HER2-positive Early Breast Cancer
Conditions
Brief summary
This study will evaluate the pharmacokinetics, efficacy, and safety of the pertuzumab and trastuzumab fixed-dose combination for subcutaneous administration (PH FDC SC) as compared with those of the pertuzumab intravenous (IV) and trastuzumab IV formulations in Chinese participants with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer.
Interventions
DRUGPertuzumab IV
Pertuzumab will be administered as a fixed non-weight-based loading dose of 840-milligrams (mg) IV and then a 420-mg IV maintenance dose Q3W.
DRUGTrastuzumab IV
Trastuzumab will be administered as an 8-milligram per kilogram of body weight (mg/kg) IV loading dose and then 6 mg/kg IV maintenance dose Q3W.
DRUGPertuzumab and Trastuzumab FDC SC
The pertuzumab and trastuzumab fixed-dose combination for subcutaneous administration (PH FDC SC) will be administered SC at a fixed non-weight-based dose. A loading dose of 1200 mg SC pertuzumab and 600 mg SC trastuzumab is then followed by a maintenance dose of 600 mg SC pertuzumab and 600 mg SC trastuzumab Q3W.
DRUGDoxorubicin
Doxorubicin 60 milligrams per meter squared of body surface area (mg/m\^2) will be administered IV on Day 1 of each cycle of treatment (as part of AC Q3W) for Cycles 1-4.
DRUGCyclophosphamide
Cyclophosphamide 600 mg/m\^2 will be administered IV on Day 1 of each cycle of treatment (as part of AC Q3W) for Cycles 1-4.
DRUGDocetaxel
Docetaxel 75 mg/m\^2 will be administered IV on Day 1 of Cycle 5. At the investigator's discretion the dose may be escalated to 100 mg/m\^2 IV for Cycles 6-8 (Q3W) provided no dose-limiting toxicity occurs.
PROCEDURESurgery
Participants in both cohorts are scheduled to undergo surgery after 8 cycles of neoadjuvant therapy. Participants may undergo breast-conserving surgery or mastectomy according to routine clinical practice.
RADIATIONPost-Operative Radiotherapy
If indicated, radiotherapy is given after chemotherapy and surgery, during adjuvant HER2-targeted therapy and hormone therapy (for hormone-receptor positive disease).
DRUGHormone Therapy
For hormone receptor positive breast cancer, tamoxifen or aromatase inhibitors will be allowed as adjuvant hormone therapy for postmenopausal participants and with ovarian suppression or ablation for premenopausal participants in countries where it has been registered for this indication. Its use must be consistent with the registered label. Hormone therapy is given after chemotherapy and surgery during adjuvant HER2-targeted therapy.
Sponsors
Hoffmann-La Roche
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
* Ability to comply with the study protocol, in the investigator's judgment * Eastern Cooperative Oncology Group (ECOG) Performance Status greater or equal to (≤)1 * Stage II-IIIC (T2-T4 plus any N, or any T plus N1-3, M0), locally advanced, inflammatory, or early-stage, unilateral, and histologically confirmed invasive breast cancer * Primary tumor greater than (\>)2 centimeters (cm) in diameter, or node-positive disease (clinically or on imaging, and node positivity confirmed with cytology and/or histopathology) * Human Epidermal Growth Factor Receptor 2 (HER2)-positive breast cancer confirmed by a central laboratory prior to study enrollment. HER2-positive status will be determined based on pretreatment breast biopsy material and defined as 3+ by immunohistochemistry (IHC) and/or positive by HER2 amplification by in situ hybridization (ISH) with a ratio of ≥2 for the number of HER2 gene copies to the number of signals for chromosome 17 copies * Hormone receptor status of the primary tumor, centrally confirmed * Patient agreement to undergo mastectomy or breast conserving surgery after neoadjuvant therapy * Availability of formalin-fixed, paraffin-embedded (FFPE) tumor tissue for central confirmation of HER2, hormone receptor status, and PIK3CA mutational analyses * Baseline left ventricular ejection fraction (LVEF) ≥55% measured by echocardiogram (ECHO) or multiple-gated acquisition scan (MUGA) * For women of childbearing potential (WOCBP) who are sexually active: agreement