Metastatic Breast Cancer
Conditions
Brief summary
First-line treatment of patients with locally recurrent or metastatic, HER2-negative breast cancer who have not received prior chemotherapy for locally recurrent or metastatic disease.
Detailed description
Arm A: Bevacizumab 10 mg/kg intravenous (i.v.), days 1 and 15, every 4 weeks Paclitaxel 90 mg/m2, days 1, 8 and 15, every 4 weeks Arm B: Bevacizumab 15 mg/kg i.v., day 1, every 3 weeks Capecitabine 1000 mg/m² twice-daily, days 1-14, every 3 weeks In both arms treatment will be given until first disease progression (PD), unacceptable toxicity or withdrawal of patient consent. For patients who stop chemotherapy for any reason before PD (e.g. toxicity) the other treatment should be given as monotherapy until PD.
Interventions
BIOLOGICALBevacizumab and Paclitaxel
A: Bevacizumab 10 mg/kg i.v., days 1 and 15, every 4 weeks Paclitaxel 90 mg/m2, days 1, 8 and 15, every 4 weeks
BIOLOGICALBevacizumab and Capecitabine
B:Bevacizumab 15 mg/kg i.v., day 1, every 3 weeks Capecitabine twice-daily 1000 mg/m², day 1 to 14, every 3 weeks
Sponsors
Central European Cooperative Oncology Group
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
1. Written informed consent obtained prior to any study-specific procedure. 2. Age ≥18 years. 3. Able to comply with the protocol. 4. Histologically or cytologically confirmed, HER2-negative, adenocarcinoma of the breast with measurable or non-measurable locally recurrent or metastatic disease, who are candidates for chemotherapy. Locally recurrent disease must not be amenable to radiotherapy or resection with curative intent. 5. Eastern Cooperative Oncology Group (ECOG) performance Status (PS) of 0-2. 6. Life expectancy more than 12 weeks. 7. Prior (neo)adjuvant chemotherapy is allowed provided that the last dose of chemotherapy was more than 6 months prior to randomization. However, if (neo)adjuvant chemotherapy was: * Taxane-based, patients are eligible only if they received their last taxane more than 12 months prior to randomization. * Anthracycline-based, the maximum cumulative dose of prior anthracycline therapy must not exceed 360 mg/m2 for doxorubicin and 720 mg/m2 for epirubicin. 8. Prior adjuvant radiotherapy is allowed as part of the treatment of early breast cancer provided that last fraction of radiotherapy occurred at least 6 months prior to randomization. Radiotherapy administered solely for the relief of metastatic bone pain is allowed prior to study entry, providing that: * no more than 30% of marrow-bearing bone was irradiated * the last fraction of radiotherapy was administered ≥ 3 weeks prior to randomization. 9. Adequate left ventricular ejection function (LVEF) at baseline, defined as LVEF ≥ 50% by either echocardiogram or multigated acquisition scan (MUGA). 10. Adequate hematological function * Absolute neutrophil count (ANC) ≥ 1.5 x 109/L * Platelet count ≥ 100 x 109/L * Hemoglobin ≥ 9 g/dL (may be transfused to maintain or exceed this level). 11. Adequate liver function * Total bilirubin ≤ 1.25 x upper normal limit (ULN) * Aspartate Aminotransferase (AST), Alanine Aminotransferase (ALT) \< 2.5 x ULN in patients without liver metastases; \< 5.0 x ULN in patients with liver metastases. 12. Adequate renal function * Serum creatinine ≤ 1.25 x ULN or calculated creatinine clearance ≥ 50 mL/min. * Urine dipstick for proteinuria \< +2. Patients discovered to have ≥ +2 proteinuria on dipstick urinalysis at baseline should undergo a 24-hour urine collection and must demonstrate ≤ 1g of protein in 24 hours 13. The use of full-dose oral or parenteral anticoagulants is permitted as long as the patient has been on a stable level of anticoagulation for at least two weeks at the time of randomization * Patients on heparin treatment should have a baseline activated partial thromboplastin time (aPTT) between 1.5 - 2.5 times ULN or patients value before starting heparin treatment * Patients on low molecular weight heparins (LMWH) should receive daily dose of 1.5 - 2 mg/kg (of enoxaparin) or appropriate doses of the correspondent anticoagulant, according to package insert * Patients on coumarin derivatives should have an international normalized ratio (INR) between 2.0 and 3.0 assessed at baseline in two consecutive measurements 1-4 days apart * Patients not receiving anticoagulant medication must have an INR ≤ 1.5 and aPTT ≤ 1.5 times ULN within 7 days prior to randomization
Exclusion criteria
1. Previous chemotherapy for metastatic or locally recurrent breast cancer. 2. Concomitant hormonal therapy for locally recurrent or metastatic disease. Note: previous hormonal therapy is allowed for adjuvant, locally recurrent or metastatic breast cancer, but must have been discontinued at least 3 weeks prior to randomization. 3. Previous radiotherapy for the treatment of metastatic disease (unless given for the relief of metastatic bone pain and with the precautions mentioned above). 4. Other primary tumors within the last 5 years, except for adequately controlled limited basal cell carcinoma of the skin, or carcinoma in situ of the cervix. 5. Pre-existing peripheral neuropathy NCI CTCAE grade \> 2 at randomization. 6. Evidence of spinal cord compression or current evidence of central nervous system (CNS) metastases (even if previously treated). If suspected, the patient should be scanned by CT or magnetic resonance imaging (MRI) within 28 days prior to randomization to rule out spinal / CNS metastases. 7. History or evidence upon physical/neurological examination of CNS disease unrelated to cancer, unless adequately treated with standard medical therapy (e.g. uncontrolled seizures). 8. Major surgical procedure, open biopsy or significant traumatic injury within 28 days prior to randomization, or anticipation of the need for major surgery during the course of the study treatment. 9. Minor surgical procedures, including insertion of an indwelling catheter, within 24 hours prior to randomization. 10. Current or recent (within 10 days of first dose of bevacizumab) use of aspirin (\> 325 mg/day) or clopidogrel (\> 75 mg/day). 11. Chronic daily treatment with corticosteroids (dose of \> 10 mg/day methylprednisolone equivalent) (excluding inhaled steroids). 12. History or evidence of inherited bleeding diathesis or coagulopathy with the risk of bleeding. 13. Uncontrolled hypertension (systolic \> 150 mmHg and/or diastolic \> 100 mmHg). 14. Clinically significant (i.e. active) cardiovascular disease, requiring medication during the study and might interfere with regularity of the study treatment, or not controlled by medication. 15. Non-healing wound, active peptic ulcer or bone fracture. 16. History of abdominal fistula, or any grade 4 non-gastrointestinal fistula, gastrointestinal perforation or intra-abdominal abscess within 6 months of randomization. 17. Active infection requiring i.v. antibiotics at randomization. 18. Pregnant or lactating females. Serum pregnancy test to be assessed within 7 days prior to study treatment start, or within 14 days with a confirmatory urine pregnancy test within 7 days prior to study treatment start. 19. Women of childbearing potential (\< 2 years after the last menstruation) not using effective, non-hormonal means of contraception (intrauterine contraceptive device, barrier method of contraception in conjunction with spermicidal jelly or surgically sterile) during the study and for a period of 6 months following the last administration of study drug. 20. Men who do not agree to use effective contraception during the study and for a period of 6 months following the last administration of study drug. 21. Current or recent (within 28 days of randomization) treatment with another investigational drug or participation in another investigational study 22. Clinically significant malabsorption syndrome or inability to take oral medication. 23. Psychiatric disability judged by the Investigator to be interfering with compliance for oral drug intake. 24. Requirement for concurrent use of the antiviral agent sorivudine or chemically related analogues, such as brivudine. 25. Evidence of any other disease, metabolic or psychological dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug, or that may affect patient compliance with study routines, or places the patient at high risk from treatment related complications. 26. Known Dihydropyrimidine Dehydrogenase (DPD) deficiency or prior unanticipated severe reaction to fluoropyrimidine therapy (with or without documented DPD deficiency) 27. Known hypersensitivity to any of the study drugs (including 5-FU) or excipients. Hypersensitivity to Chinese hamster ovary cell products or other recombinant human or humanized antibodies. History of hypersensitivity reactions with drugs formulated in Cremophor® EL (polyoxyethylated castor oil), or previous therapy with bevacizumab.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (PP Population) | Time from the date of randomization to the date of death or date last known to be alive, assessed up to approximately 6 years | Overall survival (OS) defined as time from randomization to date of death from any cause. Patients without recorded death were censored at the date the patient was last known to be alive. OS was analyzed at two looks, one interim look and the final analysis. Due to group sequential testing, the overall significance level alpha = 0.025 was spent on both looks according to Lan-DeMets spending method with O'Brien-Fleming-type boundaries. Alpha spent at Interim after 47% of information was 0.0010. Alpha spent at final analysis after 99% of information was 0.0250. |
