Breast Cancer
Conditions
Brief summary
This two-cohort, open-label, multicenter, phase 2 study will assess the safety and efficacy of pertuzumab given in combination with trastuzumab (Herceptin) and vinorelbine in first line participants with metastatic or locally advanced HER2-positive breast cancer. Participants will receive pertuzumab and trastuzumab administered sequentially as separate intravenous (IV) infusions (followed by vinorelbine) and conventional sequential administration of pertuzumab and trastuzumab in separate infusion bags, followed by vinorelbine.
Interventions
DRUGPertuzumab
Loading dose of 840 mg on Day 1 of first 21-day cycle, followed by 420 mg on Day 1 of each subsequent cycle.
DRUGTrastuzumab
Loading dose of 8 mg/kg on Day 1 of first 21-day cycle, followed by 6 mg/kg on Day 1 or 2 of each subsequent cycle.
DRUGVinorelbine
A dose of 25 mg/m\^2 followed by 30-35 mg/m\^2 on Days 2 and 9 of the first 21-day cycle and on Days 1 and 8 (or Days 2 and 9) of each subsequent cycle.
Sponsors
Hoffmann-La Roche
Study design
Allocation
NON_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 and documented adenocarcinoma of the breast with metastatic or locally advanced disease not amenable to curative resection * HER2-positive as assessed by local laboratory on primary or metastatic tumor * At least one measurable lesion and/or non-measurable disease evaluable according to RECIST v1.1 criteria * Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 * Left ventricular ejection fraction (LVEF) of at least 55% * Life expectancy of at least 12 weeks
Exclusion criteria
* Previous systemic non-hormonal anti-cancer therapy in the metastatic or locally advanced breast cancer setting * Previous approved or investigative anti-HER2 agents in any breast cancer treatment setting, except trastuzumab and/or lapatinib in the adjuvant or neoadjuvant setting * Disease progression while receiving trastuzumab and/or lapatinib in the adjuvant or neoadjuvant setting * Disease-free interval from completion of adjuvant or neoadjuvant systemic non-hormonal treatment to recurrent disease of less than 6 months * History of persistent Grade 2 or higher (National Cancer Institute Common Terminology Criteria \[NCI-CTC\], Version 4.0) hematological toxicity resulting from previous adjuvant or neoadjuvant therapy * Radiographic evidence of central nervous system metastases that are not well controlled with local therapy (irradiation or surgery) * Current peripheral neuropathy of NCI-CTC, version 4.0 Grade 3 or greater * History of other malignancy within the last 5 years, except for carcinoma in situ of the cervix, non-melanoma skin carcinoma, Stage 1 uterine cancer, or cancers with a similar curative outcome as those mentioned above * Serious uncontrolled concomitant disease that would contraindicate the use of any of the investigational drugs used in this study or would put the participants at high risk for treatment-related complications * Inadequate hematologic, liver, or renal function * Uncontrolled hypertension or clinically significant cardiovascular disease * Hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) infection * Current chronic daily treatment with corticosteroids (\>/= 10 mg/day methylprednisolone or equivalent), excluding inhaled steroids
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Best Overall Response (BOR) as Assessed by Investigator According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | Baseline, every 3 cycles up to 36 months, and every 6 cycles thereafter if progression free after 36 months, 28 days after end of treatment, every 3 months thereafter (maximum up to approximately 3.5 years) | Tumor response was assessed by investigator according to RECIST v1.1. BOR was defined as percentage of participants with a confirmed complete response (CR) or partial response (PR). All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total or pathological nodes (with short axis \[SA\] of at least (\>/=) 15 millimeter \[mm\]) were identified as target lesions (TLs) and measured and recorded at baseline. A sum of diameters (longest for non-nodal lesions, SA for nodal lesions) for all TLs was calculated and reported as baseline sum of diameters (SD). All other lesions (or sites of disease) were identified as non-TLs. CR: disappearance of all TLs and SA reduction to less than (\<) 10 mm for nodal TLs/ non-TLs. PR: \>/=30 percent (%) decrease in SD of TLs, taking as reference baseline SD. Confirmation of response at 2 consecutive tumor assessments \>/=4 weeks apart was required. The 95% confidence interval (CI) was computed using Clopper-Pearson approach. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Response (DOR) as Assessed by Investigator According to RECIST v 1.1 | Baseline, every 3 cycles up to 36 months, and every 6 cycles thereafter if progression free after 36 months, 28 days after end of treatment, every 3 months thereafter (maximum up to approximately 3.5 years) | DOR, in participants with a BOR of CR or PR, was defined as the period from the date of initial PR or CR until the date of PD or death from any cause. Participants with no documented PD or death after CR or PR were censored at the last date at which they were known to have had the CR or PR, respectively (regardless of the response at intermediate assessments). CR: the disappearance of all TLs and SA reduction to \<10 mm for nodal TLs/ non-TLs. PR: \>/=30% decrease in SD of TLs, taking as reference the baseline SD. Confirmation of response at 2 consecutive tumor assessments \>/=4 weeks apart was required. PD: \>/=20% relative increase and \>/=5 mm of absolute increase in the SD of TLs, taking as reference the smallest SD recorded since treatment started, or appearance of 1 or more new lesions. The 95% CI was computed using log-log transformation. |
| Percentage of Participants With Disease Progression as Assessed by Investigator According to RECIST v1.1 or Death From Any Cause | Baseline, every 3 cycles up to 36 months, and every 6 cycles thereafter if progression free after 36 months, 28 days after end of treatment, every 3 months thereafter (maximum up to approximately 3.5 years) | PD was defined as \>/=20% relative increase and \>/=5 mm of absolute increase in the SD of TLs, taking as reference the smallest SD recorded since treatment started, or appearance of 1 or more new lesions. Percentage of participants with radio-graphically documented PD as assessed by investigator according to RECIST v1.1 or death due to any cause was reported. |