to remain abstinent (refrain from heterosexual intercourse) or use one highly effective non-hormonal contraceptive method with a failure rate of less than (\<)1% per year, or two effective non-hormonal contraceptive methods during the treatment period and for 7 months after the last dose of HER2-targeted therapy, and agreement to refrain from donating eggs during this same period * For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use a condom in combination with a spermicidal foam, gel, film, cream, or suppository, and agreement to refrain from donating sperm, as specified in the protocol * A negative serum pregnancy test must be available prior to randomization for WOCBP (premenopausal women and women \<12 months after the onset of menopause), unless they have undergone surgical sterilization (removal of ovaries and/or uterus) * No major surgical procedure unrelated to breast cancer within 28 days prior to randomization or anticipation of the need for major surgery during the course of study treatment
Exclusion criteria
* Stage IV (metastatic) breast cancer * History of invasive breast cancer * History of concurrent or previously treated non-breast malignancies except for appropriately treated 1) non-melanoma skin cancer and/or 2) in situ carcinomas, including cervix, colon, and skin * Have received any previous systemic therapy (including chemotherapy, immunotherapy, HER2-targeted agents, endocrine therapy \[selective estrogen receptor modulators, aromatase inhibitors\], and antitumor vaccines) for treatment or prevention of breast cancer, or radiation therapy for treatment of cancer * Have a past history of ductal carcinoma in situ (DCIS) or lobular carcinoma in situ (LCIS) if they have received any systemic therapy for its treatment or radiation therapy to the ipsilateral breast * High-risk for breast cancer and have received chemopreventative drugs in the past * Multicentric (multiple tumors involving more than one quadrant) breast cancer, unless all tumors are HER2-positive * Bilateral breast cancer * Have undergone an excisional biopsy of primary tumor and/or axillary lymph nodes * Axillary lymph node dissection (ALND) prior to initiation of neoadjuvant therapy * Sentinel lymph node biopsy (SLNB) prior to neoadjuvant therapy * Treatment with any investigational drug within 28 days prior to randomization * Serious cardiac illness or medical conditions * Inadequate bone marrow function * Impaired liver function * Inadequate renal function with serum creatinine \>1.5X upper limit of normal (ULN) * Current severe, uncontrolled systemic disease that may interfere with planned treatment (e.g., clinically significant cardiovascular, pulmonary, or metabolic disease; wound-healing disorders) * Pregnant or breastfeeding, or intending to become pregnant during the study or within 7 months after the last dose of HER2-targeted therapy * Any serious medical condition or abnormality in clinical laboratory tests that, in the investigator's judgment, precludes the patient's safe participation in and completion of the study * Known active liver disease, for example, active viral hepatitis infection (i.e., hepatitis B or hepatitis C), autoimmune hepatic disorders, or sclerosing cholangitis * Concurrent, serious, uncontrolled infections, or known infection with HIV * Known hypersensitivity to study drugs, excipients, and/or murine proteins * Current chronic daily treatment with corticosteroids (dose \>10 milligrams \[mg\] methylprednisolone or equivalent excluding inhaled steroids) * History of other malignancy within 5 years prior to screening, except for appropriately treated carcinoma in situ of the cervix, colon, skin, and/or non-melanoma skin carcinoma * History of ventricular dysrhythmias or risk factors for ventricular dysrhythmias, such as structural heart disease (e.g., severe LVSD, left ventricular hypertrophy), coronary heart disease (symptomatic or with ischemia demonstrated by diagnostic testing), clinically significant electrolyte abnormalities (e.g., hypokalemia, hypomagnesemia, hypocalcemia), or family history of sudden unexplained death or long QT syndrome