| Overall Survival (ITT Population) | Time from the date of randomization to the date of death or date last known to be alive, assessed up to approximately 6 years | Overall survival (OS) defined as time from randomization to date of death from any cause. Patients without recorded death were censored at the date the patient was last known to be alive. OS was analyzed at two looks, one interim look and the final analysis. Due to group sequential testing, the overall significance level alpha = 0.025 was spent on both looks according to Lan-DeMets spending method with O'Brien-Fleming-type boundaries. Alpha spent at Interim after 50% of information was 0.0014. Alpha spent at final analysis after 99% of information was 0.0250. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Best Overall Response (PP Population) | Up to disease progression or up to 28 days after last intake of study medication, assessed up to approximately 5 years. | The best overall response according to the RECIST criteria is the best response recorded from the start of the treatment until disease progression/recurrence or within 28 days of last intake of study medication in the Study Treatment Phase |
| Unconfirmed Best Overall Response (ITT Population) | Up to disease progression or up to 28 days after last intake of study medication, assessed up to approximately 5 years. | The best overall response according to the RECIST criteria is the best response recorded from the start of the treatment until disease progression/recurrence or within 28 days of last intake of study medication in the Study Treatment Phase. Complete and partial response in this summary did not require a confirmation by a second tumor assessment. |
| Unconfirmed Best Overall Response (PP Population) | Up to disease progression or up to 28 days after last intake of study medication, assessed up to approximately 5 years. | The best overall response according to the RECIST criteria is the best response recorded from the start of the treatment until disease progression/recurrence or within 28 days of last intake of study medication in the Study Treatment Phase. Complete and partial response in this summary did not require a confirmation by a second tumor assessment. |
| Objective Response Rate and Disease Control Rate (ITT Population) | Up to disease progression or up to 28 days after last intake of study medication, assessed up to approximately 5 years. | Objective response rate (ORR) is defined as the proportion of patients with complete response or partial response. Disease control rate (DCR) is defined as the proportion of patients with complete response, partial response and stable disease. The best overall response according to the RECIST criteria is the best response recorded from the start of the treatment until disease progression/recurrence or within 28 days of last intake of study medication in the Study Treatment Phase |
| Objective Response Rate and Disease Control Rate (PP Population) | Up to disease progression or up to 28 days after last intake of study medication, assessed up to approximately 5 years. | Objective response rate (ORR) is defined as the proportion of patients with complete response or partial response. Disease control rate (DCR) is defined as the proportion of patients with complete response, partial response and stable disease. The best overall response according to the RECIST criteria is the best response recorded from the start of the treatment until disease progression/recurrence or within 28 days of last intake of study medication in the Study Treatment Phase |
| Unconfirmed Objective Response Rate and Disease Control Rate (ITT Population) | Up to disease progression or up to 28 days after last intake of study medication, assessed up to approximately 5 years. | Objective response rate (ORR) is defined as the proportion of patients with complete response or partial response. Disease control rate (DCR) is defined as the proportion of patients with complete response, partial response and stable disease. The best overall response according to the RECIST criteria is the best response recorded from the start of the treatment until disease progression/recurrence or within 28 days of last intake of study medication in the Study Treatment Phase. Complete and partial response in this summary did not require a confirmation by a second tumor assessment. |
| Unconfirmed Objective Response Rate and Disease Control Rate (PP Population) | Up to disease progression or up to 28 days after last intake of study medication, assessed up to approximately 5 years. | Objective response rate (ORR) is defined as the proportion of patients with complete response or partial response. Disease control rate (DCR) is defined as the proportion of patients with complete response, partial response and stable disease. The best overall response according to the RECIST criteria is the best response recorded from the start of the treatment until disease progression/recurrence or within 28 days of last intake of study medication in the Study Treatment Phase. Complete and partial response in this summary did not require a confirmation by a second tumor assessment |
| Observation Time (ITT Population) | Up to approximately 6 years | Median observation time estimated with reverse Kaplan-Meier methods. Observation time (in months) is defined as time from randomization to the day the patient was last confirmed to be alive. In case of patient deaths the time was censored at the day of death. |
| Progression Free Survival (PP Population) | Time from the date of randomization to disease progression, death or censoring (whichever occurred first), assessed up to approximately 5 years. | Progression Free Survival (PFS) is defined as time from randomization to date of documented progression or date of death due to any cause, whichever occurred first. Patients without recorded progression or death were censored at the last date they were known to have not progressed. Patients who were randomized and had no post-baseline tumor assessment were censored on the day of randomization. Median PFS, associated stratified Hazard Ratio (HR). |
| Time to Treatment Failure (ITT Population) | From first drug intake to progression, death or withdrawal from study treatment or study closure (whichever occurred first), assessed up to approximately 4.5 years | Time to treatment failure (TTF) was defined as time from first drug intake to progression, death or withdrawal from study treatment, whichever occurred first. Patients without an event were censored at the date of the last tumor assessment or last treatment administration, whichever occurred last. Median TTF, associated stratified Hazard Ratio (HR). |
| Time to Treatment Failure (PP Population) | From first drug intake to progression, death or withdrawal from study treatment or study closure (whichever occurred first), assessed up to approximately 4.5 years | Time to treatment failure (TTF) was defined as time from first drug intake to progression, death or withdrawal from study treatment, whichever occurred first. Patients without an event were censored at the date of the last tumor assessment or last treatment administration, whichever occurred last. Median TTF, associated stratified Hazard Ratio (HR). |
