Breast Neoplasms
Conditions
Brief summary
To investigate the efficacy and safety of BIBW 2992 in combination with vinorelbine i.v. chemotherapy as treatment in patients with HER2-overexpressing, metastatic breast cancer, who failed one prior trastuzumab (Herceptin®) treatment
Interventions
DRUGBIBW 2992
patients receive BIBW 2992 tablets once daily and can reduce dose for adverse event management
DRUGtrastuzumab
patients receive trastuzumab 2mg/kg intravenously every week
DRUGvinorelbine
patients receive vinorelbine 25mg/m² intravenously every week
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically confirmed diagnosis of HER2-overexpression breast cancer * Stage IV metastatic disease * Must have progressed on one prior trastuzumab treatment * no more than one prior trastuzumab based therapy regimen (either adjuvant or first-line) * Must have received anthracycline and/or taxane based chemotherapy for adjuvant treatment of breast cancer or first-line treatment of metastatic breast cancer * Must have (archived) tumour tissue sample available for central re-assessment of HER2-status * At least one measurable lesion according to RECIST 1.1. * Eastern Cooperative Oncology Group (ECOG) score of 0 or 1 .
Exclusion criteria
* Prior treatment with Epidermal Growth Factor Receptor/Human Epidermal Growth Factor Receptor(EGFR/HER2)-targeted small molecules or antibodies other than trastuzumab * Prior treatment with vinorelbine * Known pre-existing interstitial lung disease * Active brain metastases * History or presence of clinically relevant cardiovascular abnormalities such as uncontrolled hypertension, congestive heart failure NYHA classification of 3, unstable angina or poorly controlled arrhythmia. Myocardial infarction within 6 months prior to randomisation. * Cardiac left ventricular function with resting ejection fraction of less than 50%. * Patients unable to comply with the protocol. * Any contraindications for therapy with vinorelbine or trastuzumab. * Known hypersensitivity to BIBW 2992 or the excipients of any of the trial drugs. * Use of any investigational drug within 4 weeks of randomisation. * Inadequate hepatic, renal and haematologic organ function
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) | From randomization (07Sep2010) until disease progression, death or data cut-off (08Jun2013); Up to 34 months | PFS is defined as time from randomisation to disease progression or death whichever occurs first. Assessed by investigator according to the Response Evaluation Criteria in Solid Tumours (RECIST 1.1). RECIST is a set of published rules that define when tumors in cancer patients improve (respond), stay the same (stabilize) or worsen (progress) during treatment. Only data collected until the cut-off date for RECIST 1.1 based endpoints (08Jun2013) were considered. Progression of disease was determined if at least 1 of the following criteria applied: * At least a 20% increase in the sum of the diameters (SoD) of target lesions taking as reference the smallest SoD recorded since the treatment started, together with an absolute increase in the SoD of at least 5 mm * Appearance of 1 or more new lesions * Unequivocal progression of existing non-target lesions |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | From randomisation (07Sep2010) to database lock (30Jul2018), up to 95 months. | OS is defined as time from randomisation to death irrespective of the cause of the death. For patients who had not died up to the cut-off date (03Sep2013), the date they were last known to be alive was derived from the patient status records, the trial completion record, radiological imaging assessments, the study treatment termination record, and the randomisation date. |
