliplatin 85 mg/m\^2 via IV infusion over 2 hours will be administered every 2 weeks until disease progression or unacceptable toxicity.
DRUGCapecitabine
Capecitabine 850 or 1000 mg/m\^2 may be offered in the event of unacceptable toxicity to oxaliplatin or irinotecan, to be given orally twice a day on Days 1 to 14 in 3-week cycles.
Sponsors
Genentech, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically or cytologically confirmed colorectal cancer (CRC) with at least one measurable metastatic lesion by RECIST Version 1.1 * Archival tumor tissue sample must be requested and available prior to study entry. If no archival tumor tissue sample is available, a fresh biopsy tissue sample must be obtained but should be discussed first with the medical monitor. A copy of the local pathology report must be submitted along with the specimens. * Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 * Participants with treated brain metastases are eligible for study participation. Participants may not receive ongoing treatment with steroids at Screening. Anticonvulsants (at stable dose) are allowed. Treatment for brain metastases may be whole-brain radiotherapy, radiosurgery, neurosurgery, or a combination as deemed appropriate by the treating physician. Radiotherapy and stereotactic radiosurgery must be completed at least 28 days prior to randomization. * Female participants should not be pregnant or breastfeeding. Female participants with childbearing potential should agree to use effective, non-hormonal means of contraception during the study and for a period of at least 6 months following the last administration of study drugs. Female participants with an intact uterus (unless amenorrheic for the last 24 months) must have a negative serum pregnancy test within 7 days prior to randomization into the study. * Male participants must agree to use effective contraception during the study and for a period of at least 6 months following the last administration of study drugs, even if they have been surgically sterilized.
Exclusion criteria
* Any prior systemic treatment for mCRC * Adjuvant chemotherapy for CRC completed \<12 months * Evidence of Gilbert's syndrome or of homozygosity for the UGT1A1\*28 allele * Known positivity for human immunodeficiency virus (HIV) * Malignancies other than mCRC within 5 years prior to randomization, except for adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer, localized prostate cancer treated surgically with curative intent, and ductal carcinoma in situ treated surgically with curative intent * Radiotherapy to any site for any reason within 28 days prior to randomization, except for palliative radiotherapy to bone lesions within 14 days prior to randomization * Clinically detectable third-space fluid collections that cannot be controlled by drainage or other procedures prior to study entry * Treatment with any other investigational agent, or participation in another investigational drug trial within 28 days prior to randomization
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 | From Baseline until death or disease progression; assessed every 6 weeks (maximum up to 45 months overall) | 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. |
| PFS According to RECIST Version 1.1 in Participants With High ERCC-1 Levels | From Baseline until death or disease progression; assessed every 6 weeks (maximum up to 45 months overall) | 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. |
| PFS According to RECIST Version 1.1 in Participants With Low ERCC-1 Levels | From Baseline until death or disease progression; assessed every 6 weeks (maximum up to 45 months overall) | 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. |
| PFS According to RECIST Version 1.1 in Participants With High ERCC-1 Levels Versus Participants With Low ERCC-1 Levels | From Baseline until death or disease progression; assessed every 6 weeks (maximum up to 45 months overall) | 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. |
| PFS According to RECIST Version 1.1 in Participants With High Vascular Endothelial Growth Factor (VEGF)-A Levels Versus Participants With Low VEGF-A Levels | From Baseline until death or disease progression; assessed every 6 weeks (maximum up to 45 months overall) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| OS in Participants With High ERCC-1 Levels | From Baseline until death (maximum up to 45 months overall) | 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. |
| OS in Participants With Low ERCC-1 Levels | From Baseline until death (maximum up to 45 months overall) | 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. |
| OS in Participants With High ERCC-1 Levels Versus Participants With Low ERCC-1 Levels | From Baseline until death (maximum up to 45 months overall) | 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. |
| Percentage of Participants With Objective Response According to RECIST Version 1.1 | From Baseline until disease progression; assessed every 6 weeks (maximum up to 45 months overall) | 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. |
| Percentage of Participants With Objective Response According to RECIST Version 1.1 in Participants With High ERCC-1 Levels | From Baseline until disease progression; assessed every 6 weeks (maximum up to 45 months overall) | 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. |
| Percentage of Participants With Objective Response According to RECIST Version 1.1 in Participants With Low ERCC-1 Levels | From Baseline until disease progression; assessed every 6 weeks (maximum up to 45 months overall) | 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. |
| 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 | From Baseline until disease progression; assessed every 6 weeks (maximum up to 45 months overall) | 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. |
| Percentage of Participants With Disease Control According to RECIST Version 1.1 | From Baseline until disease progression; assessed every 6 weeks (maximum up to 45 months overall) | 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. |