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Serum Trough Concentration (Ctrough) of Pertuzumab During Cycle 7 (Pre-Dose Cycle 8) | Pre-dose at Cycle 8 (one cycle is 21 days) | The observed pertuzumab trough serum concentration (Ctrough) at Cycle 7 was assessed following 3 cycles of pertuzumab IV and trastuzumab IV or the fixed-dose combination (FDC) of pertuzumab and trastuzumab SC. The Per Protocol Pharmacokinetics (PK) analysis population includes all enrolled participants who adhered to the protocol. Exclusions from the Per Protocol PK analysis population were made for the following reasons: participants were missing the Ctrough pre-dose Cycle 8 PK sample, participants with a Ctrough sample collected with at least 2 days deviation from the planned date on Day 21 (i.e., before Day 19 or after Day 23), participants given a dose amount that deviated from the planned dose by \>20% within 3 cycles (from Cycle 5), participants with a dose delay of more than 7 days, a Cycle 7 subcutaneous injection site other than thigh was used, if the Cycle 8 IV pre-dose and post-dose PK samples were switched, and an assay error impacting Ctrough measurement. |
| Serum Ctrough of Trastuzumab During Cycle 7 (Pre-Dose Cycle 8) | Pre-dose at Cycle 8 (one cycle is 21 days) | The observed trastuzumab trough serum concentration (Ctrough) at Cycle 7 was assessed following 3 cycles of pertuzumab IV and trastuzumab IV or the fixed-dose combination (FDC) of pertuzumab and trastuzumab SC. The Per Protocol Pharmacokinetics (PK) analysis population includes all enrolled participants who adhered to the protocol. Exclusions from the Per Protocol PK analysis population were made for the following reasons: participants were missing the Ctrough pre-dose Cycle 8 PK sample, participants with a Ctrough sample collected with at least 2 days deviation from the planned date on Day 21 (i.e., before Day 19 or after Day 23), participants given a dose amount that deviated from the planned dose by \>20% within 3 cycles (from Cycle 5), participants with a dose delay of more than 7 days, a Cycle 7 subcutaneous injection site other than thigh was used, if the Cycle 8 IV pre-dose and post-dose PK samples were switched, and an assay error impacting Ctrough measurement. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Total Pathological Complete Response (tpCR), According to Local Pathologist Assessment | Following completion of surgery (up to 33 weeks) | Total pathological complete response (tpCR) was defined as eradication of invasive disease in the breast and axilla; that is, ypT0/is ypN0, according to the local pathologists' assessment. Pathologic response to therapy was determined at the time of surgery. The tpCR rate is the percentage of participants in the ITT population who achieved a tpCR. Participants with missing data for tpCR (i.e., do not undergo surgery or have an invalid pCR assessment) were included in the analysis and classified as non-responders. Rates of tpCR were calculated in each treatment arm and were assessed using the difference between the Arm B: Pertuzumab and Trastuzumab FDC SC and the Arm A: Pertuzumab IV and Trastuzumab IV tpCR rates and corresponding 95% Clopper-Pearson confidence intervals (CIs). The difference between the tpCR rates along with corresponding 95% Hauck-Anderson CIs were calculated. |
| Kaplan-Meier Estimate of the Percentage of Participants Who Are Event-Free According to Invasive Disease-Free Survival (iDFS; Excluding Second Primary Non-Breast Cancer [SPNBC]) Criteria | From date of surgery to iDFS (excluding SPNBC) event (up to 5 years) | iDFS (excluding SPNBC) is defined as the time from the first date of no disease (i.e., the date of primary surgery) to the first occurrence of one of the following events: ipsilateral invasive breast tumor recurrence; ipsilateral local-regional invasive breast cancer reccurrence; distant recurrence; contralateral invasive breast cancer; or death attributable to any cause. Ipsilateral or contralateral in situ disease and SPNBC (including in situ carcinomas and non-melanoma skin cancers) will not be counted as progressive disease or relapse. |