| Progression-free Survival (PFS) as Assessed by Investigator According to RECIST v 1.1 | Baseline, every 3 cycles up to 36 months, and every 6 cycles thereafter if progression free after 36 months, 28 days after end of treatment, every 3 months thereafter (maximum up to approximately 3.5 years) | PFS was defined as the time from first intake of any study medication until the first radio-graphically documented PD as assessed by investigator according to RECIST v1.1 or death due to any cause, whichever occurred first. Participants with no PFS events were censored at the time of the last evaluable tumor assessment. Participants with no baseline or no tumor assessment after the baseline visit were censored on the date of first study treatment. PD: \>/=20% relative increase and \>/=5 mm of absolute increase in the SD of TLs, taking as reference the smallest SD recorded since treatment started, or appearance of 1 or more new lesions. Participants who had radio-graphically documented PD as assessed by investigator according to RECIST v1.1 or died due to any cause were considered as having an event. The median PFS was estimated using Kaplan-Meier method. The 95% CI was computed using log-log transformation. |
| Percentage of Participants With Disease Progression as Assessed by Investigator According to RECIST v1.1 | Baseline, every 3 cycles up to 36 months, and every 6 cycles thereafter if progression free after 36 months, 28 days after end of treatment, every 3 months thereafter (maximum up to approximately 3.5 years) | PD was defined as \>/=20% relative increase and \>/=5 mm of absolute increase in the SD of TLs, taking as reference the smallest SD recorded since treatment started, or appearance of 1 or more new lesions. Percentage of participants with radio-graphically documented PD as assessed by investigator according to RECIST v1.1 was reported. |
| Time to Response as Assessed by Investigator According to RECIST v 1.1 | Baseline, every 3 cycles up to 36 months, and every 6 cycles thereafter if progression free after 36 months, 28 days after end of treatment, every 3 months thereafter (maximum up to approximately 3.5 years) | For participants with a BOR of CR or PR, time to response = (Date of first confirmed CR/PR - Date of first study treatment) + 1. For participants without a CR or PR, time to response = (Date of adequate last tumor assessment - Date of first study treatment) + 1. For participant with no tumor assessment (or if all assessments were progressive disease \[PD\]) the censoring day was set to date of first study treatment +1. CR: the disappearance of all TLs and SA reduction to \<10 mm for nodal TLs/ non-TLs. PR: \>/=30% decrease in SD of TLs, taking as reference the baseline SD. Confirmation of response at 2 consecutive tumor assessments \>/=4 weeks apart was required. PD: \>/=20% relative increase and \>/=5 mm of absolute increase in the SD of TLs, taking as reference the smallest SD recorded since treatment started, or appearance of 1 or more new lesions. The 95% CI was computed using log-log transformation. |
| Percentage of Participants Who Died From Any Cause | Baseline until death (up to approximately 3.5 years) | Percentage of participants who died due to any cause was reported. |
| Overall Survival (OS) | Baseline until death (up to approximately 3.5 years) | OS was defined as the time from first intake of any study medication to the date of death, regardless of the cause of death. Participants who were known to be alive at the time of the analysis were censored at the date of the last follow-up assessment. Participants without follow-up assessment were censored at the day of last study treatment, and participants with no post-baseline information were censored at the date of first study treatment plus 1 day. Participants who died due to any cause were considered as having an event. The median OS was estimated using Kaplan-Meier method. The 95% CI was computed using log-log transformation. |
| Change From Baseline in European Quality of Life-5 Dimensions (EQ-5D) Questionnaire Visual Analogue Scale (VAS) Score | Baseline, thereafter every 3 cycles from Cycle 3 to Cycle 45 (each cycle = 21 days) | EQ-5D VAS: participant rated questionnaire to assess health-related quality of life (QoL) in terms of a single index value. The VAS component rates current health state on a scale from 0 mm (worst imaginable health state) to 100 mm (best imaginable health state); higher scores indicate a better health state. |
| Change From Baseline in Functional Assessment of Cancer Therapy-Breast (FACT-B) Questionnaire Score | Baseline, thereafter every 3 cycles from Cycle 3 to Cycle 45 (each cycle = 21 days) | FACT-B questionnaire is used for assessment of health-related QoL in participants with breast cancer. It consists of 36 items, summarized to 5 subscales: physical (7 items), functional (7 items), social/family (7 items); all 3 ranged from 0 to 28, emotional (6 items) ranging from 0 to 24, and breast cancer subscale (9 items) ranging from 0 to 36; high subscale score represents a better QoL. All single-item measures ranges from 0='Not at all' to 4='Very much'. Total possible score ranged from 0 to 144. High scale score represents a better QoL. |
| Time to Progression (TTP) as Assessed by Investigator According to RECIST v 1.1 | Baseline, every 3 cycles up to 36 months, and every 6 cycles thereafter if progression free after 36 months, 28 days after end of treatment, every 3 months thereafter (maximum up to approximately 3.5 years) | TTP was defined as the time from first intake of any study medication until the first radio-graphically documented PD as assessed by investigator according to RECIST v1.1. Participants who did not have a radio-graphically documented PD and had died due to reason other than PD were censored on the last available tumor assessment prior to the death date. Participants with no baseline or no tumor assessment after the baseline visit were censored on the date of first study treatment. PD was defined as \>/=20% relative increase and \>/=5 mm of absolute increase in the SD of TLs, taking as reference the smallest SD recorded since treatment started, or appearance of 1 or more new lesions. Participants who had radio-graphically documented PD as assessed by investigator according to RECIST v1.1 were considered as having an event. The median TTP was estimated using Kaplan-Meier method. The 95% CI was computed using log-log transformation. |
Countries
Brazil, Denmark, France, Germany, Italy, Spain, United States
Participant flow
Pre-assignment details
Due to non-randomized nature of the study (single infusion cohort started enrollment only after separate infusion cohort recruitment was completed) and different baseline characteristics of participants, the comparison between the 2 cohorts was not performed. Hence, the efficacy and safety results for the 2 cohorts should be considered separately.