| Percentage of Participants With Disease Control According to RECIST Version 1.1 in Participants With High ERCC-1 Levels | From Baseline until disease progression; assessed every 6 weeks (maximum up to 45 months overall) | 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. |
| Percentage of Participants With Disease Control According to RECIST Version 1.1 in Participants With Low ERCC-1 Levels | From Baseline until disease progression; assessed every 6 weeks (maximum up to 45 months overall) | 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. |
| 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 | From Baseline until disease progression; assessed every 6 weeks (maximum up to 45 months overall) | 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. |
| Percentage of Participants With Liver Metastasis Resection | At time of resective surgery during study (maximum up to 45 months overall) | 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. |
| Percentage of Participants With Complete Liver Metastasis Resection | At time of resective surgery during study (maximum up to 45 months overall) | 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. |
| PFS According to RECIST Version 1.1 in Participants With High ERCC-1 and High VEGF-A Levels | From Baseline until death or disease progression; assessed every 6 weeks (maximum up to 45 months overall) | 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. |
| Percentage of Participants With Complete Liver Metastasis Resection in Participants With High ERCC-1 Levels | At time of resective surgery during study (maximum up to 45 months overall) | 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. |
| Percentage of Participants With Liver Metastasis Resection in Participants With Low ERCC-1 Levels | At time of resective surgery during study (maximum up to 45 months overall) | 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. |
| Percentage of Participants With Complete Liver Metastasis Resection in Participants With Low ERCC-1 Levels | At time of resective surgery during study (maximum up to 45 months overall) | 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. |
| Percentage of Participants With Liver Metastasis Resection in Participants With High ERCC-1 Levels Versus Participants With Low ERCC-1 Levels | At time of resective surgery during study (maximum up to 45 months overall) | 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. |
| Percentage of Participants With Complete Liver Metastasis Resection in Participants With High ERCC-1 Levels Versus Participants With Low ERCC-1 Levels | At time of resective surgery during study (maximum up to 45 months overall) | 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. |
| PFS According to RECIST Version 1.1 in Participants With Wild-Type V-Ki-ras2 Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) Versus Participants With Mutant KRAS | From Baseline until death or disease progression; assessed every 6 weeks (maximum up to 45 months overall) | 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. |
| OS in Participants With High VEGF-A Levels Versus Participants With Low VEGF-A Levels | From Baseline until death (maximum up to 45 months overall) | 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. |
| OS in Participants With Wild-Type KRAS Versus Participants With Mutant KRAS | From Baseline until death (maximum up to 45 months overall) | 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. |
| 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 | From Baseline until disease progression; assessed every 6 weeks (maximum up to 45 months overall) | 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. |
| Percentage of Participants With Objective Response According to RECIST Version 1.1 in Participants With Wild-Type KRAS Versus Participants With Mutant KRAS | From Baseline until disease progression; assessed every 6 weeks (maximum up to 45 months overall) | 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. |
| 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 | From Baseline until disease progression; assessed every 6 weeks (maximum up to 45 months overall) | 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. |
| Percentage of Participants With Liver Metastasis Resection in Participants With High VEGF-A Levels Versus Participants With Low VEGF-A Levels | At time of resective surgery during study (maximum up to 45 months overall) | 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. |
| Percentage of Participants With Complete Liver Metastasis Resection in Participants With High VEGF-A Levels Versus Participants With Low VEGF-A Levels | At time of resective surgery during study (maximum up to 45 months overall) | 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. |
| Percentage of Participants With Liver Metastasis Resection in Participants With High ERCC-1 Levels | At time of resective surgery during study (maximum up to 45 months overall) | 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. |
| PFS According to RECIST Version 1.1 in Participants With High ERCC-1 and Low VEGF-A Levels | From Baseline until death or disease progression; assessed every 6 weeks (maximum up to 45 months overall) | 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. |
| PFS According to RECIST Version 1.1 in Participants With Low ERCC-1 and High VEGF-A Levels | From Baseline until death or disease progression; assessed every 6 weeks (maximum up to 45 months overall) | 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. |
| PFS According to RECIST Version 1.1 in Participants With Low ERCC-1 and Low VEGF-A Levels | From Baseline until death or disease progression; assessed every 6 weeks (maximum up to 45 months overall) | 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. |
| Overall Survival (OS) | From Baseline until death (maximum up to 45 months overall) | 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. |
Countries
Canada, Estonia, Ireland, Norway, Portugal, Switzerland, United States
Participant flow
Pre-assignment 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.