| Best RECIST Assessment | From randomization (07Sep2010) until disease progression, death or data cut-off (08Jun2013); Up to 34 months | Best RECIST assessment is defined as CR, PR, stable disease (SD), progressive disease (PD) or not evaluable by investigator (RECIST version 1.1). CR for target lesions (TL): Disappearance of all target lesions. CR for non-target lesions (NTL): Disappearance of all non-target lesions and normalization of tumour marker level. All lymph nodes must be non-pathological in size (\<10mm short axis). PR: At least a 30% decrease in the sum of diameters (SoD) of target lesions taking as reference the baseline sum diameters. SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as references the smallest SoD while on study. PD: At least a 20% increase in the SoD of target lesions, taking as references the smallest sum on study (this includes the baseline sum if that is the smallest on study). Also, the sum must also demonstrate an absolute increase of a least 5mm. Appearance of one or more new lesions. |
| Objective Response (OR) | Post baseline tumour-imaging was performed at Week 8, 16, 24, 32, 40, 48, 56 and then every 12 weeks (Until final data-base lock on 30 Jul 2018; Up to 95 months) | OR is defined as complete response (CR) and partial response (PR). Assessed by investigator according to Response Evaluation Criteria in Solid Tumours (RECIST) 1.1. Complete Response (CR) for target lesions (TL): Disappearance of all target lesions. Complete Response (CR) for non-target lesions (NTL): Disappearance of all non-target lesions and normalization of tumour marker level. All lymph nodes must be non-pathological in size (\<10mm short axis) Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum diameters. Other factors which add to the overall response of an imaging timepoint as PR are as below:- * CR in TL, but non-CR/Non-PD in NTL leads to PR * CR in TL, but not evaluated NTL leads to PR * PR in TL, but non-PD NTL or not all evaluated NTL leads to PR |
Countries
Argentina, Australia, Austria, Belarus, Belgium, Brazil, Canada, Chile, China, Czechia, Egypt, France, Germany, India, Ireland, Israel, Italy, Japan, Latvia, Lebanon, Lithuania, Mexico, Netherlands, Peru, Poland, Portugal, Russia, Singapore, Slovakia, Slovenia, South Africa, South Korea, Spain, Sri Lanka, Taiwan, Turkey (Türkiye), United Kingdom, United States
Participant flow
Recruitment details
This was randomised, active-controlled, open-label, parallel-group, 2 arm (2:1 ratio) trial in participants with metastatic human epidermal growth factor receptor 2 (HER2)-overexpressing breast cancer failing one prior trastuzumab treatment.
Pre-assignment details
Participants were treated in the study until disease progression, undue toxicity, or withdrawal of consent. The cut-off date for RECIST-based efficacy was 08 Jun 2013; a second analysis (primarily for assessing Overall Survival (OS)) contains all data until final database lock (30 Jul 2018).
Participants by arm
| Arm | Count |
|---|---|
| Afatinib + Vinorelbine (AV) Participants received oral treatment of film-coated Afatinib tablet at a starting dose of 40 milligram (mg) once daily and weekly 10 minutes intravenous infusion of Vinorelbine 25 mg/meter\^2 (meter=m) on days 1, 8, 15, and 22 of each course. The treatment was administered in treatment courses of 28 days. For Afatinib, a protocol-defined dose-reduction scheme was to be followed if a participant experienced certain pre-specified adverse events. From 26 April 2013, any participant who had been randomised to the AV arm stopped treatment, had the option to switch to Trastuzamb + Vinorelbine. | 332 |
| Trastuzumab + Vinorelbine (TV) Participants received an intravenous infusion of Trastuzumab 2 mg/kilogram (kg) weekly, following an initial loading dose of 4 mg/kg and weekly 10 minutes intravenous infusion of Vinorelbine 25 mg/m\^2 on days 1, 8, 15, and 22 of each course. The treatment was administered in treatment courses of 28 days. | 168 |
| Total | 500 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Patients Before the Switch (26Apr2013) | Adverse Event | 25 | 5 | 0 |
| Patients Before the Switch (26Apr2013) | Lost to Follow-up | 1 | 1 | 0 |
| Patients Before the Switch (26Apr2013) | Not treated | 2 | 0 | 0 |
| Patients Before the Switch (26Apr2013) | Other than listed above | 25 | 13 | 0 |
| Patients Before the Switch (26Apr2013) | Progressive disease according to RECIST | 182 | 119 | 0 |