Participants by arm
| Arm | Count |
|---|---|
| Pertuzumab + Trastuzumab + Vinorelbine: Separate Infusion Pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (cycle length = 21 days), followed by 420 mg on Day 1 of each subsequent cycle. Trastuzumab IV infusion at a loading dose of 8 mg/kg on Day 2 of Cycle 1, followed by 6 mg/kg on Day 2 of each subsequent cycle. Vinorelbine IV infusion (administered after trastuzumab) at a dose of 25 mg/m\^2 on Day 2 and Day 9 of Cycle 1, followed by 30-35 mg/m\^2 on Day 2 and Day 9 of each subsequent cycle. Pertuzumab and trastuzumab were administered sequentially in separate infusion bags, followed by vinorelbine until disease progression, unacceptable toxicity, withdrawal of consent, death, or predefined study end (up to 47 cycles). | 106 |
| Pertuzumab + Trastuzumab + Vinorelbine: Single Infusion Pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (cycle length = 21 days), followed by 420 mg on Day 1 of each subsequent cycle. Trastuzumab IV infusion at a loading dose of 8 mg/kg on Day 2 of Cycle 1, followed by 6 mg/kg on Day 1 of each subsequent cycle. Vinorelbine IV infusion at a dose of 25 mg/m\^2 on Day 2 and Day 9 of Cycle 1, followed by 30-35 mg/m\^2 on Day 1 and Day 8 of each subsequent cycle. If administration of all 3 drugs was well tolerated in Cycle 1, then on Day 1 of each subsequent cycle, pertuzumab 420 mg and trastuzumab 6 mg/kg was administered in a single infusion bag, followed by vinorelbine until disease progression, unacceptable toxicity, withdrawal of consent, death, or predefined study end (up to 47 cycles). | 107 |
| Total | 213 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 22 | 23 |
| Overall Study | Lost to Follow-up | 2 | 7 |
| Overall Study | Other | 3 | 5 |
| Overall Study | Withdrawal by Subject | 6 | 4 |
Baseline characteristics
| Characteristic | Pertuzumab + Trastuzumab + Vinorelbine: Separate Infusion | Pertuzumab + Trastuzumab + Vinorelbine: Single Infusion | Total |
|---|---|---|---|
| Age, Continuous | 56.9 years STANDARD_DEVIATION 11.8 | 55.6 years STANDARD_DEVIATION 13.17 | 56.2 years STANDARD_DEVIATION 12.5 |
| Sex: Female, Male Female | 106 Participants | 106 Participants | 212 Participants |
| Sex: Female, Male Male | 0 Participants | 1 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 103 / 106 | 106 / 107 |
| serious Total, serious adverse events | 32 / 106 | 44 / 107 |
Outcome results
Primary
Percentage of Participants With Best Overall Response (BOR) as Assessed by Investigator According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1)
Tumor response was assessed by investigator according to RECIST v1.1. BOR was defined as percentage of participants with a confirmed complete response (CR) or partial response (PR). All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total or pathological nodes (with short axis \[SA\] of at least (\>/=) 15 millimeter \[mm\]) were identified as target lesions (TLs) and measured and recorded at baseline. A sum of diameters (longest for non-nodal lesions, SA for nodal lesions) for all TLs was calculated and reported as baseline sum of diameters (SD). All other lesions (or sites of disease) were identified as non-TLs. CR: disappearance of all TLs and SA reduction to less than (\<) 10 mm for nodal TLs/ non-TLs. PR: \>/=30 percent (%) decrease in SD of TLs, taking as reference baseline SD. Confirmation of response at 2 consecutive tumor assessments \>/=4 weeks apart was required. The 95% confidence interval (CI) was computed using Clopper-Pearson approach.
Time frame: Baseline, every 3 cycles up to 36 months, and every 6 cycles thereafter if progression free after 36 months, 28 days after end of treatment, every 3 months thereafter (maximum up to approximately 3.5 years)
Population: ITT population. Only participants with measurable disease at baseline were included in the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pertuzumab + Trastuzumab + Vinorelbine: Separate Infusion | Percentage of Participants With Best Overall Response (BOR) as Assessed by Investigator According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | 74.2 percentage of participants |
| Pertuzumab + Trastuzumab + Vinorelbine: Single Infusion | Percentage of Participants With Best Overall Response (BOR) as Assessed by Investigator According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | 63.7 percentage of participants |
Secondary
Change From Baseline in European Quality of Life-5 Dimensions (EQ-5D) Questionnaire Visual Analogue Scale (VAS) Score
EQ-5D VAS: participant rated questionnaire to assess health-related quality of life (QoL) in terms of a single index value. The VAS component rates current health state on a scale from 0 mm (worst imaginable health state) to 100 mm (best imaginable health state); higher scores indicate a better health state.