| Time to Response (ITT Population) | Time from randomization until occurrence of response, assessed up 1.7 years | Time to response (TR) was defined as time from randomization until occurrence of response (complete response (CR) or partial response (PR)) according to RECIST criteria. Patients without response were censored after the longest time to response observed in any patient. Median TR, associated stratified Hazard Ratio (HR). Since the median TR was not observed, the number of subjects with a response at given timepoints were reported. |
| Time to Response (PP Population) | Time from randomization until occurrence of response, assessed up 1.7 years | Time to response (TR) was defined as time from randomization until occurrence of response (complete response (CR) or partial response (PR)) according to RECIST criteria. Patients without response were censored after the longest time to response observed in any patient. Median TR, associated stratified Hazard Ratio (HR). Since the median TR was not observed, the number of subjects with a response at given timepoints were reported. |
| Duration of Response (ITT Population) | Time from first occurrence of CR or PR until disease progression, death or study closure, whichever occurred first, assessed up to 3.4 years after occurrence of response. | Duration of response (DR) was defined as time from date of first occurrence of any response (complete response (CR) or partial response (PR)) until the occurrence of progression of disease or death. Patients with response who neither progressed nor died were censored at the date of their last tumor assessment. Median DR, associated stratified Hazard Ratio (HR). |
| Duration of Response (PP Population) | Time from first occurrence of CR or PR until disease progression, death or study closure, whichever occurred first, assessed up to 3.4 years after occurrence of response. | Duration of response (DR) was defined as time from date of first occurrence of any response (complete response (CR) or partial response (PR)) until the occurrence of progression of disease or death. Patients with response who neither progressed nor died were censored at the date of their last tumor assessment. Median DR, associated stratified Hazard Ratio (HR). |
| Progression Free Survival (ITT Population) | Time from the date of randomization to disease progression, death or censoring (whichever occurred first), assessed up to approximately 5 years. | Progression Free Survival (PFS) is defined as time from randomization to date of documented progression or date of death due to any cause, whichever occurred first. Patients without recorded progression or death were censored at the last date they were known to have not progressed. Patients who were randomized and had no post-baseline tumor assessment were censored on the day of randomization. Median PFS, associated stratified Hazard Ratio (HR). |
| Best Overall Response (ITT Population) | Up to disease progression or up to 28 days after last intake of study medication, assessed up to approximately 5 years. | The best overall response according to the RECIST criteria is the best response recorded from the start of the treatment until disease progression/recurrence or within 28 days of last intake of study medication in the Study Treatment Phase |
Countries
Austria, Bosnia and Herzegovina, Bulgaria, Croatia, Czechia, Hungary, Israel, Latvia, Poland, Romania, Serbia, Slovakia
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Bevacizumab Plus Paclitaxel Bevacizumab 10 mg/kg i.v., days 1 and 15, every 4 weeks, Paclitaxel 90 mg/m2, days 1, 8 and 15, every 4 weeks | 285 |
| Bevacizumab Plus Capecitabine Bevacizumab 15 mg/kg i.v., day 1, every 3 weeks, Capecitabine twice-daily 1000 mg/m², day 1 to 14, every 3 weeks | 279 |
| Total | 564 |
Baseline characteristics
| Characteristic | Bevacizumab Plus Paclitaxel | Bevacizumab Plus Capecitabine | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 67 Participants | 78 Participants | 145 Participants |
| Age, Categorical Between 18 and 65 years | 218 Participants | 201 Participants | 419 Participants |
| Age, Continuous | 59 years | 59 years | 56.6 years STANDARD_DEVIATION 11.32 |
| Body Surface Area (BSA) | 1.76 m² STANDARD_DEVIATION 0.1834 | 1.773 m² STANDARD_DEVIATION 0.1688 | 1.767 m² STANDARD_DEVIATION 0.1763 |
| Body temperature | 36.55 °C STANDARD_DEVIATION 0.265 | 36.47 °C STANDARD_DEVIATION 0.305 | 36.51 °C STANDARD_DEVIATION 0.288 |
| Current stage of locally recurrent/ metastatic tumor Locally recurrent breast cancer | 2 Participants | 0 Participants | 2 Participants |
| Current stage of locally recurrent/ metastatic tumor Metastatic breast cancer | 282 Participants | 279 Participants | 561 Participants |
| Current stage of locally recurrent/ metastatic tumor Missing | 1 Participants | 0 Participants | 1 Participants |
| Diastolic blood pressure | 78.1 mmHg STANDARD_DEVIATION 8.23 | 77.9 mmHg STANDARD_DEVIATION 9.34 | 78.0 mmHg STANDARD_DEVIATION 8.79 |
| Disease free interval DFI >12 and <=24 months | 52 Participants | 34 Participants | 86 Participants |
| Disease free interval DFI <=12 months | 14 Participants | 10 Participants | 24 Participants |
| Disease free interval DFI >24 months | 148 Participants | 171 Participants | 319 Participants |
| Disease free interval No DFI | 71 Participants | 64 Participants | 135 Participants |
| Disease free interval | 43.6 months STANDARD_DEVIATION 48.84 | 48.0 months STANDARD_DEVIATION 48.53 | 45.8 months STANDARD_DEVIATION 48.7 |
| Disease free interval after therapy of primary breast cancer No | 71 Participants | 64 Participants | 135 Participants |
| Disease free interval after therapy of primary breast cancer Yes | 214 Participants | 215 Participants | 429 Participants |
| Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0 | 193 Participants | 179 Participants | 372 Participants |
| Eastern Cooperative Oncology Group Performance Status (ECOG PS) 1 | 75 Participants | 91 Participants | 166 Participants |
| Eastern Cooperative Oncology Group Performance Status (ECOG PS) 2 | 16 Participants | 7 Participants | 23 Participants |
| Eastern Cooperative Oncology Group Performance Status (ECOG PS) Missing | 1 Participants | 2 Participants | 3 Participants |
| Electrocardiogram (ECG) result Abnormal | 39 Participants | 30 Participants | 69 Participants |
| Electrocardiogram (ECG) result Normal | 243 Participants | 246 Participants | 489 Participants |
| Electrocardiogram (ECG) result Not performed | 3 Participants | 3 Participants | 6 Participants |
| Estrogen and progesterone receptor ER and PgR negative | 63 Participants | 67 Participants | 130 Participants |
| Estrogen and progesterone receptor ER and PR unknown or negative | 1 Participants | 0 Participants | 1 Participants |
| Estrogen and progesterone receptor ER or PgR positive | 221 Participants | 212 Participants | 433 Participants |
| Estrogen receptor (ER) Negative | 68 Participants | 77 Participants | 145 Participants |
| Estrogen receptor (ER) Positive | 215 Participants | 201 Participants | 416 Participants |
| Estrogen receptor (ER) Unknown | 2 Participants | 1 Participants | 3 Participants |
| Heart rate | 79.7 bpm STANDARD_DEVIATION 11.27 | 79.1 bpm STANDARD_DEVIATION 11.41 | 79.4 bpm STANDARD_DEVIATION 11.33 |
| Height | 162 cm STANDARD_DEVIATION 6.6 | 162.3 cm STANDARD_DEVIATION 6.48 | 162.2 cm STANDARD_DEVIATION 6.54 |
| Hormonal therapy for LR/MBC only Anti-estrogens | 18 Participants | 29 Participants | 47 Participants |
| Hormonal therapy for LR/MBC only Aromatase inhibitors | 17 Participants | 23 Participants | 40 Participants |
| Hormonal therapy for LR/MBC only LH-RH analogues | 1 Participants | 4 Participants | 5 Participants |
| Imaging methods CT | 270 Participants | 261 Participants | 531 Participants |
| Imaging methods MRI | 8 Participants | 12 Participants | 20 Participants |
| Imaging methods X-ray | 7 Participants | 6 Participants | 13 Participants |
| Left Ventricular Ejection Fraction (LVEF) | 63.4 percentage of ejected blood STANDARD_DEVIATION 5.32 | 62.6 percentage of ejected blood STANDARD_DEVIATION 6.26 | 63.0 percentage of ejected blood STANDARD_DEVIATION 5.81 |
| Menopausal status Male patients | 1 Participants | 4 Participants | 5 Participants |
| Menopausal status Post-menopausal | 232 Participants | 223 Participants | 455 Participants |