Participants by arm
| Arm | Count |
|---|---|
| Bevacizumab + mFOLFOX6 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. | 188 |
| Bevacizumab + FOLFIRI 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. | 188 |
| Total | 376 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 29 | 18 |
| Overall Study | Clinical Disease Progression | 9 | 6 |
| Overall Study | Death (Adverse Event) | 2 | 4 |
| Overall Study | Death (Progression of Disease) | 1 | 0 |
| Overall Study | Lost to Follow-up | 2 | 1 |
| Overall Study | Other | 41 | 43 |
| Overall Study | Protocol Violation | 2 | 3 |
| Overall Study | Radiographic Disease Progression | 86 | 81 |
| Overall Study | Refused Treatment | 10 | 24 |
| Overall Study | Sponsor Decision | 0 | 1 |
| Overall Study | Withdrawal by Subject | 6 | 7 |
Baseline characteristics
| Characteristic | Bevacizumab + mFOLFOX6 | Bevacizumab + FOLFIRI | Total |
|---|---|---|---|
| Age, Continuous | 59.2 years STANDARD_DEVIATION 10.88 | 60.7 years STANDARD_DEVIATION 10.66 | 59.9 years STANDARD_DEVIATION 10.78 |
| Sex: Female, Male Female | 66 Participants | 71 Participants | 137 Participants |
| Sex: Female, Male Male | 122 Participants | 117 Participants | 239 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 185 / 185 | 181 / 183 |
| serious Total, serious adverse events | 79 / 185 | 87 / 183 |
Outcome results
Primary
PFS According to RECIST Version 1.1 in Participants With High ERCC-1 Levels
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.
Time frame: From Baseline until death or disease progression; assessed every 6 weeks (maximum up to 45 months overall)
Population: ITT Population. The Number of Participants Analyzed reflects the number of evaluable participants for the outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bevacizumab + mFOLFOX6 | PFS According to RECIST Version 1.1 in Participants With High ERCC-1 Levels | 9.92 months |
| Bevacizumab + FOLFIRI | PFS According to RECIST Version 1.1 in Participants With High ERCC-1 Levels | 11.17 months |
Comparison: Analysis stratified by region of enrollment.p-value: 0.394495% CI: [0.56, 1.26]Log Rank
Primary
PFS According to RECIST Version 1.1 in Participants With High ERCC-1 Levels Versus Participants With Low ERCC-1 Levels
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.
Time frame: From Baseline until death or disease progression; assessed every 6 weeks (maximum up to 45 months overall)
Population: ITT Population. The Number of Participants Analyzed reflects the number of evaluable participants for the outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bevacizumab + mFOLFOX6 | PFS According to RECIST Version 1.1 in Participants With High ERCC-1 Levels Versus Participants With Low ERCC-1 Levels | 10.87 months |
| Bevacizumab + FOLFIRI | PFS According to RECIST Version 1.1 in Participants With High ERCC-1 Levels Versus Participants With Low ERCC-1 Levels | 11.56 months |
Comparison: Analysis stratified by region of enrollment.p-value: 0.957695% CI: [0.77, 1.28]Log Rank
Primary
PFS According to RECIST Version 1.1 in Participants With High Vascular Endothelial Growth Factor (VEGF)-A Levels Versus Participants With Low VEGF-A Levels
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.
Time frame: From Baseline until death or disease progression; assessed every 6 weeks (maximum up to 45 months overall)
Population: ITT Population. The Number of Participants Analyzed reflects the number of evaluable participants for the outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bevacizumab + mFOLFOX6 | PFS According to RECIST Version 1.1 in Participants With High Vascular Endothelial Growth Factor (VEGF)-A Levels Versus Participants With Low VEGF-A Levels | 10.02 months |
| Bevacizumab + FOLFIRI | PFS According to RECIST Version 1.1 in Participants With High Vascular Endothelial Growth Factor (VEGF)-A Levels Versus Participants With Low VEGF-A Levels | 12.68 months |
Comparison: Analysis stratified by high/low ERCC-1 level and region of enrollment.p-value: 0.165895% CI: [0.93, 1.53]Log Rank
Primary
PFS According to RECIST Version 1.1 in Participants With Low ERCC-1 Levels
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.