Time frame: Baseline, thereafter every 3 cycles from Cycle 3 to Cycle 45 (each cycle = 21 days)
Population: ITT population. Here, 'Number of Participants Analyzed' signifies the number of participants evaluable for this outcome measure and 'n' signifies the number of participants evaluable at specified time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Pertuzumab + Trastuzumab + Vinorelbine: Separate Infusion | Change From Baseline in European Quality of Life-5 Dimensions (EQ-5D) Questionnaire Visual Analogue Scale (VAS) Score | Change at Cycle 21 (n=30, 27) | 3.2 units on a scale | Standard Deviation 20 |
| Pertuzumab + Trastuzumab + Vinorelbine: Separate Infusion | Change From Baseline in European Quality of Life-5 Dimensions (EQ-5D) Questionnaire Visual Analogue Scale (VAS) Score | Change at Cycle 3 (n = 83, 90) | 0.9 units on a scale | Standard Deviation 19.31 |
| Pertuzumab + Trastuzumab + Vinorelbine: Separate Infusion | Change From Baseline in European Quality of Life-5 Dimensions (EQ-5D) Questionnaire Visual Analogue Scale (VAS) Score | Change at Cycle 24 (n=25, 26) | 3.1 units on a scale | Standard Deviation 17.06 |
| Pertuzumab + Trastuzumab + Vinorelbine: Separate Infusion | Change From Baseline in European Quality of Life-5 Dimensions (EQ-5D) Questionnaire Visual Analogue Scale (VAS) Score | Change at Cycle 30 (n=18, 19) | 5.4 units on a scale | Standard Deviation 19.87 |
| Pertuzumab + Trastuzumab + Vinorelbine: Separate Infusion | Change From Baseline in European Quality of Life-5 Dimensions (EQ-5D) Questionnaire Visual Analogue Scale (VAS) Score | Change at Cycle 27 (n=21, 24) | 5.9 units on a scale | Standard Deviation 18.79 |
| Pertuzumab + Trastuzumab + Vinorelbine: Separate Infusion | Change From Baseline in European Quality of Life-5 Dimensions (EQ-5D) Questionnaire Visual Analogue Scale (VAS) Score | Change at Cycle 6 (n=68, 82) | 1.0 units on a scale | Standard Deviation 23.59 |
| Pertuzumab + Trastuzumab + Vinorelbine: Separate Infusion | Change From Baseline in European Quality of Life-5 Dimensions (EQ-5D) Questionnaire Visual Analogue Scale (VAS) Score | Change at Cycle 33 (n=15, 15) | 2.9 units on a scale | Standard Deviation 24.03 |
| Pertuzumab + Trastuzumab + Vinorelbine: Separate Infusion | Change From Baseline in European Quality of Life-5 Dimensions (EQ-5D) Questionnaire Visual Analogue Scale (VAS) Score | Baseline (n = 102, 102) | 69.7 units on a scale | Standard Deviation 22.74 |
| Pertuzumab + Trastuzumab + Vinorelbine: Separate Infusion | Change From Baseline in European Quality of Life-5 Dimensions (EQ-5D) Questionnaire Visual Analogue Scale (VAS) Score | Change at Cycle 36 (n=14, 7) | 4.8 units on a scale | Standard Deviation 17.37 |
| Pertuzumab + Trastuzumab + Vinorelbine: Separate Infusion | Change From Baseline in European Quality of Life-5 Dimensions (EQ-5D) Questionnaire Visual Analogue Scale (VAS) Score | Change at Cycle 9 (n=67, 68) | 2.2 units on a scale | Standard Deviation 23 |
| Pertuzumab + Trastuzumab + Vinorelbine: Separate Infusion | Change From Baseline in European Quality of Life-5 Dimensions (EQ-5D) Questionnaire Visual Analogue Scale (VAS) Score | Change at Cycle 39 (n=6, 1) | 15.8 units on a scale | Standard Deviation 19.85 |
| Pertuzumab + Trastuzumab + Vinorelbine: Separate Infusion | Change From Baseline in European Quality of Life-5 Dimensions (EQ-5D) Questionnaire Visual Analogue Scale (VAS) Score | Change at Cycle 15 (n=43, 43) | 6.3 units on a scale | Standard Deviation 19.34 |
| Pertuzumab + Trastuzumab + Vinorelbine: Separate Infusion | Change From Baseline in European Quality of Life-5 Dimensions (EQ-5D) Questionnaire Visual Analogue Scale (VAS) Score | Change at Cycle 42 (n=2, 0) | -5.0 units on a scale | Standard Deviation 14.14 |
| Pertuzumab + Trastuzumab + Vinorelbine: Separate Infusion | Change From Baseline in European Quality of Life-5 Dimensions (EQ-5D) Questionnaire Visual Analogue Scale (VAS) Score | Change at Cycle 12 (n=53, 59) | -1.4 units on a scale | Standard Deviation 30.19 |
| Pertuzumab + Trastuzumab + Vinorelbine: Separate Infusion | Change From Baseline in European Quality of Life-5 Dimensions (EQ-5D) Questionnaire Visual Analogue Scale (VAS) Score | Change at Cycle 45 (n=1, 0) | 5.0 units on a scale | — |
| Pertuzumab + Trastuzumab + Vinorelbine: Separate Infusion | Change From Baseline in European Quality of Life-5 Dimensions (EQ-5D) Questionnaire Visual Analogue Scale (VAS) Score | Change at Cycle 18 (n=32, 28) | 5.7 units on a scale | Standard Deviation 21.83 |