| Patients Before the Switch (26Apr2013) | Protocol Violation | 0 | 2 | 0 |
| Patients Before the Switch (26Apr2013) | Refused to continue taking medication | 24 | 23 | 0 |
| Patients Before the Switch (26Apr2013) | Worsening of underlying cancer disease | 6 | 6 | 0 |
| Patients Who Switched From AV to TV | Other than listed above | 0 | 0 | 4 |
| Patients Who Switched From AV to TV | Progressive disease according to RECIST | 0 | 0 | 59 |
| Patients Who Switched From AV to TV | Refused to continue taking medication | 0 | 0 | 7 |
| Patients Who Switched From AV to TV | Worsening of underlying cancer disease | 0 | 0 | 3 |
Baseline characteristics
| Characteristic | Trastuzumab + Vinorelbine (TV) | Total | Afatinib + Vinorelbine (AV) |
|---|---|---|---|
| Age, Continuous | 53.1 Years STANDARD_DEVIATION 12.3 | 52.2 Years STANDARD_DEVIATION 11.6 | 51.8 Years STANDARD_DEVIATION 11.3 |
| Ethnicity (NIH/OMB) Hispanic or Latino | — | 0 Participants | — |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | — | 0 Participants | — |
| Ethnicity (NIH/OMB) Unknown or Not Reported | — | 0 Participants | — |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 81 Participants | 253 Participants | 172 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 9 Participants | 6 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 11 Participants | 28 Participants | 17 Participants |
| Race (NIH/OMB) White | 72 Participants | 208 Participants | 136 Participants |
| Sex: Female, Male Female | 168 Participants | 500 Participants | 332 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 235 / 337 | 111 / 169 | 3 / 75 |
| other Total, other adverse events | 331 / 337 | 163 / 169 | 64 / 75 |
| serious Total, serious adverse events | 123 / 337 | 45 / 169 | 15 / 75 |
Outcome results
Primary
Progression-free Survival (PFS)
PFS is defined as time from randomisation to disease progression or death whichever occurs first. Assessed by investigator according to the Response Evaluation Criteria in Solid Tumours (RECIST 1.1). RECIST is a set of published rules that define when tumors in cancer patients improve (respond), stay the same (stabilize) or worsen (progress) during treatment. Only data collected until the cut-off date for RECIST 1.1 based endpoints (08Jun2013) were considered. Progression of disease was determined if at least 1 of the following criteria applied: * At least a 20% increase in the sum of the diameters (SoD) of target lesions taking as reference the smallest SoD recorded since the treatment started, together with an absolute increase in the SoD of at least 5 mm * Appearance of 1 or more new lesions * Unequivocal progression of existing non-target lesions
Time frame: From randomization (07Sep2010) until disease progression, death or data cut-off (08Jun2013); Up to 34 months
Population: Randomised set (RS): The randomised set included all participants who were randomised to receive treatment, whether treated or not.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Afatinib + Vinorelbine (AV) | Progression-free Survival (PFS) | 5.49 Months |
| Trastuzumab + Vinorelbine (TV) | Progression-free Survival (PFS) | 5.55 Months |
p-value: 0.422495% CI: [0.87, 1.41]Regression, Cox
Secondary
Best RECIST Assessment
Best RECIST assessment is defined as CR, PR, stable disease (SD), progressive disease (PD) or not evaluable by investigator (RECIST version 1.1). CR for target lesions (TL): Disappearance of all target lesions. CR for non-target lesions (NTL): Disappearance of all non-target lesions and normalization of tumour marker level. All lymph nodes must be non-pathological in size (\<10mm short axis). PR: At least a 30% decrease in the sum of diameters (SoD) of target lesions taking as reference the baseline sum diameters. SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as references the smallest SoD while on study. PD: At least a 20% increase in the SoD of target lesions, taking as references the smallest sum on study (this includes the baseline sum if that is the smallest on study). Also, the sum must also demonstrate an absolute increase of a least 5mm. Appearance of one or more new lesions.