| Menopausal status Pre-menopausal | 52 Participants | 52 Participants | 104 Participants |
| Metastatic lesions At least one metastatic lesion | 282 Participants | 279 Participants | 561 Participants |
| Metastatic lesions Bone | 158 Participants | 151 Participants | 309 Participants |
| Metastatic lesions Liver | 113 Participants | 126 Participants | 239 Participants |
| Metastatic lesions Lung | 112 Participants | 122 Participants | 234 Participants |
| Metastatic lesions Lung and / or liver | 185 Participants | 203 Participants | 388 Participants |
| Metastatic lesions Lymph nodes | 146 Participants | 171 Participants | 317 Participants |
| Metastatic lesions Other | 19 Participants | 25 Participants | 44 Participants |
| Metastatic lesions Skin | 13 Participants | 9 Participants | 22 Participants |
| Metastatic lesions Soft tissue | 69 Participants | 63 Participants | 132 Participants |
| Metastatic lesions Soft tissue and/or bone only | 41 Participants | 23 Participants | 64 Participants |
| Method for brain imaging CT | 18 Participants | 19 Participants | 37 Participants |
| Method for brain imaging MRI | 3 Participants | 2 Participants | 5 Participants |
| Method for brain imaging No brain CT/MRI | 264 Participants | 258 Participants | 522 Participants |
| Neoadjuvant/ adjuvant hormonal therapy only Anti-estrogens | 87 Participants | 89 Participants | 176 Participants |
| Neoadjuvant/ adjuvant hormonal therapy only Aromatase inhibitors | 56 Participants | 56 Participants | 112 Participants |
| Neoadjuvant/ adjuvant hormonal therapy only LR-RH analogues | 12 Participants | 15 Participants | 27 Participants |
| Neoadjuvant/ adjuvant hormonal therapy only Other | 0 Participants | 1 Participants | 1 Participants |
| Neoadjuvant/ adjuvant hormonal therapy only Progesterone | 0 Participants | 1 Participants | 1 Participants |
| Number of organs with metastases < 3 | 180 Participants | 155 Participants | 335 Participants |
| Number of organs with metastases >= 3 | 105 Participants | 124 Participants | 229 Participants |
| Number of target lesions 0 lesions | 66 Participants | 49 Participants | 115 Participants |
| Number of target lesions 1 lesions | 48 Participants | 49 Participants | 97 Participants |
| Number of target lesions 2 lesions | 41 Participants | 49 Participants | 90 Participants |
| Number of target lesions 3 lesions | 47 Participants | 39 Participants | 86 Participants |
| Number of target lesions 4-5 lesions | 44 Participants | 57 Participants | 101 Participants |
| Number of target lesions >= 6 lesions | 39 Participants | 36 Participants | 75 Participants |
| Number of target lesions | 2.7 number of lesions STANDARD_DEVIATION 2.52 | 2.8 number of lesions STANDARD_DEVIATION 2.42 | 2.7 number of lesions STANDARD_DEVIATION 2.47 |
| Previous adjuvant chemotherapy Anthracycline and taxane | 21 Participants | 25 Participants | 46 Participants |
| Previous adjuvant chemotherapy Anthracycline, no taxane | 83 Participants | 89 Participants | 172 Participants |
| Previous adjuvant chemotherapy No anthracycline, no taxane, other | 30 Participants | 25 Participants | 55 Participants |
| Previous adjuvant chemotherapy None | 135 Participants | 128 Participants | 263 Participants |
| Previous adjuvant chemotherapy Taxane, no anthracycline | 16 Participants | 12 Participants | 28 Participants |
| Previous hormonal therapy Both | 37 Participants | 25 Participants | 62 Participants |
| Previous hormonal therapy LR/MBC only | 25 Participants | 33 Participants | 58 Participants |
| Previous hormonal therapy Neoadjuvant/adjuvant only | 113 Participants | 112 Participants | 225 Participants |
| Previous hormonal therapy None | 110 Participants | 108 Participants | 218 Participants |
| Previous hormonal therapy Other | 0 Participants | 1 Participants | 1 Participants |
| Previous neoadjuvant/adjuvant chemotherapy Anthracycline and taxane | 37 Participants | 35 Participants | 72 Participants |
| Previous neoadjuvant/adjuvant chemotherapy Anthracycline, no taxane | 110 Participants | 112 Participants | 222 Participants |
| Previous neoadjuvant/adjuvant chemotherapy No anthracycline, no taxane, other | 32 Participants | 28 Participants | 60 Participants |
| Previous neoadjuvant/adjuvant chemotherapy None | 105 Participants | 103 Participants | 208 Participants |
| Previous neoadjuvant/adjuvant chemotherapy Taxane, no anthracycline | 21 Participants | 16 Participants | 37 Participants |
| Previous neoadjuvant/adjuvant chemotherapy medications Anthracycline | 145 Participants | 144 Participants | 289 Participants |
| Previous neoadjuvant/adjuvant chemotherapy medications No anthracycline, no taxane, other | 26 Participants | 26 Participants | 52 Participants |
| Previous neoadjuvant/adjuvant chemotherapy medications None | 105 Participants | 103 Participants | 208 Participants |
| Previous neoadjuvant/adjuvant chemotherapy medications Taxane | 57 Participants | 50 Participants | 107 Participants |
| Previous neoadjuvant chemotherapy Anthracycline and taxane | 16 Participants | 11 Participants | 27 Participants |
| Previous neoadjuvant chemotherapy Anthracycline, no taxane | 41 Participants | 33 Participants | 74 Participants |
| Previous neoadjuvant chemotherapy No anthracycline, no taxane, other | 2 Participants | 3 Participants | 5 Participants |
| Previous neoadjuvant chemotherapy None | 221 Participants | 227 Participants | 448 Participants |
| Previous neoadjuvant chemotherapy Taxane, no anthracycline | 5 Participants | 5 Participants | 10 Participants |
| Previous radiotherapy Adjuvant | 167 Participants | 171 Participants | 338 Participants |
| Previous radiotherapy For relief of metastatic bone pain | 32 Participants | 44 Participants | 76 Participants |
| Previous radiotherapy Neoadjuvant | 8 Participants | 9 Participants | 17 Participants |
| Previous surgery Biopsy/Aspiration | 54 Participants | 48 Participants | 102 Participants |
| Previous surgery Breast conserving surgery | 111 Participants | 99 Participants | 210 Participants |
| Previous surgery Other | 35 Participants | 29 Participants | 64 Participants |
| Previous surgery Total mastectomy | 131 Participants | 135 Participants | 266 Participants |
| Progesterone Receptor (PgR) Negative | 118 Participants | 109 Participants | 227 Participants |
| Progesterone Receptor (PgR) Positive | 167 Participants | 168 Participants | 335 Participants |
| Progesterone Receptor (PgR) Unknown | 0 Participants | 2 Participants | 2 Participants |
| Race/Ethnicity, Customized Black | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Caucasian/ White | 283 Participants | 278 Participants | 561 Participants |
| Race/Ethnicity, Customized Other | 1 Participants | 1 Participants | 2 Participants |
| Region of Enrollment Austria | 38 participants | 37 participants | 75 participants |
| Region of Enrollment Bosnia and Herzegovina | 13 participants | 13 participants | 26 participants |
| Region of Enrollment Bulgaria | 7 participants | 6 participants | 13 participants |
| Region of Enrollment Croatia | 7 participants | 5 participants | 12 participants |
| Region of Enrollment Czechia | 18 participants | 19 participants | 37 participants |
| Region of Enrollment Hungary | 82 participants | 80 participants | 162 participants |
| Region of Enrollment Israel | 54 participants | 51 participants | 105 participants |
| Region of Enrollment Latvia | 15 participants | 12 participants | 27 participants |
| Region of Enrollment Poland | 19 participants | 17 participants | 36 participants |
| Region of Enrollment Romania | 20 participants | 22 participants | 42 participants |
| Region of Enrollment Serbia | 6 participants | 8 participants | 14 participants |
| Region of Enrollment Slovakia | 6 participants | 9 participants | 15 participants |
| Result of brain CT/MRI No brain CT/MRI | 264 Participants | 258 Participants | 522 Participants |
| Result of brain CT/MRI No metastasis | 21 Participants | 21 Participants | 42 Participants |
| Sex: Female, Male Female | 284 Participants | 275 Participants | 559 Participants |
| Sex: Female, Male Male | 1 Participants | 4 Participants | 5 Participants |
| Stage at primary diagnosis: Distant metastasis (M) M0 | 222 Participants | 219 Participants | 441 Participants |
| Stage at primary diagnosis: Distant metastasis (M) M1 | 62 Participants | 59 Participants | 121 Participants |
| Stage at primary diagnosis: Distant metastasis (M) Missing | 1 Participants | 1 Participants | 2 Participants |