| Pertuzumab + Trastuzumab + Vinorelbine: Single Infusion | Change From Baseline in European Quality of Life-5 Dimensions (EQ-5D) Questionnaire Visual Analogue Scale (VAS) Score | Change at Cycle 45 (n=1, 0) | NA units on a scale | — |
| Pertuzumab + Trastuzumab + Vinorelbine: Single Infusion | Change From Baseline in European Quality of Life-5 Dimensions (EQ-5D) Questionnaire Visual Analogue Scale (VAS) Score | Change at Cycle 15 (n=43, 43) | 8.1 units on a scale | Standard Deviation 24.45 |
| Pertuzumab + Trastuzumab + Vinorelbine: Single Infusion | Change From Baseline in European Quality of Life-5 Dimensions (EQ-5D) Questionnaire Visual Analogue Scale (VAS) Score | Change at Cycle 18 (n=32, 28) | 6.5 units on a scale | Standard Deviation 22.12 |
| Pertuzumab + Trastuzumab + Vinorelbine: Single Infusion | Change From Baseline in European Quality of Life-5 Dimensions (EQ-5D) Questionnaire Visual Analogue Scale (VAS) Score | Change at Cycle 27 (n=21, 24) | 1.1 units on a scale | Standard Deviation 20.16 |
| Pertuzumab + Trastuzumab + Vinorelbine: Single Infusion | Change From Baseline in European Quality of Life-5 Dimensions (EQ-5D) Questionnaire Visual Analogue Scale (VAS) Score | Baseline (n = 102, 102) | 68.6 units on a scale | Standard Deviation 23.58 |
| Pertuzumab + Trastuzumab + Vinorelbine: Single Infusion | Change From Baseline in European Quality of Life-5 Dimensions (EQ-5D) Questionnaire Visual Analogue Scale (VAS) Score | Change at Cycle 3 (n = 83, 90) | 1.7 units on a scale | Standard Deviation 23.16 |
| Pertuzumab + Trastuzumab + Vinorelbine: Single Infusion | Change From Baseline in European Quality of Life-5 Dimensions (EQ-5D) Questionnaire Visual Analogue Scale (VAS) Score | Change at Cycle 6 (n=68, 82) | 4.3 units on a scale | Standard Deviation 24.49 |
| Pertuzumab + Trastuzumab + Vinorelbine: Single Infusion | Change From Baseline in European Quality of Life-5 Dimensions (EQ-5D) Questionnaire Visual Analogue Scale (VAS) Score | Change at Cycle 9 (n=67, 68) | 6.6 units on a scale | Standard Deviation 26.29 |
| Pertuzumab + Trastuzumab + Vinorelbine: Single Infusion | Change From Baseline in European Quality of Life-5 Dimensions (EQ-5D) Questionnaire Visual Analogue Scale (VAS) Score | Change at Cycle 21 (n=30, 27) | 1.3 units on a scale | Standard Deviation 28.5 |
| Pertuzumab + Trastuzumab + Vinorelbine: Single Infusion | Change From Baseline in European Quality of Life-5 Dimensions (EQ-5D) Questionnaire Visual Analogue Scale (VAS) Score | Change at Cycle 24 (n=25, 26) | 2.8 units on a scale | Standard Deviation 23.16 |
| Pertuzumab + Trastuzumab + Vinorelbine: Single Infusion | Change From Baseline in European Quality of Life-5 Dimensions (EQ-5D) Questionnaire Visual Analogue Scale (VAS) Score | Change at Cycle 30 (n=18, 19) | 9.5 units on a scale | Standard Deviation 19.68 |
| Pertuzumab + Trastuzumab + Vinorelbine: Single Infusion | Change From Baseline in European Quality of Life-5 Dimensions (EQ-5D) Questionnaire Visual Analogue Scale (VAS) Score | Change at Cycle 33 (n=15, 15) | 13.4 units on a scale | Standard Deviation 19.65 |
| Pertuzumab + Trastuzumab + Vinorelbine: Single Infusion | Change From Baseline in European Quality of Life-5 Dimensions (EQ-5D) Questionnaire Visual Analogue Scale (VAS) Score | Change at Cycle 36 (n=14, 7) | 7.3 units on a scale | Standard Deviation 21.72 |
| Pertuzumab + Trastuzumab + Vinorelbine: Single Infusion | Change From Baseline in European Quality of Life-5 Dimensions (EQ-5D) Questionnaire Visual Analogue Scale (VAS) Score | Change at Cycle 39 (n=6, 1) | 50.0 units on a scale | — |
| Pertuzumab + Trastuzumab + Vinorelbine: Single Infusion | Change From Baseline in European Quality of Life-5 Dimensions (EQ-5D) Questionnaire Visual Analogue Scale (VAS) Score | Change at Cycle 42 (n=2, 0) | NA units on a scale | — |
| Pertuzumab + Trastuzumab + Vinorelbine: Single Infusion | Change From Baseline in European Quality of Life-5 Dimensions (EQ-5D) Questionnaire Visual Analogue Scale (VAS) Score | Change at Cycle 12 (n=53, 59) | 6.8 units on a scale | Standard Deviation 23.59 |
Secondary
Change From Baseline in Functional Assessment of Cancer Therapy-Breast (FACT-B) Questionnaire Score
FACT-B questionnaire is used for assessment of health-related QoL in participants with breast cancer. It consists of 36 items, summarized to 5 subscales: physical (7 items), functional (7 items), social/family (7 items); all 3 ranged from 0 to 28, emotional (6 items) ranging from 0 to 24, and breast cancer subscale (9 items) ranging from 0 to 36; high subscale score represents a better QoL. All single-item measures ranges from 0='Not at all' to 4='Very much'. Total possible score ranged from 0 to 144. High scale score represents a better QoL.