Time frame: From Baseline until death or disease progression; assessed every 6 weeks (maximum up to 45 months overall)
Population: ITT Population. The Number of Participants Analyzed reflects the number of evaluable participants for the outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bevacizumab + mFOLFOX6 | PFS According to RECIST Version 1.1 in Participants With Low ERCC-1 Levels | 10.97 months |
| Bevacizumab + FOLFIRI | PFS According to RECIST Version 1.1 in Participants With Low ERCC-1 Levels | 12.68 months |
Comparison: Analysis stratified by region of enrollment.p-value: 0.078695% CI: [0.55, 1.03]Log Rank
Primary
Progression-Free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1
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.
Time frame: From Baseline until death or disease progression; assessed every 6 weeks (maximum up to 45 months overall)
Population: Intent-to-treat (ITT) Population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bevacizumab + mFOLFOX6 | Progression-Free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 | 10.09 months |
| Bevacizumab + FOLFIRI | Progression-Free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 | 12.55 months |
Comparison: Analysis stratified by high/low excision repair cross-complementing (ERCC)-1 level and region of enrollment.p-value: 0.055595% CI: [0.61, 1.01]Log Rank
Secondary
OS in Participants With High ERCC-1 Levels
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.
Time frame: From Baseline until death (maximum up to 45 months overall)
Population: ITT Population. The Number of Participants Analyzed reflects the number of evaluable participants for the outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bevacizumab + mFOLFOX6 | OS in Participants With High ERCC-1 Levels | 22.54 months |
| Bevacizumab + FOLFIRI | OS in Participants With High ERCC-1 Levels | 26.51 months |
Comparison: Analysis stratified by region of enrollment.p-value: 0.329595% CI: [0.51, 1.26]Log Rank
Secondary
OS in Participants With High ERCC-1 Levels Versus Participants With Low ERCC-1 Levels
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.
Time frame: From Baseline until death (maximum up to 45 months overall)
Population: ITT Population. The Number of Participants Analyzed reflects the number of evaluable participants for the outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bevacizumab + mFOLFOX6 | OS in Participants With High ERCC-1 Levels Versus Participants With Low ERCC-1 Levels | 23.23 months |
| Bevacizumab + FOLFIRI | OS in Participants With High ERCC-1 Levels Versus Participants With Low ERCC-1 Levels | 27.27 months |
Comparison: Analysis stratified by region of enrollment.p-value: 0.277495% CI: [0.87, 1.62]Log Rank
Secondary
OS in Participants With High VEGF-A Levels Versus Participants With Low VEGF-A Levels
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.
Time frame: From Baseline until death (maximum up to 45 months overall)
Population: ITT Population. The Number of Participants Analyzed reflects the number of evaluable participants for the outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bevacizumab + mFOLFOX6 | OS in Participants With High VEGF-A Levels Versus Participants With Low VEGF-A Levels | 22.83 months |
| Bevacizumab + FOLFIRI | OS in Participants With High VEGF-A Levels Versus Participants With Low VEGF-A Levels | 27.93 months |
Comparison: Analysis stratified by high/low ERCC-1 level and region of enrollment.p-value: 0.00295% CI: [1.2, 2.24]Log Rank
Secondary
OS in Participants With Low ERCC-1 Levels
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.
Time frame: From Baseline until death (maximum up to 45 months overall)
Population: ITT Population. The Number of Participants Analyzed reflects the number of evaluable participants for the outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bevacizumab + mFOLFOX6 | OS in Participants With Low ERCC-1 Levels | 25.53 months |
| Bevacizumab + FOLFIRI | OS in Participants With Low ERCC-1 Levels | 27.93 months |
Comparison: Analysis stratified by region of enrollment.p-value: 0.151995% CI: [0.49, 1.12]Log Rank
Secondary
OS in Participants With Wild-Type KRAS Versus Participants With Mutant KRAS
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.
Time frame: From Baseline until death (maximum up to 45 months overall)
Population: ITT Population. The Number of Participants Analyzed reflects the number of evaluable participants for the outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bevacizumab + mFOLFOX6 | OS in Participants With Wild-Type KRAS Versus Participants With Mutant KRAS | 28.75 months |
| Bevacizumab + FOLFIRI | OS in Participants With Wild-Type KRAS Versus Participants With Mutant KRAS | 24.64 months |
Comparison: Analysis stratified by high/low ERCC-1 level and region of enrollment.p-value: 0.095595% CI: [0.95, 1.88]Log Rank
Secondary
Overall Survival (OS)
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.
Time frame: From Baseline until death (maximum up to 45 months overall)
Population: ITT Population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bevacizumab + mFOLFOX6 | Overall Survival (OS) | 23.85 months |
| Bevacizumab + FOLFIRI | Overall Survival (OS) | 27.47 months |
Comparison: Analysis stratified by high/low ERCC-1 level and region of enrollment.p-value: 0.086195% CI: [0.56, 1.04]Log Rank
Secondary
Percentage of Participants With Complete Liver Metastasis Resection
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.