| Stage at primary diagnosis: Primary tumor (T) Missing | 1 Participants | 1 Participants | 2 Participants |
| Stage at primary diagnosis: Primary tumor (T) T1 | 66 Participants | 72 Participants | 138 Participants |
| Stage at primary diagnosis: Primary tumor (T) T2 | 130 Participants | 118 Participants | 248 Participants |
| Stage at primary diagnosis: Primary tumor (T) T3 | 26 Participants | 32 Participants | 58 Participants |
| Stage at primary diagnosis: Primary tumor (T) T4 | 45 Participants | 38 Participants | 83 Participants |
| Stage at primary diagnosis: Primary tumor (T) Tis | 1 Participants | 2 Participants | 3 Participants |
| Stage at primary diagnosis: Primary tumor (T) TX | 16 Participants | 16 Participants | 32 Participants |
| Stage at primary diagnosis: Regional lymph nodes (N) Missing | 1 Participants | 1 Participants | 2 Participants |
| Stage at primary diagnosis: Regional lymph nodes (N) N0 | 78 Participants | 62 Participants | 140 Participants |
| Stage at primary diagnosis: Regional lymph nodes (N) N1 | 97 Participants | 116 Participants | 213 Participants |
| Stage at primary diagnosis: Regional lymph nodes (N) N2 | 55 Participants | 51 Participants | 106 Participants |
| Stage at primary diagnosis: Regional lymph nodes (N) N3 | 26 Participants | 22 Participants | 48 Participants |
| Stage at primary diagnosis: Regional lymph nodes (N) NX | 28 Participants | 27 Participants | 55 Participants |
| Sum of longest diameter of target lesion >10 cm | 69 Participants | 70 Participants | 139 Participants |
| Sum of longest diameter of target lesion 1-5 cm | 86 Participants | 83 Participants | 169 Participants |
| Sum of longest diameter of target lesion >5-10 cm | 64 Participants | 77 Participants | 141 Participants |
| Sum of longest diameter of target lesion No lesions | 66 Participants | 49 Participants | 115 Participants |
| Sum of longest diameter of target lesions | 6.758 cm STANDARD_DEVIATION 7.4372 | 6.872 cm STANDARD_DEVIATION 6.6679 | 6.815 cm STANDARD_DEVIATION 7.061 |
| Systolic blood pressure | 127.9 mmHg STANDARD_DEVIATION 12.91 | 128.7 mmHg STANDARD_DEVIATION 13.85 | 128.3 mmHg STANDARD_DEVIATION 13.38 |
| Target and non-target lesions Both | 185 Participants | 208 Participants | 393 Participants |
| Target and non-target lesions None | 1 Participants | 0 Participants | 1 Participants |
| Target and non-target lesions Non-target lesions only | 65 Participants | 49 Participants | 114 Participants |
| Target and non-target lesions Target lesions only | 34 Participants | 22 Participants | 56 Participants |
| Time since diagnosis of adenocarcinoma | 55.2 months STANDARD_DEVIATION 56.46 | 58.9 months STANDARD_DEVIATION 55.09 | 57.0 months STANDARD_DEVIATION 55.77 |
| Time since diagnosis of LR or MT | 5.7 months STANDARD_DEVIATION 14.77 | 7.6 months STANDARD_DEVIATION 19.11 | 6.7 months STANDARD_DEVIATION 17.07 |
| Weight | 71.97 kg STANDARD_DEVIATION 15.679 | 72.90 kg STANDARD_DEVIATION 14.35 | 72.43 kg STANDARD_DEVIATION 15.03 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 196 / 284 | 209 / 277 |
| other Total, other adverse events | 264 / 284 | 240 / 277 |
| serious Total, serious adverse events | 65 / 284 | 68 / 277 |
Outcome results
Primary
Overall Survival (ITT Population)
Overall survival (OS) defined as time from randomization to date of death from any cause. Patients without recorded death were censored at the date the patient was last known to be alive. OS was analyzed at two looks, one interim look and the final analysis. Due to group sequential testing, the overall significance level alpha = 0.025 was spent on both looks according to Lan-DeMets spending method with O'Brien-Fleming-type boundaries. Alpha spent at Interim after 50% of information was 0.0014. Alpha spent at final analysis after 99% of information was 0.0250.
Time frame: Time from the date of randomization to the date of death or date last known to be alive, assessed up to approximately 6 years
Population: Intent-to-Treat Population (ITT)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bevacizumab Plus Paclitaxel | Overall Survival (ITT Population) | 29.5 months |
| Bevacizumab Plus Capecitabine | Overall Survival (ITT Population) | 26.0 months |
Comparison: HR of Bevacizumab Plus Capecitabine vs. Bevacizumab plus Paclitaxel for OS (interim, stratified).p-value: 0.1534Regression, Cox
Comparison: HR of Bevacizumab Plus Capecitabine vs. Bevacizumab plus Paclitaxel for OS (final, stratified).p-value: 0.0085Regression, Cox
Comparison: HR of Bevacizumab Plus Capecitabine vs. Bevacizumab plus Paclitaxel for OS (interim, unstratified).p-value: 0.1778Regression, Cox
Comparison: HR of Bevacizumab Plus Capecitabine vs. Bevacizumab plus Paclitaxel for OS (final, unstratified).p-value: 0.049Regression, Cox
Primary
Overall Survival (PP Population)
Overall survival (OS) defined as time from randomization to date of death from any cause. Patients without recorded death were censored at the date the patient was last known to be alive. OS was analyzed at two looks, one interim look and the final analysis. Due to group sequential testing, the overall significance level alpha = 0.025 was spent on both looks according to Lan-DeMets spending method with O'Brien-Fleming-type boundaries. Alpha spent at Interim after 47% of information was 0.0010. Alpha spent at final analysis after 99% of information was 0.0250.
Time frame: Time from the date of randomization to the date of death or date last known to be alive, assessed up to approximately 6 years
Population: Per Protocol Population (PP)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bevacizumab Plus Paclitaxel | Overall Survival (PP Population) | 30.2 months |
| Bevacizumab Plus Capecitabine | Overall Survival (PP Population) | 26.1 months |
Comparison: HR of Bevacizumab plus Capecitabine vs. Bevacizumab plus Paclitaxel for OS (interim, stratified).p-value: 0.1983Regression, Cox
Comparison: HR of Bevacizumab Plus Capecitabine vs. Bevacizumab plus Paclitaxel for OS (final, stratified).p-value: 0.007Regression, Cox
Comparison: HR of Bevacizumab Plus Capecitabine vs. Bevacizumab plus Paclitaxel for OS (interim, unstratified).p-value: 0.2024Regression, Cox
Comparison: HR of Bevacizumab Plus Capecitabine vs. Bevacizumab plus Paclitaxel for OS (final, unstratified).p-value: 0.0612Regression, Cox
Secondary
Best Overall Response (ITT Population)
The best overall response according to the RECIST criteria is the best response recorded from the start of the treatment until disease progression/recurrence or within 28 days of last intake of study medication in the Study Treatment Phase
Time frame: Up to disease progression or up to 28 days after last intake of study medication, assessed up to approximately 5 years.
Population: Intent-to-Treat population
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Bevacizumab Plus Paclitaxel | Best Overall Response (ITT Population) | Partial response | 115 Participants |
| Bevacizumab Plus Paclitaxel | Best Overall Response (ITT Population) | Progressive disease | 18 Participants |
| Bevacizumab Plus Paclitaxel | Best Overall Response (ITT Population) | Stable disease | 127 Participants |
| Bevacizumab Plus Paclitaxel | Best Overall Response (ITT Population) | Not evaluable | 15 Participants |
| Bevacizumab Plus Paclitaxel | Best Overall Response (ITT Population) | Complete response | 10 Participants |
| Bevacizumab Plus Capecitabine | Best Overall Response (ITT Population) | Not evaluable | 18 Participants |
| Bevacizumab Plus Capecitabine | Best Overall Response (ITT Population) | Complete response | 2 Participants |
| Bevacizumab Plus Capecitabine | Best Overall Response (ITT Population) | Partial response | 74 Participants |
| Bevacizumab Plus Capecitabine | Best Overall Response (ITT Population) | Stable disease | 138 Participants |
| Bevacizumab Plus Capecitabine | Best Overall Response (ITT Population) | Progressive disease | 47 Participants |
Secondary
Best Overall Response (PP Population)
The best overall response according to the RECIST criteria is the best response recorded from the start of the treatment until disease progression/recurrence or within 28 days of last intake of study medication in the Study Treatment Phase
Time frame: Up to disease progression or up to 28 days after last intake of study medication, assessed up to approximately 5 years.