Time frame: Baseline, thereafter every 3 cycles from Cycle 3 to Cycle 45 (each cycle = 21 days)
Population: ITT population. Here, 'Number of Participants Analyzed' signifies the number of participants evaluable for this outcome measure and 'n' signifies the number of participants evaluable at specified time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Pertuzumab + Trastuzumab + Vinorelbine: Separate Infusion | Change From Baseline in Functional Assessment of Cancer Therapy-Breast (FACT-B) Questionnaire Score | Change at Cycle 3 (n = 82, 90) | -1.96 units on a scale | Standard Deviation 10.872 |
| Pertuzumab + Trastuzumab + Vinorelbine: Separate Infusion | Change From Baseline in Functional Assessment of Cancer Therapy-Breast (FACT-B) Questionnaire Score | Change at Cycle 24 (n= 26, 23) | 1.19 units on a scale | Standard Deviation 10.66 |
| Pertuzumab + Trastuzumab + Vinorelbine: Separate Infusion | Change From Baseline in Functional Assessment of Cancer Therapy-Breast (FACT-B) Questionnaire Score | Change at Cycle 30 (n=18, 24) | 3.96 units on a scale | Standard Deviation 11.082 |
| Pertuzumab + Trastuzumab + Vinorelbine: Separate Infusion | Change From Baseline in Functional Assessment of Cancer Therapy-Breast (FACT-B) Questionnaire Score | Change at Cycle 27 (n=20, 22) | 4.91 units on a scale | Standard Deviation 9.9 |
| Pertuzumab + Trastuzumab + Vinorelbine: Separate Infusion | Change From Baseline in Functional Assessment of Cancer Therapy-Breast (FACT-B) Questionnaire Score | Change at Cycle 9 (n=65, 60) | 1.44 units on a scale | Standard Deviation 13.189 |
| Pertuzumab + Trastuzumab + Vinorelbine: Separate Infusion | Change From Baseline in Functional Assessment of Cancer Therapy-Breast (FACT-B) Questionnaire Score | Change at Cycle 15 (n=43, 44) | 2.72 units on a scale | Standard Deviation 10.989 |
| Pertuzumab + Trastuzumab + Vinorelbine: Separate Infusion | Change From Baseline in Functional Assessment of Cancer Therapy-Breast (FACT-B) Questionnaire Score | Change at Cycle 33 (n=14, 17) | 5.75 units on a scale | Standard Deviation 13.272 |
| Pertuzumab + Trastuzumab + Vinorelbine: Separate Infusion | Change From Baseline in Functional Assessment of Cancer Therapy-Breast (FACT-B) Questionnaire Score | Baseline (n = 100, 100) | 76.7 units on a scale | Standard Deviation 13.46 |
| Pertuzumab + Trastuzumab + Vinorelbine: Separate Infusion | Change From Baseline in Functional Assessment of Cancer Therapy-Breast (FACT-B) Questionnaire Score | Change at Cycle 36 (n=15, 13) | 1.26 units on a scale | Standard Deviation 9.21 |
| Pertuzumab + Trastuzumab + Vinorelbine: Separate Infusion | Change From Baseline in Functional Assessment of Cancer Therapy-Breast (FACT-B) Questionnaire Score | Change at Cycle 18 (n=32, 32) | 4.58 units on a scale | Standard Deviation 11.801 |
| Pertuzumab + Trastuzumab + Vinorelbine: Separate Infusion | Change From Baseline in Functional Assessment of Cancer Therapy-Breast (FACT-B) Questionnaire Score | Change at Cycle 39 (n=6, 6) | -3.68 units on a scale | Standard Deviation 16.866 |
| Pertuzumab + Trastuzumab + Vinorelbine: Separate Infusion | Change From Baseline in Functional Assessment of Cancer Therapy-Breast (FACT-B) Questionnaire Score | Change at Cycle 12 (n=52, 51) | 0.40 units on a scale | Standard Deviation 12.057 |
| Pertuzumab + Trastuzumab + Vinorelbine: Separate Infusion | Change From Baseline in Functional Assessment of Cancer Therapy-Breast (FACT-B) Questionnaire Score | Change at Cycle 42 (n=4, 0) | -0.17 units on a scale | Standard Deviation 10.599 |
| Pertuzumab + Trastuzumab + Vinorelbine: Separate Infusion | Change From Baseline in Functional Assessment of Cancer Therapy-Breast (FACT-B) Questionnaire Score | Change at Cycle 21 (n=29, 24) | 3.22 units on a scale | Standard Deviation 13.178 |
| Pertuzumab + Trastuzumab + Vinorelbine: Separate Infusion | Change From Baseline in Functional Assessment of Cancer Therapy-Breast (FACT-B) Questionnaire Score | Change at Cycle 45 (n=1, 0) | 1.00 units on a scale | — |
| Pertuzumab + Trastuzumab + Vinorelbine: Separate Infusion | Change From Baseline in Functional Assessment of Cancer Therapy-Breast (FACT-B) Questionnaire Score | Change at Cycle 6 (n=70, 79) | -0.97 units on a scale | Standard Deviation 12.749 |
| Pertuzumab + Trastuzumab + Vinorelbine: Single Infusion | Change From Baseline in Functional Assessment of Cancer Therapy-Breast (FACT-B) Questionnaire Score | Change at Cycle 45 (n=1, 0) | NA units on a scale | — |
| Pertuzumab + Trastuzumab + Vinorelbine: Single Infusion | Change From Baseline in Functional Assessment of Cancer Therapy-Breast (FACT-B) Questionnaire Score | Change at Cycle 6 (n=70, 79) | 0.47 units on a scale | Standard Deviation 13.724 |
| Pertuzumab + Trastuzumab + Vinorelbine: Single Infusion | Change From Baseline in Functional Assessment of Cancer Therapy-Breast (FACT-B) Questionnaire Score | Change at Cycle 9 (n=65, 60) | -0.42 units on a scale | Standard Deviation 14.602 |
| Pertuzumab + Trastuzumab + Vinorelbine: Single Infusion | Change From Baseline in Functional Assessment of Cancer Therapy-Breast (FACT-B) Questionnaire Score | Change at Cycle 12 (n=52, 51) | 0.51 units on a scale | Standard Deviation 14.51 |
| Pertuzumab + Trastuzumab + Vinorelbine: Single Infusion | Change From Baseline in Functional Assessment of Cancer Therapy-Breast (FACT-B) Questionnaire Score | Baseline (n = 100, 100) | 78.5 units on a scale | Standard Deviation 16.06 |
| Pertuzumab + Trastuzumab + Vinorelbine: Single Infusion | Change From Baseline in Functional Assessment of Cancer Therapy-Breast (FACT-B) Questionnaire Score | Change at Cycle 3 (n = 82, 90) | -2.57 units on a scale | Standard Deviation 13.159 |
| Pertuzumab + Trastuzumab + Vinorelbine: Single Infusion | Change From Baseline in Functional Assessment of Cancer Therapy-Breast (FACT-B) Questionnaire Score | Change at Cycle 15 (n=43, 44) | 0.09 units on a scale | Standard Deviation 13.713 |