| Kaplan-Meier Estimate of the Percentage of Participants Who Are Event-Free According to iDFS (Including SPNBC) Criteria | From date of surgery to iDFS (including SPNBC) event (up to 5 years) | iDFS including SPNBC is defined in the same way as iDFS but including SPNBC as an event (with the exception of non-melanoma skin cancers and in situ carcinoma of any site). |
| Kaplan-Meier Estimate of the Percentage of Participants Who Are Event-Free According to Event-Free Survival (EFS; Excluding SPNBC) Criteria | From baseline to EFS (excluding SPNBC) event (up to 5.5 years) | EFS (excluding SPNBC) is defined as the time from enrollment to the first occurrence of one of the following events: breast cancer progression; breast cancer recurrence; or death from any cause. Ipsilateral or contralateral in situ disease and SPNBC (including in situ carcinomas and non-melanoma skin cancers) will not be counted as progressive disease or relapse. |
| Kaplan-Meier Estimate of the Percentage of Participants Who Are Event-Free According to EFS (Including SPNBC) Criteria | From baseline to EFS (including SPNBC) event (up to 5.5 years) | EFS including SPNBC is defined in the same way as EFS, but including SPNBC as an event (with the exception of non-melanoma skin cancers and in situ carcinoma of any site). |
| Kaplan-Meier Estimate of the Percentage of Participants Who Are Event-Free According to Distant Recurrence-Free Interval (DRFI) Criteria | From baseline to DFRI event (up to 5.5 years) | DRFI is defined as the time between randomization and the date of distant breast cancer recurrence. |
| Kaplan-Meier Estimate of the Percentage of Participants in Overall Survival | From baseline to death from any cause (up to 5.5 years) | — |
| Number of Participants With at Least One Adverse Event by Severity, Determined According to National Cancer Institute Common Terminology Criteria for Adverse Events Version 4 (NCI CTCAE v4) | From baseline until study completion (up to 5.5 years) | — |
| Number of Participants With a Primary Cardiac Event | From baseline until study completion (up to 5.5 years) | A primary cardiac event is defined as either a symptomatic ejection fraction decrease (heart failure) of New York Heart Association (NYHA) Class III/IV and a drop in left ventricular ejection fraction (LVEF) of at least 10-percentage points from baseline and to below 50%, or a definite or probable cardiac death. NYHA Class III is defined as: marked limitation of physical activity; comfortable at rest, but less than ordinary activity causes fatigue, palpitation, or dyspnea. NYHA Class IV is defined as: Inability to carry on any physical activity without discomfort; symptoms of cardiac insufficiency at rest; if any physical activity is undertaken, discomfort is increased. Definite cardiac death is defined as death due to heart failure, myocardial infarction, or documented primary arrhythmia. Probable cardiac death is defined as sudden unexpected death within 24 hours of a definite or probable cardiac event (e.g., syncope, cardiac arrest, chest pain, etc.) without documented etiology. |
| Number of Participants With a Secondary Cardiac Event, Defined as an Asymptomatic or Mildly Symptomatic Left Ventricular Systolic Dysfunction (LVSD) of NYHA Class II | From baseline until study completion (up to 5.5 years) | An LVSD ("Ejection fraction decreased") of NYHA Class II is defined as a left ventricular ejection fraction (LVEF) decrease of ≥10-percentage points below the baseline measurement to an absolute LVEF value of \<50%, confirmed by a second LVEF assessment within approximately 3 weeks also showing a documented drop. |
Countries
China
Contacts
STUDY_DIRECTORClinical Trials
Hoffmann-La Roche
Participant flow
Recruitment details
Participants were enrolled at 18 investigational sites in China.
Pre-assignment details
Participants with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer, who were candidates for preoperative neoadjuvant treatment in the clinical practice, were enrolled in the study.