Time frame: From randomization (07Sep2010) until disease progression, death or data cut-off (08Jun2013); Up to 34 months
Population: RS including participants with available data for best RECIST assessment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Afatinib + Vinorelbine (AV) | Best RECIST Assessment | Partial response (PR) | 43.1 Percentage of participants |
| Afatinib + Vinorelbine (AV) | Best RECIST Assessment | Progressive Disease (PD) | 12.6 Percentage of participants |
| Afatinib + Vinorelbine (AV) | Best RECIST Assessment | Stable disease (SD) | 31.7 Percentage of participants |
| Afatinib + Vinorelbine (AV) | Best RECIST Assessment | Missing | 9.3 Percentage of participants |
| Afatinib + Vinorelbine (AV) | Best RECIST Assessment | Complete response (CR) | 3.3 Percentage of participants |
| Trastuzumab + Vinorelbine (TV) | Best RECIST Assessment | Missing | 8.3 Percentage of participants |
| Trastuzumab + Vinorelbine (TV) | Best RECIST Assessment | Complete response (CR) | 3.0 Percentage of participants |
| Trastuzumab + Vinorelbine (TV) | Best RECIST Assessment | Partial response (PR) | 44.0 Percentage of participants |
| Trastuzumab + Vinorelbine (TV) | Best RECIST Assessment | Stable disease (SD) | 26.8 Percentage of participants |
| Trastuzumab + Vinorelbine (TV) | Best RECIST Assessment | Progressive Disease (PD) | 17.9 Percentage of participants |
Comparison: Results of presented analyses are to be seen as exploratory (no confirmatory testing was performed)p-value: 0.643195% CI: [0.756, 1.572]Regression, Logistic
Secondary
Objective Response (OR)
OR is defined as complete response (CR) and partial response (PR). Assessed by investigator according to Response Evaluation Criteria in Solid Tumours (RECIST) 1.1. Complete Response (CR) for target lesions (TL): Disappearance of all target lesions. Complete Response (CR) for non-target lesions (NTL): Disappearance of all non-target lesions and normalization of tumour marker level. All lymph nodes must be non-pathological in size (\<10mm short axis) Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum diameters. Other factors which add to the overall response of an imaging timepoint as PR are as below:- * CR in TL, but non-CR/Non-PD in NTL leads to PR * CR in TL, but not evaluated NTL leads to PR * PR in TL, but non-PD NTL or not all evaluated NTL leads to PR
Time frame: Post baseline tumour-imaging was performed at Week 8, 16, 24, 32, 40, 48, 56 and then every 12 weeks (Until final data-base lock on 30 Jul 2018; Up to 95 months)
Population: RS including participants with available data for OR.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Afatinib + Vinorelbine (AV) | Objective Response (OR) | 46.4 Percentage of participants (%) |
| Trastuzumab + Vinorelbine (TV) | Objective Response (OR) | 47.0 Percentage of participants (%) |
Comparison: Results of presented analyses are to be seen as exploratory (no confirmatory testing was performed)p-value: 0.882995% CI: [0.707, 1.496]Regression, Logistic
Secondary
Overall Survival (OS)
OS is defined as time from randomisation to death irrespective of the cause of the death. For patients who had not died up to the cut-off date (03Sep2013), the date they were last known to be alive was derived from the patient status records, the trial completion record, radiological imaging assessments, the study treatment termination record, and the randomisation date.
Time frame: From randomisation (07Sep2010) to database lock (30Jul2018), up to 95 months.
Population: RS including participants with available data for OS.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Afatinib + Vinorelbine (AV) | Overall Survival (OS) | 20.17 Months |
| Trastuzumab + Vinorelbine (TV) | Overall Survival (OS) | 29.60 Months |
Comparison: Results of presented analyses are to be seen as exploratory (no confirmatory testing was performed)p-value: 0.02495% CI: [1.03, 1.63]Regression, Cox