Time frame: At time of resective surgery during study (maximum up to 45 months overall)
Population: ITT Population; only those participants with liver or liver plus lymph node metastases were included in the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bevacizumab + mFOLFOX6 | Percentage of Participants With Complete Liver Metastasis Resection | 11.9 percentage of participants |
| Bevacizumab + FOLFIRI | Percentage of Participants With Complete Liver Metastasis Resection | 5.5 percentage of participants |
95% CI: [-16.3, 3.3]
Secondary
Percentage of Participants With Complete Liver Metastasis Resection in Participants With High ERCC-1 Levels
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.
Time frame: At time of resective surgery during study (maximum up to 45 months overall)
Population: ITT Population; only those participants with liver or liver plus lymph node metastases were included in the analysis. The Number of Participants Analyzed reflects the number of evaluable participants for the outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bevacizumab + mFOLFOX6 | Percentage of Participants With Complete Liver Metastasis Resection in Participants With High ERCC-1 Levels | 17.6 percentage of participants |
| Bevacizumab + FOLFIRI | Percentage of Participants With Complete Liver Metastasis Resection in Participants With High ERCC-1 Levels | 6.7 percentage of participants |
95% CI: [-33.1, 11.1]
Secondary
Percentage of Participants With Complete Liver Metastasis Resection in Participants With High ERCC-1 Levels Versus Participants With Low ERCC-1 Levels
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.
Time frame: At time of resective surgery during study (maximum up to 45 months overall)
Population: ITT Population; only those participants with liver or liver plus lymph node metastases were included in the analysis. The Number of Participants Analyzed reflects the number of evaluable participants for the outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bevacizumab + mFOLFOX6 | Percentage of Participants With Complete Liver Metastasis Resection in Participants With High ERCC-1 Levels Versus Participants With Low ERCC-1 Levels | 4.6 percentage of participants |
| Bevacizumab + FOLFIRI | Percentage of Participants With Complete Liver Metastasis Resection in Participants With High ERCC-1 Levels Versus Participants With Low ERCC-1 Levels | 6.1 percentage of participants |
95% CI: [-6.2, 3.1]
Secondary
Percentage of Participants With Complete Liver Metastasis Resection in Participants With High VEGF-A Levels Versus Participants With Low VEGF-A Levels
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.
Time frame: At time of resective surgery during study (maximum up to 45 months overall)
Population: ITT Population; only those participants with liver or liver plus lymph node metastases were included in the analysis. The Number of Participants Analyzed reflects the number of evaluable participants for the outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bevacizumab + mFOLFOX6 | Percentage of Participants With Complete Liver Metastasis Resection in Participants With High VEGF-A Levels Versus Participants With Low VEGF-A Levels | 3.2 percentage of participants |
| Bevacizumab + FOLFIRI | Percentage of Participants With Complete Liver Metastasis Resection in Participants With High VEGF-A Levels Versus Participants With Low VEGF-A Levels | 8.1 percentage of participants |
95% CI: [-9.6, -0.2]
Secondary
Percentage of Participants With Complete Liver Metastasis Resection in Participants With Low ERCC-1 Levels
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.
Time frame: At time of resective surgery during study (maximum up to 45 months overall)
Population: ITT Population; only those participants with liver or liver plus lymph node metastases were included in the analysis. The Number of Participants Analyzed reflects the number of evaluable participants for the outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bevacizumab + mFOLFOX6 | Percentage of Participants With Complete Liver Metastasis Resection in Participants With Low ERCC-1 Levels | 8.9 percentage of participants |
| Bevacizumab + FOLFIRI | Percentage of Participants With Complete Liver Metastasis Resection in Participants With Low ERCC-1 Levels | 3.3 percentage of participants |
95% CI: [-11.5, 0.4]
Secondary
Percentage of Participants With Disease Control According to RECIST Version 1.1
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.
Time frame: From Baseline until disease progression; assessed every 6 weeks (maximum up to 45 months overall)
Population: ITT Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bevacizumab + mFOLFOX6 | Percentage of Participants With Disease Control According to RECIST Version 1.1 | 93.1 percentage of participants |
| Bevacizumab + FOLFIRI | Percentage of Participants With Disease Control According to RECIST Version 1.1 | 91.0 percentage of participants |
95% CI: [-7.6, 3.3]
Secondary
Percentage of Participants With Disease Control According to RECIST Version 1.1 in Participants With High ERCC-1 Levels
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.