Population: Per protocol population
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Bevacizumab Plus Paclitaxel | Best Overall Response (PP Population) | Complete response | 10 Participants |
| Bevacizumab Plus Paclitaxel | Best Overall Response (PP Population) | Stable disease | 117 Participants |
| Bevacizumab Plus Paclitaxel | Best Overall Response (PP Population) | Partial response | 111 Participants |
| Bevacizumab Plus Paclitaxel | Best Overall Response (PP Population) | Progressive disease | 17 Participants |
| Bevacizumab Plus Paclitaxel | Best Overall Response (PP Population) | Not evaluable | 11 Participants |
| Bevacizumab Plus Capecitabine | Best Overall Response (PP Population) | Progressive disease | 45 Participants |
| Bevacizumab Plus Capecitabine | Best Overall Response (PP Population) | Not evaluable | 16 Participants |
| Bevacizumab Plus Capecitabine | Best Overall Response (PP Population) | Complete response | 2 Participants |
| Bevacizumab Plus Capecitabine | Best Overall Response (PP Population) | Partial response | 72 Participants |
| Bevacizumab Plus Capecitabine | Best Overall Response (PP Population) | Stable disease | 130 Participants |
Secondary
Duration of Response (ITT Population)
Duration of response (DR) was defined as time from date of first occurrence of any response (complete response (CR) or partial response (PR)) until the occurrence of progression of disease or death. Patients with response who neither progressed nor died were censored at the date of their last tumor assessment. Median DR, associated stratified Hazard Ratio (HR).
Time frame: Time from first occurrence of CR or PR until disease progression, death or study closure, whichever occurred first, assessed up to 3.4 years after occurrence of response.
Population: ITT population restricted to patients who experienced a partial or complete response
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bevacizumab Plus Paclitaxel | Duration of Response (ITT Population) | 11.2 months |
| Bevacizumab Plus Capecitabine | Duration of Response (ITT Population) | 10.3 months |
Comparison: HR of Bevacizumab Plus Capecitabine vs. Bevacizumab plus Paclitaxel for DR (stratified)~Based on Cox proportional hazards model adjusted by stratification factors at randomization:~1. estrogen and/or progesterone status (positive vs. other)~2. country~3. menopausal status (premenopausal or male \<=50 years of age vs. postmenopausal or male \>50 years of age)p-value: 0.058295% CI: [0.99, 2.02]Log Rank
Secondary
Duration of Response (PP Population)
Duration of response (DR) was defined as time from date of first occurrence of any response (complete response (CR) or partial response (PR)) until the occurrence of progression of disease or death. Patients with response who neither progressed nor died were censored at the date of their last tumor assessment. Median DR, associated stratified Hazard Ratio (HR).
Time frame: Time from first occurrence of CR or PR until disease progression, death or study closure, whichever occurred first, assessed up to 3.4 years after occurrence of response.
Population: PP population restricted to patients who experienced a partial or complete response
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bevacizumab Plus Paclitaxel | Duration of Response (PP Population) | 11.2 months |
| Bevacizumab Plus Capecitabine | Duration of Response (PP Population) | 10.3 months |
Comparison: HR of Arm B vs. Arm A for DR (stratified)~Based on Cox proportional hazards model adjusted by stratification factors at randomization:~1. estrogen and/or progesterone status (positive vs. other)~2. country~3. menopausal status (premenopausal or male \<=50 years of age vs. postmenopausal or male \>50 years of age)p-value: 0.042995% CI: [1.01, 2.1]Log Rank
Secondary
Objective Response Rate and Disease Control Rate (ITT Population)
Objective response rate (ORR) is defined as the proportion of patients with complete response or partial response. Disease control rate (DCR) is defined as the proportion of patients with complete response, partial response and stable disease. The best overall response according to the RECIST criteria is the best response recorded from the start of the treatment until disease progression/recurrence or within 28 days of last intake of study medication in the Study Treatment Phase
Time frame: Up to disease progression or up to 28 days after last intake of study medication, assessed up to approximately 5 years.
Population: ITT population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Bevacizumab Plus Paclitaxel | Objective Response Rate and Disease Control Rate (ITT Population) | Objective response | 125 Participants |
| Bevacizumab Plus Paclitaxel | Objective Response Rate and Disease Control Rate (ITT Population) | Disease control | 252 Participants |
| Bevacizumab Plus Capecitabine | Objective Response Rate and Disease Control Rate (ITT Population) | Objective response | 76 Participants |
| Bevacizumab Plus Capecitabine | Objective Response Rate and Disease Control Rate (ITT Population) | Disease control | 214 Participants |
Comparison: Odds Ratio (OR) of objective response and Cochran-Mantel-Haenszel (CMH) test (stratified)p-value: <0.000195% CI: [0.33, 0.67]Cochran-Mantel-Haenszel
Comparison: Difference in ORR in Bevacizumab Plus Capecitabine vs. Bevacizumab plus Paclitaxel95% CI: [-24, -9]
Comparison: OR of disease control and CMH test (stratified)p-value: 0.000695% CI: [0.27, 0.7]Cochran-Mantel-Haenszel
Comparison: Difference in DCR in Bevacizumab Plus Capecitabine vs. Bevacizumab plus Paclitaxel95% CI: [-18, -6]
Secondary
Objective Response Rate and Disease Control Rate (PP Population)
Objective response rate (ORR) is defined as the proportion of patients with complete response or partial response. Disease control rate (DCR) is defined as the proportion of patients with complete response, partial response and stable disease. The best overall response according to the RECIST criteria is the best response recorded from the start of the treatment until disease progression/recurrence or within 28 days of last intake of study medication in the Study Treatment Phase
Time frame: Up to disease progression or up to 28 days after last intake of study medication, assessed up to approximately 5 years.
Population: PP population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Bevacizumab Plus Paclitaxel | Objective Response Rate and Disease Control Rate (PP Population) | Objective response | 121 Participants |
| Bevacizumab Plus Paclitaxel | Objective Response Rate and Disease Control Rate (PP Population) | Disease control | 238 Participants |
| Bevacizumab Plus Capecitabine | Objective Response Rate and Disease Control Rate (PP Population) | Objective response | 74 Participants |
| Bevacizumab Plus Capecitabine | Objective Response Rate and Disease Control Rate (PP Population) | Disease control | 204 Participants |
Comparison: OR of objective response and CMH test (stratified)p-value: <0.000195% CI: [0.31, 0.65]Cochran-Mantel-Haenszel
Comparison: Difference in ORR in Bevacizumab Plus Capecitabine vs. Bevacizumab plus Paclitaxel95% CI: [-26, -10]
Comparison: OR of disease control and CMH test (stratified)p-value: 0.000395% CI: [0.24, 0.65]Cochran-Mantel-Haenszel
Comparison: Difference in DCR in Bevacizumab Plus Capecitabine vs. Bevacizumab plus Paclitaxel95% CI: [-19, -6]
Secondary
Observation Time (ITT Population)
Median observation time estimated with reverse Kaplan-Meier methods. Observation time (in months) is defined as time from randomization to the day the patient was last confirmed to be alive. In case of patient deaths the time was censored at the day of death.