| Pertuzumab + Trastuzumab + Vinorelbine: Single Infusion | Change From Baseline in Functional Assessment of Cancer Therapy-Breast (FACT-B) Questionnaire Score | Change at Cycle 18 (n=32, 32) | 0.51 units on a scale | Standard Deviation 16.512 |
| Pertuzumab + Trastuzumab + Vinorelbine: Single Infusion | Change From Baseline in Functional Assessment of Cancer Therapy-Breast (FACT-B) Questionnaire Score | Change at Cycle 21 (n=29, 24) | -0.23 units on a scale | Standard Deviation 16.116 |
| Pertuzumab + Trastuzumab + Vinorelbine: Single Infusion | Change From Baseline in Functional Assessment of Cancer Therapy-Breast (FACT-B) Questionnaire Score | Change at Cycle 24 (n= 26, 23) | -1.03 units on a scale | Standard Deviation 14.546 |
| Pertuzumab + Trastuzumab + Vinorelbine: Single Infusion | Change From Baseline in Functional Assessment of Cancer Therapy-Breast (FACT-B) Questionnaire Score | Change at Cycle 27 (n=20, 22) | 0.55 units on a scale | Standard Deviation 14.185 |
| Pertuzumab + Trastuzumab + Vinorelbine: Single Infusion | Change From Baseline in Functional Assessment of Cancer Therapy-Breast (FACT-B) Questionnaire Score | Change at Cycle 30 (n=18, 24) | -0.26 units on a scale | Standard Deviation 17.381 |
| Pertuzumab + Trastuzumab + Vinorelbine: Single Infusion | Change From Baseline in Functional Assessment of Cancer Therapy-Breast (FACT-B) Questionnaire Score | Change at Cycle 33 (n=14, 17) | 1.76 units on a scale | Standard Deviation 19.179 |
| Pertuzumab + Trastuzumab + Vinorelbine: Single Infusion | Change From Baseline in Functional Assessment of Cancer Therapy-Breast (FACT-B) Questionnaire Score | Change at Cycle 36 (n=15, 13) | 2.74 units on a scale | Standard Deviation 14.354 |
| Pertuzumab + Trastuzumab + Vinorelbine: Single Infusion | Change From Baseline in Functional Assessment of Cancer Therapy-Breast (FACT-B) Questionnaire Score | Change at Cycle 39 (n=6, 6) | 7.33 units on a scale | Standard Deviation 20.992 |
| Pertuzumab + Trastuzumab + Vinorelbine: Single Infusion | Change From Baseline in Functional Assessment of Cancer Therapy-Breast (FACT-B) Questionnaire Score | Change at Cycle 42 (n=4, 0) | NA units on a scale | — |
Secondary
Duration of Response (DOR) as Assessed by Investigator According to RECIST v 1.1
DOR, in participants with a BOR of CR or PR, was defined as the period from the date of initial PR or CR until the date of PD or death from any cause. Participants with no documented PD or death after CR or PR were censored at the last date at which they were known to have had the CR or PR, respectively (regardless of the response at intermediate assessments). CR: the disappearance of all TLs and SA reduction to \<10 mm for nodal TLs/ non-TLs. PR: \>/=30% decrease in SD of TLs, taking as reference the baseline SD. Confirmation of response at 2 consecutive tumor assessments \>/=4 weeks apart was required. PD: \>/=20% relative increase and \>/=5 mm of absolute increase in the SD of TLs, taking as reference the smallest SD recorded since treatment started, or appearance of 1 or more new lesions. The 95% CI was computed using log-log transformation.
Time frame: Baseline, every 3 cycles up to 36 months, and every 6 cycles thereafter if progression free after 36 months, 28 days after end of treatment, every 3 months thereafter (maximum up to approximately 3.5 years)
Population: ITT population. Only participants with a BOR of CR or PR and with measurable disease at baseline were included in the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pertuzumab + Trastuzumab + Vinorelbine: Separate Infusion | Duration of Response (DOR) as Assessed by Investigator According to RECIST v 1.1 | 13.3 months |
| Pertuzumab + Trastuzumab + Vinorelbine: Single Infusion | Duration of Response (DOR) as Assessed by Investigator According to RECIST v 1.1 | 11.8 months |
Secondary
Overall Survival (OS)
OS was defined as the time from first intake of any study medication to the date of death, regardless of the cause of death. Participants who were known to be alive at the time of the analysis were censored at the date of the last follow-up assessment. Participants without follow-up assessment were censored at the day of last study treatment, and participants with no post-baseline information were censored at the date of first study treatment plus 1 day. Participants who died due to any cause were considered as having an event. The median OS was estimated using Kaplan-Meier method. The 95% CI was computed using log-log transformation.
Time frame: Baseline until death (up to approximately 3.5 years)
Population: ITT population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pertuzumab + Trastuzumab + Vinorelbine: Separate Infusion | Overall Survival (OS) | NA months |
| Pertuzumab + Trastuzumab + Vinorelbine: Single Infusion | Overall Survival (OS) | NA months |
Secondary
Percentage of Participants Who Died From Any Cause
Percentage of participants who died due to any cause was reported.
Time frame: Baseline until death (up to approximately 3.5 years)
Population: ITT population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pertuzumab + Trastuzumab + Vinorelbine: Separate Infusion | Percentage of Participants Who Died From Any Cause | 21.7 percentage of participants |
| Pertuzumab + Trastuzumab + Vinorelbine: Single Infusion | Percentage of Participants Who Died From Any Cause | 21.5 percentage of participants |
Secondary
Percentage of Participants With Disease Progression as Assessed by Investigator According to RECIST v1.1
PD was defined as \>/=20% relative increase and \>/=5 mm of absolute increase in the SD of TLs, taking as reference the smallest SD recorded since treatment started, or appearance of 1 or more new lesions. Percentage of participants with radio-graphically documented PD as assessed by investigator according to RECIST v1.1 was reported.