Time frame: From Baseline until disease progression; assessed every 6 weeks (maximum up to 45 months overall)
Population: ITT Population. The Number of Participants Analyzed reflects the number of evaluable participants for the outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bevacizumab + mFOLFOX6 | Percentage of Participants With Disease Control According to RECIST Version 1.1 in Participants With High ERCC-1 Levels | 93.8 percentage of participants |
| Bevacizumab + FOLFIRI | Percentage of Participants With Disease Control According to RECIST Version 1.1 in Participants With High ERCC-1 Levels | 85.1 percentage of participants |
95% CI: [-19.1, 1.7]
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
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.
Time frame: From Baseline until disease progression; assessed every 6 weeks (maximum up to 45 months overall)
Population: ITT Population. The Number of Participants Analyzed reflects the number of evaluable participants for the outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bevacizumab + mFOLFOX6 | 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 | 89.3 percentage of participants |
| Bevacizumab + FOLFIRI | 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 | 93.9 percentage of participants |
95% CI: [-10.6, 1.5]
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
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.
Time frame: From Baseline until disease progression; assessed every 6 weeks (maximum up to 45 months overall)
Population: ITT Population. The Number of Participants Analyzed reflects the number of evaluable participants for the outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bevacizumab + mFOLFOX6 | 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 | 91.9 percentage of participants |
| Bevacizumab + FOLFIRI | 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 | 93.0 percentage of participants |
95% CI: [-6.5, 4.3]
Secondary
Percentage of Participants With Disease Control According to RECIST Version 1.1 in Participants With Low ERCC-1 Levels
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.
Time frame: From Baseline until disease progression; assessed every 6 weeks (maximum up to 45 months overall)
Population: ITT Population. The Number of Participants Analyzed reflects the number of evaluable participants for the outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bevacizumab + mFOLFOX6 | Percentage of Participants With Disease Control According to RECIST Version 1.1 in Participants With Low ERCC-1 Levels | 92.7 percentage of participants |
| Bevacizumab + FOLFIRI | Percentage of Participants With Disease Control According to RECIST Version 1.1 in Participants With Low ERCC-1 Levels | 95.0 percentage of participants |
95% CI: [-3.7, 8.3]
Secondary
Percentage of Participants With Liver Metastasis Resection
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.
Time frame: At time of resective surgery during study (maximum up to 45 months overall)
Population: ITT Population; only those participants with liver or liver plus lymph node metastases were included in the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bevacizumab + mFOLFOX6 | Percentage of Participants With Liver Metastasis Resection | 14.9 percentage of participants |
| Bevacizumab + FOLFIRI | Percentage of Participants With Liver Metastasis Resection | 10.9 percentage of participants |
95% CI: [-15.9, 7.8]
Secondary
Percentage of Participants With Liver Metastasis Resection in Participants With High ERCC-1 Levels
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.
Time frame: At time of resective surgery during study (maximum up to 45 months overall)
Population: ITT Population; only those participants with liver or liver plus lymph node metastases were included in the analysis. The Number of Participants Analyzed reflects the number of evaluable participants for the outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bevacizumab + mFOLFOX6 | Percentage of Participants With Liver Metastasis Resection in Participants With High ERCC-1 Levels | 17.6 percentage of participants |
| Bevacizumab + FOLFIRI | Percentage of Participants With Liver Metastasis Resection in Participants With High ERCC-1 Levels | 6.7 percentage of participants |
95% CI: [-33.1, 11.1]
Secondary
Percentage of Participants With Liver Metastasis Resection in Participants With High ERCC-1 Levels Versus Participants With Low ERCC-1 Levels
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.
Time frame: At time of resective surgery during study (maximum up to 45 months overall)
Population: ITT Population; only those participants with liver or liver plus lymph node metastases were included in the analysis. The Number of Participants Analyzed reflects the number of evaluable participants for the outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bevacizumab + mFOLFOX6 | Percentage of Participants With Liver Metastasis Resection in Participants With High ERCC-1 Levels Versus Participants With Low ERCC-1 Levels | 4.6 percentage of participants |
| Bevacizumab + FOLFIRI | Percentage of Participants With Liver Metastasis Resection in Participants With High ERCC-1 Levels Versus Participants With Low ERCC-1 Levels | 9.0 percentage of participants |
95% CI: [-9.5, 0.6]
Secondary
Percentage of Participants With Liver Metastasis Resection in Participants With High VEGF-A Levels Versus Participants With Low VEGF-A Levels
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.