Time frame: Up to approximately 6 years
Population: Intention-to-Treat population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bevacizumab Plus Paclitaxel | Observation Time (ITT Population) | 54.3 months |
| Bevacizumab Plus Capecitabine | Observation Time (ITT Population) | 55.7 months |
Secondary
Progression Free Survival (ITT Population)
Progression Free Survival (PFS) is defined as time from randomization to date of documented progression or date of death due to any cause, whichever occurred first. Patients without recorded progression or death were censored at the last date they were known to have not progressed. Patients who were randomized and had no post-baseline tumor assessment were censored on the day of randomization. Median PFS, associated stratified Hazard Ratio (HR).
Time frame: Time from the date of randomization to disease progression, death or censoring (whichever occurred first), assessed up to approximately 5 years.
Population: ITT population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bevacizumab Plus Paclitaxel | Progression Free Survival (ITT Population) | 10.9 months |
| Bevacizumab Plus Capecitabine | Progression Free Survival (ITT Population) | 8.1 months |
Comparison: HR of Bevacizumab Plus Capecitabine vs. Bevacizumab plus Paclitaxel for PFS (stratified)~Based on Cox proportional hazards model adjusted by stratification factors at randomization:~1. estrogen and/or progesterone status (positive vs. other)~2. country~3. menopausal status (premenopausal or male \<=50 years of age vs. postmenopausal or male \>50 years of age)p-value: 0.006695% CI: [1.08, 1.61]Log Rank
Secondary
Progression Free Survival (PP Population)
Progression Free Survival (PFS) is defined as time from randomization to date of documented progression or date of death due to any cause, whichever occurred first. Patients without recorded progression or death were censored at the last date they were known to have not progressed. Patients who were randomized and had no post-baseline tumor assessment were censored on the day of randomization. Median PFS, associated stratified Hazard Ratio (HR).
Time frame: Time from the date of randomization to disease progression, death or censoring (whichever occurred first), assessed up to approximately 5 years.
Population: PP population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bevacizumab Plus Paclitaxel | Progression Free Survival (PP Population) | 10.9 months |
| Bevacizumab Plus Capecitabine | Progression Free Survival (PP Population) | 8.2 months |
Comparison: HR of Bevacizumab plus Capecitabine vs. Bevacizumab plus Paclitaxel for PFS (stratified)~Based on Cox proportional hazards model adjusted by stratification factors at randomization:~1. estrogen and/or progesterone status (positive vs. other)~2. country~3. menopausal status (premenopausal or male \<=50 years of age vs. postmenopausal or male \>50 years of age)p-value: 0.009495% CI: [1.07, 1.61]Log Rank
Secondary
Time to Response (ITT Population)
Time to response (TR) was defined as time from randomization until occurrence of response (complete response (CR) or partial response (PR)) according to RECIST criteria. Patients without response were censored after the longest time to response observed in any patient. Median TR, associated stratified Hazard Ratio (HR). Since the median TR was not observed, the number of subjects with a response at given timepoints were reported.
Time frame: Time from randomization until occurrence of response, assessed up 1.7 years
Population: ITT population, median not reached
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Bevacizumab Plus Paclitaxel | Time to Response (ITT Population) | Month 6 | 111 Participants |
| Bevacizumab Plus Paclitaxel | Time to Response (ITT Population) | Month 12 | 123 Participants |
| Bevacizumab Plus Paclitaxel | Time to Response (ITT Population) | Month 9 | 121 Participants |
| Bevacizumab Plus Paclitaxel | Time to Response (ITT Population) | Month 15 | 123 Participants |
| Bevacizumab Plus Paclitaxel | Time to Response (ITT Population) | Month 3 | 83 Participants |
| Bevacizumab Plus Capecitabine | Time to Response (ITT Population) | Month 15 | 75 Participants |
| Bevacizumab Plus Capecitabine | Time to Response (ITT Population) | Month 3 | 57 Participants |
| Bevacizumab Plus Capecitabine | Time to Response (ITT Population) | Month 6 | 69 Participants |
| Bevacizumab Plus Capecitabine | Time to Response (ITT Population) | Month 9 | 74 Participants |
| Bevacizumab Plus Capecitabine | Time to Response (ITT Population) | Month 12 | 75 Participants |
Comparison: HR of Bevacizumab Plus Capecitabine vs. Bevacizumab plus Paclitaxel for TR (stratified)~Based on Cox proportional hazards model adjusted by stratification factors at randomization:~1. estrogen and/or progesterone status (positive vs. other)~2. country~3. menopausal status (premenopausal or male \<=50 years of age vs. postmenopausal or male \>50 years of age)p-value: 0.000195% CI: [0.43, 0.77]Log Rank
Secondary
Time to Response (PP Population)
Time to response (TR) was defined as time from randomization until occurrence of response (complete response (CR) or partial response (PR)) according to RECIST criteria. Patients without response were censored after the longest time to response observed in any patient. Median TR, associated stratified Hazard Ratio (HR). Since the median TR was not observed, the number of subjects with a response at given timepoints were reported.
Time frame: Time from randomization until occurrence of response, assessed up 1.7 years
Population: PP population, median not reached
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Bevacizumab Plus Paclitaxel | Time to Response (PP Population) | Month 6 | 108 Participants |
| Bevacizumab Plus Paclitaxel | Time to Response (PP Population) | Month 12 | 119 Participants |
| Bevacizumab Plus Paclitaxel | Time to Response (PP Population) | Month 9 | 118 Participants |
| Bevacizumab Plus Paclitaxel | Time to Response (PP Population) | Month 15 | 119 Participants |
| Bevacizumab Plus Paclitaxel | Time to Response (PP Population) | Month 3 | 81 Participants |
| Bevacizumab Plus Capecitabine | Time to Response (PP Population) | Month 15 | 73 Participants |
| Bevacizumab Plus Capecitabine | Time to Response (PP Population) | Month 3 | 56 Participants |
| Bevacizumab Plus Capecitabine | Time to Response (PP Population) | Month 6 | 68 Participants |
| Bevacizumab Plus Capecitabine | Time to Response (PP Population) | Month 9 | 72 Participants |
| Bevacizumab Plus Capecitabine | Time to Response (PP Population) | Month 12 | 73 Participants |
Comparison: HR of Bevacizumab Plus Capecitabine vs. Bevacizumab plus Paclitaxel for TR (stratified)~Based on Cox proportional hazards model adjusted by stratification factors at randomization:~1. estrogen and/or progesterone status (positive vs. other)~2. country~3. menopausal status (premenopausal or male \<=50 years of age vs. postmenopausal or male \>50 years of age)p-value: 0.000195% CI: [0.41, 0.75]Log Rank
Secondary
Time to Treatment Failure (ITT Population)
Time to treatment failure (TTF) was defined as time from first drug intake to progression, death or withdrawal from study treatment, whichever occurred first. Patients without an event were censored at the date of the last tumor assessment or last treatment administration, whichever occurred last. Median TTF, associated stratified Hazard Ratio (HR).
Time frame: From first drug intake to progression, death or withdrawal from study treatment or study closure (whichever occurred first), assessed up to approximately 4.5 years
Population: ITT population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bevacizumab Plus Paclitaxel | Time to Treatment Failure (ITT Population) | 8.4 months |
| Bevacizumab Plus Capecitabine | Time to Treatment Failure (ITT Population) | 7.2 months |
Comparison: HR of Bevacizumab plus Capecitabine vs. Bevacizumab plus Paclitaxel for TTF (stratified)~Based on Cox proportional hazards model adjusted by stratification factors at randomization:~1. estrogen and/or progesterone status (positive vs. other)~2. country~3. menopausal status (premenopausal or male \<=50 years of age vs. postmenopausal or male \>50 years of age)p-value: 0.195795% CI: [0.94, 1.35]Log Rank
Secondary
Time to Treatment Failure (PP Population)
Time to treatment failure (TTF) was defined as time from first drug intake to progression, death or withdrawal from study treatment, whichever occurred first. Patients without an event were censored at the date of the last tumor assessment or last treatment administration, whichever occurred last. Median TTF, associated stratified Hazard Ratio (HR).