Time frame: Baseline, every 3 cycles up to 36 months, and every 6 cycles thereafter if progression free after 36 months, 28 days after end of treatment, every 3 months thereafter (maximum up to approximately 3.5 years)
Population: ITT population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pertuzumab + Trastuzumab + Vinorelbine: Separate Infusion | Percentage of Participants With Disease Progression as Assessed by Investigator According to RECIST v1.1 | 67.9 percentage of participants |
| Pertuzumab + Trastuzumab + Vinorelbine: Single Infusion | Percentage of Participants With Disease Progression as Assessed by Investigator According to RECIST v1.1 | 61.7 percentage of participants |
Secondary
Percentage of Participants With Disease Progression as Assessed by Investigator According to RECIST v1.1 or Death From Any Cause
PD was defined as \>/=20% relative increase and \>/=5 mm of absolute increase in the SD of TLs, taking as reference the smallest SD recorded since treatment started, or appearance of 1 or more new lesions. Percentage of participants with radio-graphically documented PD as assessed by investigator according to RECIST v1.1 or death due to any cause was reported.
Time frame: Baseline, every 3 cycles up to 36 months, and every 6 cycles thereafter if progression free after 36 months, 28 days after end of treatment, every 3 months thereafter (maximum up to approximately 3.5 years)
Population: ITT population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pertuzumab + Trastuzumab + Vinorelbine: Separate Infusion | Percentage of Participants With Disease Progression as Assessed by Investigator According to RECIST v1.1 or Death From Any Cause | 69.8 percentage of participants |
| Pertuzumab + Trastuzumab + Vinorelbine: Single Infusion | Percentage of Participants With Disease Progression as Assessed by Investigator According to RECIST v1.1 or Death From Any Cause | 67.3 percentage of participants |
Secondary
Progression-free Survival (PFS) as Assessed by Investigator According to RECIST v 1.1
PFS was defined as the time from first intake of any study medication until the first radio-graphically documented PD as assessed by investigator according to RECIST v1.1 or death due to any cause, whichever occurred first. Participants with no PFS events were censored at the time of the last evaluable tumor assessment. Participants with no baseline or no tumor assessment after the baseline visit were censored on the date of first study treatment. PD: \>/=20% relative increase and \>/=5 mm of absolute increase in the SD of TLs, taking as reference the smallest SD recorded since treatment started, or appearance of 1 or more new lesions. Participants who had radio-graphically documented PD as assessed by investigator according to RECIST v1.1 or died due to any cause were considered as having an event. The median PFS was estimated using Kaplan-Meier method. The 95% CI was computed using log-log transformation.
Time frame: Baseline, every 3 cycles up to 36 months, and every 6 cycles thereafter if progression free after 36 months, 28 days after end of treatment, every 3 months thereafter (maximum up to approximately 3.5 years)
Population: ITT population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pertuzumab + Trastuzumab + Vinorelbine: Separate Infusion | Progression-free Survival (PFS) as Assessed by Investigator According to RECIST v 1.1 | 14.3 months |
| Pertuzumab + Trastuzumab + Vinorelbine: Single Infusion | Progression-free Survival (PFS) as Assessed by Investigator According to RECIST v 1.1 | 11.5 months |
Secondary
Time to Progression (TTP) as Assessed by Investigator According to RECIST v 1.1
TTP was defined as the time from first intake of any study medication until the first radio-graphically documented PD as assessed by investigator according to RECIST v1.1. Participants who did not have a radio-graphically documented PD and had died due to reason other than PD were censored on the last available tumor assessment prior to the death date. Participants with no baseline or no tumor assessment after the baseline visit were censored on the date of first study treatment. PD was defined as \>/=20% relative increase and \>/=5 mm of absolute increase in the SD of TLs, taking as reference the smallest SD recorded since treatment started, or appearance of 1 or more new lesions. Participants who had radio-graphically documented PD as assessed by investigator according to RECIST v1.1 were considered as having an event. The median TTP was estimated using Kaplan-Meier method. The 95% CI was computed using log-log transformation.
Time frame: Baseline, every 3 cycles up to 36 months, and every 6 cycles thereafter if progression free after 36 months, 28 days after end of treatment, every 3 months thereafter (maximum up to approximately 3.5 years)
Population: ITT population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pertuzumab + Trastuzumab + Vinorelbine: Separate Infusion | Time to Progression (TTP) as Assessed by Investigator According to RECIST v 1.1 | 14.9 months |
| Pertuzumab + Trastuzumab + Vinorelbine: Single Infusion | Time to Progression (TTP) as Assessed by Investigator According to RECIST v 1.1 | 12.8 months |
Secondary
Time to Response as Assessed by Investigator According to RECIST v 1.1
For participants with a BOR of CR or PR, time to response = (Date of first confirmed CR/PR - Date of first study treatment) + 1. For participants without a CR or PR, time to response = (Date of adequate last tumor assessment - Date of first study treatment) + 1. For participant with no tumor assessment (or if all assessments were progressive disease \[PD\]) the censoring day was set to date of first study treatment +1. CR: the disappearance of all TLs and SA reduction to \<10 mm for nodal TLs/ non-TLs. PR: \>/=30% decrease in SD of TLs, taking as reference the baseline SD. Confirmation of response at 2 consecutive tumor assessments \>/=4 weeks apart was required. PD: \>/=20% relative increase and \>/=5 mm of absolute increase in the SD of TLs, taking as reference the smallest SD recorded since treatment started, or appearance of 1 or more new lesions. The 95% CI was computed using log-log transformation.
Time frame: Baseline, every 3 cycles up to 36 months, and every 6 cycles thereafter if progression free after 36 months, 28 days after end of treatment, every 3 months thereafter (maximum up to approximately 3.5 years)
Population: ITT population. Only participants with measurable disease at baseline were included in the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pertuzumab + Trastuzumab + Vinorelbine: Separate Infusion | Time to Response as Assessed by Investigator According to RECIST v 1.1 | 2.1 months |
| Pertuzumab + Trastuzumab + Vinorelbine: Single Infusion | Time to Response as Assessed by Investigator According to RECIST v 1.1 | 2.2 months |