Time frame: At time of resective surgery during study (maximum up to 45 months overall)
Population: ITT Population; only those participants with liver or liver plus lymph node metastases were included in the analysis. The Number of Participants Analyzed reflects the number of evaluable participants for the outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bevacizumab + mFOLFOX6 | Percentage of Participants With Liver Metastasis Resection in Participants With High VEGF-A Levels Versus Participants With Low VEGF-A Levels | 5.9 percentage of participants |
| Bevacizumab + FOLFIRI | Percentage of Participants With Liver Metastasis Resection in Participants With High VEGF-A Levels Versus Participants With Low VEGF-A Levels | 9.2 percentage of participants |
95% CI: [-8.6, 2.1]
Secondary
Percentage of Participants With Liver Metastasis Resection in Participants With Low ERCC-1 Levels
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.
Time frame: At time of resective surgery during study (maximum up to 45 months overall)
Population: ITT Population; only those participants with liver or liver plus lymph node metastases were included in the analysis. The Number of Participants Analyzed reflects the number of evaluable participants for the outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bevacizumab + mFOLFOX6 | Percentage of Participants With Liver Metastasis Resection in Participants With Low ERCC-1 Levels | 10.5 percentage of participants |
| Bevacizumab + FOLFIRI | Percentage of Participants With Liver Metastasis Resection in Participants With Low ERCC-1 Levels | 7.5 percentage of participants |
95% CI: [-10.1, 4.2]
Secondary
Percentage of Participants With Objective Response According to RECIST Version 1.1
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.
Time frame: From Baseline until disease progression; assessed every 6 weeks (maximum up to 45 months overall)
Population: ITT Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bevacizumab + mFOLFOX6 | Percentage of Participants With Objective Response According to RECIST Version 1.1 | 61.2 percentage of participants |
| Bevacizumab + FOLFIRI | Percentage of Participants With Objective Response According to RECIST Version 1.1 | 65.4 percentage of participants |
95% CI: [-5.5, 14]
Secondary
Percentage of Participants With Objective Response According to RECIST Version 1.1 in Participants With High ERCC-1 Levels
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.
Time frame: From Baseline until disease progression; assessed every 6 weeks (maximum up to 45 months overall)
Population: ITT Population. The Number of Participants Analyzed reflects the number of evaluable participants for the outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bevacizumab + mFOLFOX6 | Percentage of Participants With Objective Response According to RECIST Version 1.1 in Participants With High ERCC-1 Levels | 56.3 percentage of participants |
| Bevacizumab + FOLFIRI | Percentage of Participants With Objective Response According to RECIST Version 1.1 in Participants With High ERCC-1 Levels | 65.7 percentage of participants |
95% CI: [7.2, 26.1]
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
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.
Time frame: From Baseline until disease progression; assessed every 6 weeks (maximum up to 45 months overall)
Population: ITT Population. The Number of Participants Analyzed reflects the number of evaluable participants for the outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bevacizumab + mFOLFOX6 | 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 | 61.1 percentage of participants |
| Bevacizumab + FOLFIRI | 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 | 64.8 percentage of participants |
95% CI: [-14, 6.6]
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
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.
Time frame: From Baseline until disease progression; assessed every 6 weeks (maximum up to 45 months overall)
Population: ITT Population. The Number of Participants Analyzed reflects the number of evaluable participants for the outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bevacizumab + mFOLFOX6 | 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 | 60.5 percentage of participants |
| Bevacizumab + FOLFIRI | 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 | 66.5 percentage of participants |
95% CI: [-15.7, 3.8]
Secondary
Percentage of Participants With Objective Response According to RECIST Version 1.1 in Participants With Low ERCC-1 Levels
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.
Time frame: From Baseline until disease progression; assessed every 6 weeks (maximum up to 45 months overall)
Population: ITT Population. The Number of Participants Analyzed reflects the number of evaluable participants for the outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bevacizumab + mFOLFOX6 | Percentage of Participants With Objective Response According to RECIST Version 1.1 in Participants With Low ERCC-1 Levels | 63.7 percentage of participants |
| Bevacizumab + FOLFIRI | Percentage of Participants With Objective Response According to RECIST Version 1.1 in Participants With Low ERCC-1 Levels | 65.8 percentage of participants |
95% CI: [-9.9, 14.1]
Secondary
Percentage of Participants With Objective Response According to RECIST Version 1.1 in Participants With Wild-Type KRAS Versus Participants With Mutant KRAS
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.