Time frame: From first drug intake to progression, death or withdrawal from study treatment or study closure (whichever occurred first), assessed up to approximately 4.5 years
Population: PP population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bevacizumab Plus Paclitaxel | Time to Treatment Failure (PP Population) | 8.3 months |
| Bevacizumab Plus Capecitabine | Time to Treatment Failure (PP Population) | 7.3 months |
Comparison: HR of Bevacizumab plus Capecitabine vs. Bevacizumab plus Paclitaxel for TTF (stratified)~Based on Cox proportional hazards model adjusted by stratification factors at randomization:~1. estrogen and/or progesterone status (positive vs. other)~2. country~3. menopausal status (premenopausal or male \<=50 years of age vs. postmenopausal or male \>50 years of age)p-value: 0.258395% CI: [0.92, 1.34]Log Rank
Secondary
Unconfirmed Best Overall Response (ITT Population)
The best overall response according to the RECIST criteria is the best response recorded from the start of the treatment until disease progression/recurrence or within 28 days of last intake of study medication in the Study Treatment Phase. Complete and partial response in this summary did not require a confirmation by a second tumor assessment.
Time frame: Up to disease progression or up to 28 days after last intake of study medication, assessed up to approximately 5 years.
Population: ITT population
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Bevacizumab Plus Paclitaxel | Unconfirmed Best Overall Response (ITT Population) | Partial response | 147 Participants |
| Bevacizumab Plus Paclitaxel | Unconfirmed Best Overall Response (ITT Population) | Progressive disease | 18 Participants |
| Bevacizumab Plus Paclitaxel | Unconfirmed Best Overall Response (ITT Population) | Stable disease | 89 Participants |
| Bevacizumab Plus Paclitaxel | Unconfirmed Best Overall Response (ITT Population) | Not evaluable | 15 Participants |
| Bevacizumab Plus Paclitaxel | Unconfirmed Best Overall Response (ITT Population) | Complete response | 16 Participants |
| Bevacizumab Plus Capecitabine | Unconfirmed Best Overall Response (ITT Population) | Not evaluable | 18 Participants |
| Bevacizumab Plus Capecitabine | Unconfirmed Best Overall Response (ITT Population) | Complete response | 4 Participants |
| Bevacizumab Plus Capecitabine | Unconfirmed Best Overall Response (ITT Population) | Partial response | 101 Participants |
| Bevacizumab Plus Capecitabine | Unconfirmed Best Overall Response (ITT Population) | Stable disease | 109 Participants |
| Bevacizumab Plus Capecitabine | Unconfirmed Best Overall Response (ITT Population) | Progressive disease | 47 Participants |
Secondary
Unconfirmed Best Overall Response (PP Population)
The best overall response according to the RECIST criteria is the best response recorded from the start of the treatment until disease progression/recurrence or within 28 days of last intake of study medication in the Study Treatment Phase. Complete and partial response in this summary did not require a confirmation by a second tumor assessment.
Time frame: Up to disease progression or up to 28 days after last intake of study medication, assessed up to approximately 5 years.
Population: PP population
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Bevacizumab Plus Paclitaxel | Unconfirmed Best Overall Response (PP Population) | Partial response | 141 Participants |
| Bevacizumab Plus Paclitaxel | Unconfirmed Best Overall Response (PP Population) | Progressive disease | 17 Participants |
| Bevacizumab Plus Paclitaxel | Unconfirmed Best Overall Response (PP Population) | Stable disease | 81 Participants |
| Bevacizumab Plus Paclitaxel | Unconfirmed Best Overall Response (PP Population) | Not evaluable | 11 Participants |
| Bevacizumab Plus Paclitaxel | Unconfirmed Best Overall Response (PP Population) | Complete response | 16 Participants |
| Bevacizumab Plus Capecitabine | Unconfirmed Best Overall Response (PP Population) | Not evaluable | 16 Participants |
| Bevacizumab Plus Capecitabine | Unconfirmed Best Overall Response (PP Population) | Complete response | 4 Participants |
| Bevacizumab Plus Capecitabine | Unconfirmed Best Overall Response (PP Population) | Partial response | 96 Participants |
| Bevacizumab Plus Capecitabine | Unconfirmed Best Overall Response (PP Population) | Stable disease | 104 Participants |
| Bevacizumab Plus Capecitabine | Unconfirmed Best Overall Response (PP Population) | Progressive disease | 45 Participants |
Secondary
Unconfirmed Objective Response Rate and Disease Control Rate (ITT Population)
Objective response rate (ORR) is defined as the proportion of patients with complete response or partial response. Disease control rate (DCR) is defined as the proportion of patients with complete response, partial response and stable disease. The best overall response according to the RECIST criteria is the best response recorded from the start of the treatment until disease progression/recurrence or within 28 days of last intake of study medication in the Study Treatment Phase. Complete and partial response in this summary did not require a confirmation by a second tumor assessment.
Time frame: Up to disease progression or up to 28 days after last intake of study medication, assessed up to approximately 5 years.
Population: ITT population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Bevacizumab Plus Paclitaxel | Unconfirmed Objective Response Rate and Disease Control Rate (ITT Population) | Objective response | 163 Participants |
| Bevacizumab Plus Paclitaxel | Unconfirmed Objective Response Rate and Disease Control Rate (ITT Population) | Disease control | 252 Participants |
| Bevacizumab Plus Capecitabine | Unconfirmed Objective Response Rate and Disease Control Rate (ITT Population) | Objective response | 105 Participants |
| Bevacizumab Plus Capecitabine | Unconfirmed Objective Response Rate and Disease Control Rate (ITT Population) | Disease control | 214 Participants |
Comparison: OR of objective response and CMH test (stratified)p-value: <0.000195% CI: [0.31, 0.63]Cochran-Mantel-Haenszel
Comparison: Difference in ORR in Bevacizumab Plus Capecitabine vs. Bevacizumab plus Paclitaxel95% CI: [-28, -11]
Comparison: OR of disease control and CMH test (stratified)p-value: 0.000695% CI: [0.27, 0.7]Cochran-Mantel-Haenszel
Comparison: Difference in DCR in Bevacizumab Plus Capecitabine vs. Bevacizumab plus Paclitaxel95% CI: [-18, -6]
Secondary
Unconfirmed Objective Response Rate and Disease Control Rate (PP Population)
Objective response rate (ORR) is defined as the proportion of patients with complete response or partial response. Disease control rate (DCR) is defined as the proportion of patients with complete response, partial response and stable disease. The best overall response according to the RECIST criteria is the best response recorded from the start of the treatment until disease progression/recurrence or within 28 days of last intake of study medication in the Study Treatment Phase. Complete and partial response in this summary did not require a confirmation by a second tumor assessment
Time frame: Up to disease progression or up to 28 days after last intake of study medication, assessed up to approximately 5 years.
Population: PP population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Bevacizumab Plus Paclitaxel | Unconfirmed Objective Response Rate and Disease Control Rate (PP Population) | Objective response | 157 Participants |
| Bevacizumab Plus Paclitaxel | Unconfirmed Objective Response Rate and Disease Control Rate (PP Population) | Disease control | 238 Participants |
| Bevacizumab Plus Capecitabine | Unconfirmed Objective Response Rate and Disease Control Rate (PP Population) | Objective response | 100 Participants |
| Bevacizumab Plus Capecitabine | Unconfirmed Objective Response Rate and Disease Control Rate (PP Population) | Disease control | 204 Participants |
Comparison: Difference in DCR in Bevacizumab Plus Capecitabine vs. Bevacizumab plus Paclitaxel95% CI: [-19, -6]
Comparison: OR of objective response and CMH test (stratified)p-value: <0.000195% CI: [0.29, 0.6]Cochran-Mantel-Haenszel
Comparison: Difference in ORR in Bevacizumab Plus Capecitabine vs. Bevacizumab plus Paclitaxel95% CI: [-30, -13]
Comparison: OR of disease control and CMH test (stratified)p-value: 0.000395% CI: [0.24, 0.65]Cochran-Mantel-Haenszel