Participants by arm
| Arm | Count |
|---|---|
| Arm A: Pertuzumab IV + Trastuzumab IV + Chemotherapy Participants received 8 cycles of neoadjuvant chemotherapy: 4 cycles of doxorubicin plus cyclophosphamide (AC) once every 3 weeks (Q3W) followed by docetaxel Q3W for 4 cycles. Pertuzumab and trastuzumab were given intravenously (IV) for 4 cycles Q3W concurrently with the taxane component of chemotherapy. After completing their neoadjuvant therapy, participants underwent surgery. Thereafter, participants received an additional 14 cycles of pertuzumab IV and trastuzumab IV for a total of 18 cycles. | 101 |
| Arm B: Pertuzumab and Trastuzumab FDC SC + Chemotherapy Participants received 8 cycles of neoadjuvant chemotherapy: 4 cycles of AC Q3W followed by docetaxel Q3W for 4 cycles. The pertuzumab and trastuzumab fixed-dose combination for subcutaneous administration (PH FDC SC) were given subcutaneously (SC) for 4 cycles (Q3W) concurrently with the taxane component of chemotherapy. After completing their neoadjuvant therapy, participants underwent surgery. Thereafter, participants received an additional 14 cycles of the PH FDC SC for a total of 18 cycles. | 99 |
| Total | 200 |
Baseline characteristics
| Characteristic | Arm A: Pertuzumab IV + Trastuzumab IV + Chemotherapy | Arm B: Pertuzumab and Trastuzumab FDC SC + Chemotherapy | Total |
|---|---|---|---|
| Age, Continuous | 51.17 Years STANDARD_DEVIATION 10.55 | 50.42 Years STANDARD_DEVIATION 10.01 | 50.80 Years STANDARD_DEVIATION 10.27 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 101 Participants | 99 Participants | 200 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 101 Participants | 99 Participants | 200 Participants |
| Randomization Stratification Factors: Clinical Stage at Presentation Stage IIIB-IIIC | 31 Participants | 29 Participants | 60 Participants |
| Randomization Stratification Factors: Clinical Stage at Presentation Stage II-IIIA | 70 Participants | 70 Participants | 140 Participants |
| Randomization Stratification Factors: Hormone Receptor Status ER Negative and PgR Negative | 51 Participants | 51 Participants | 102 Participants |
| Randomization Stratification Factors: Hormone Receptor Status ER Positive and PgR Positive | 50 Participants | 48 Participants | 98 Participants |
| Sex: Female, Male Female | 101 Participants | 99 Participants | 200 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 100 | 1 / 100 |
| other Total, other adverse events | 96 / 100 | 98 / 100 |
| serious Total, serious adverse events | 19 / 100 | 18 / 100 |
Outcome results
Primary
Serum Ctrough of Trastuzumab During Cycle 7 (Pre-Dose Cycle 8)
The observed trastuzumab trough serum concentration (Ctrough) at Cycle 7 was assessed following 3 cycles of pertuzumab IV and trastuzumab IV or the fixed-dose combination (FDC) of pertuzumab and trastuzumab SC. The Per Protocol Pharmacokinetics (PK) analysis population includes all enrolled participants who adhered to the protocol. Exclusions from the Per Protocol PK analysis population were made for the following reasons: participants were missing the Ctrough pre-dose Cycle 8 PK sample, participants with a Ctrough sample collected with at least 2 days deviation from the planned date on Day 21 (i.e., before Day 19 or after Day 23), participants given a dose amount that deviated from the planned dose by \>20% within 3 cycles (from Cycle 5), participants with a dose delay of more than 7 days, a Cycle 7 subcutaneous injection site other than thigh was used, if the Cycle 8 IV pre-dose and post-dose PK samples were switched, and an assay error impacting Ctrough measurement.
Time frame: Pre-dose at Cycle 8 (one cycle is 21 days)
Population: Trastuzumab Per Protocol PK Population: includes only participants who adhered to the pre-specified criteria for the schedule of pharmacokinetic assessments.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Arm A: Pertuzumab IV + Trastuzumab IV + Chemotherapy | Serum Ctrough of Trastuzumab During Cycle 7 (Pre-Dose Cycle 8) | 33.6 micrograms per milllilitre (μg/mL) | Geometric Coefficient of Variation 28.8 |
| Arm B: Pertuzumab and Trastuzumab FDC SC + Chemotherapy | Serum Ctrough of Trastuzumab During Cycle 7 (Pre-Dose Cycle 8) | 52.1 micrograms per milllilitre (μg/mL) | Geometric Coefficient of Variation 32.5 |
Comparison: The null hypothesis was that the trastuzumab Arm B SC dose is inferior to the Arm A trastuzumab IV dose (i.e., the CtroughSC/CtroughIV geometric mean ratio of the SC dose of trastuzumab relative to the IV dose is not greater than 0.8).90% CI: [1.44, 1.67]
Primary
Serum Trough Concentration (Ctrough) of Pertuzumab During Cycle 7 (Pre-Dose Cycle 8)
The observed pertuzumab trough serum concentration (Ctrough) at Cycle 7 was assessed following 3 cycles of pertuzumab IV and trastuzumab IV or the fixed-dose combination (FDC) of pertuzumab and trastuzumab SC. The Per Protocol Pharmacokinetics (PK) analysis population includes all enrolled participants who adhered to the protocol. Exclusions from the Per Protocol PK analysis population were made for the following reasons: participants were missing the Ctrough pre-dose Cycle 8 PK sample, participants with a Ctrough sample collected with at least 2 days deviation from the planned date on Day 21 (i.e., before Day 19 or after Day 23), participants given a dose amount that deviated from the planned dose by \>20% within 3 cycles (from Cycle 5), participants with a dose delay of more than 7 days, a Cycle 7 subcutaneous injection site other than thigh was used, if the Cycle 8 IV pre-dose and post-dose PK samples were switched, and an assay error impacting Ctrough measurement.