Time frame: From Baseline until disease progression; assessed every 6 weeks (maximum up to 45 months overall)
Population: ITT Population. The Number of Participants Analyzed reflects the number of evaluable participants for the outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bevacizumab + mFOLFOX6 | Percentage of Participants With Objective Response According to RECIST Version 1.1 in Participants With Wild-Type KRAS Versus Participants With Mutant KRAS | 66.3 percentage of participants |
| Bevacizumab + FOLFIRI | Percentage of Participants With Objective Response According to RECIST Version 1.1 in Participants With Wild-Type KRAS Versus Participants With Mutant KRAS | 60.9 percentage of participants |
95% CI: [-16, 5.2]
Secondary
PFS According to RECIST Version 1.1 in Participants With High ERCC-1 and High VEGF-A Levels
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.
Time frame: From Baseline until death or disease progression; assessed every 6 weeks (maximum up to 45 months overall)
Population: ITT Population. The Number of Participants Analyzed reflects the number of evaluable participants for the outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bevacizumab + mFOLFOX6 | PFS According to RECIST Version 1.1 in Participants With High ERCC-1 and High VEGF-A Levels | 8.80 months |
| Bevacizumab + FOLFIRI | PFS According to RECIST Version 1.1 in Participants With High ERCC-1 and High VEGF-A Levels | 11.17 months |
Comparison: Analysis stratified by region of enrollment.p-value: 0.301995% CI: [0.41, 1.32]Log Rank
Secondary
PFS According to RECIST Version 1.1 in Participants With High ERCC-1 and Low VEGF-A Levels
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.
Time frame: From Baseline until death or disease progression; assessed every 6 weeks (maximum up to 45 months overall)
Population: ITT Population. The Number of Participants Analyzed reflects the number of evaluable participants for the outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bevacizumab + mFOLFOX6 | PFS According to RECIST Version 1.1 in Participants With High ERCC-1 and Low VEGF-A Levels | 12.52 months |
| Bevacizumab + FOLFIRI | PFS According to RECIST Version 1.1 in Participants With High ERCC-1 and Low VEGF-A Levels | 12.68 months |
Comparison: Analysis stratified by region of enrollment.p-value: 0.603595% CI: [0.48, 1.53]Log Rank
Secondary
PFS According to RECIST Version 1.1 in Participants With Low ERCC-1 and High VEGF-A Levels
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.
Time frame: From Baseline until death or disease progression; assessed every 6 weeks (maximum up to 45 months overall)
Population: ITT Population. The Number of Participants Analyzed reflects the number of evaluable participants for the outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bevacizumab + mFOLFOX6 | PFS According to RECIST Version 1.1 in Participants With Low ERCC-1 and High VEGF-A Levels | 9.76 months |
| Bevacizumab + FOLFIRI | PFS According to RECIST Version 1.1 in Participants With Low ERCC-1 and High VEGF-A Levels | 11.07 months |
Comparison: Analysis stratified by region of enrollment.p-value: 0.403295% CI: [0.54, 1.28]Log Rank
Secondary
PFS According to RECIST Version 1.1 in Participants With Low ERCC-1 and Low VEGF-A Levels
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.
Time frame: From Baseline until death or disease progression; assessed every 6 weeks (maximum up to 45 months overall)
Population: ITT Population. The Number of Participants Analyzed reflects the number of evaluable participants for the outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bevacizumab + mFOLFOX6 | PFS According to RECIST Version 1.1 in Participants With Low ERCC-1 and Low VEGF-A Levels | 11.10 months |
| Bevacizumab + FOLFIRI | PFS According to RECIST Version 1.1 in Participants With Low ERCC-1 and Low VEGF-A Levels | 14.32 months |
Comparison: Analysis stratified by region of enrollment.p-value: 0.064795% CI: [0.41, 1.03]Log Rank
Secondary
PFS According to RECIST Version 1.1 in Participants With Wild-Type V-Ki-ras2 Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) Versus Participants With Mutant KRAS
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.
Time frame: From Baseline until death or disease progression; assessed every 6 weeks (maximum up to 45 months overall)
Population: ITT Population. The Number of Participants Analyzed reflects the number of evaluable participants for the outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bevacizumab + mFOLFOX6 | PFS According to RECIST Version 1.1 in Participants With Wild-Type V-Ki-ras2 Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) Versus Participants With Mutant KRAS | 12.45 months |
| Bevacizumab + FOLFIRI | PFS According to RECIST Version 1.1 in Participants With Wild-Type V-Ki-ras2 Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) Versus Participants With Mutant KRAS | 10.94 months |
Comparison: Analysis stratified by high/low ERCC-1 level and region of enrollment.p-value: 0.059395% CI: [0.99, 1.69]Log Rank