Time frame: Pre-dose at Cycle 8 (one cycle is 21 days)
Population: Pertuzumab Per Protocol PK Population: includes only participants who adhered to the pre-specified criteria for the schedule of pharmacokinetic assessments.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Arm A: Pertuzumab IV + Trastuzumab IV + Chemotherapy | Serum Trough Concentration (Ctrough) of Pertuzumab During Cycle 7 (Pre-Dose Cycle 8) | 69.9 micrograms per millilitre (μg/mL) | Geometric Coefficient of Variation 30.8 |
| Arm B: Pertuzumab and Trastuzumab FDC SC + Chemotherapy | Serum Trough Concentration (Ctrough) of Pertuzumab During Cycle 7 (Pre-Dose Cycle 8) | 74.6 micrograms per millilitre (μg/mL) | Geometric Coefficient of Variation 30.5 |
Comparison: The null hypothesis was that the pertuzumab Arm B SC dose is inferior to the pertuzumab Arm A IV dose (i.e., the CtroughSC/CtroughIV geometric mean ratio of the SC dose of pertuzumab relative to the IV dose is not greater than 0.8).90% CI: [0.99, 1.15]
Secondary
Kaplan-Meier Estimate of the Percentage of Participants in Overall Survival
Time frame: From baseline to death from any cause (up to 5.5 years)
Secondary
Kaplan-Meier Estimate of the Percentage of Participants Who Are Event-Free According to Distant Recurrence-Free Interval (DRFI) Criteria
DRFI is defined as the time between randomization and the date of distant breast cancer recurrence.
Time frame: From baseline to DFRI event (up to 5.5 years)
Secondary
Kaplan-Meier Estimate of the Percentage of Participants Who Are Event-Free According to EFS (Including SPNBC) Criteria
EFS including SPNBC is defined in the same way as EFS, but including SPNBC as an event (with the exception of non-melanoma skin cancers and in situ carcinoma of any site).
Time frame: From baseline to EFS (including SPNBC) event (up to 5.5 years)
Secondary
Kaplan-Meier Estimate of the Percentage of Participants Who Are Event-Free According to Event-Free Survival (EFS; Excluding SPNBC) Criteria
EFS (excluding SPNBC) is defined as the time from enrollment to the first occurrence of one of the following events: breast cancer progression; breast cancer recurrence; or death from any cause. Ipsilateral or contralateral in situ disease and SPNBC (including in situ carcinomas and non-melanoma skin cancers) will not be counted as progressive disease or relapse.
Time frame: From baseline to EFS (excluding SPNBC) event (up to 5.5 years)
Secondary
Kaplan-Meier Estimate of the Percentage of Participants Who Are Event-Free According to iDFS (Including SPNBC) Criteria
iDFS including SPNBC is defined in the same way as iDFS but including SPNBC as an event (with the exception of non-melanoma skin cancers and in situ carcinoma of any site).
Time frame: From date of surgery to iDFS (including SPNBC) event (up to 5 years)
Secondary
Kaplan-Meier Estimate of the Percentage of Participants Who Are Event-Free According to Invasive Disease-Free Survival (iDFS; Excluding Second Primary Non-Breast Cancer [SPNBC]) Criteria
iDFS (excluding SPNBC) is defined as the time from the first date of no disease (i.e., the date of primary surgery) to the first occurrence of one of the following events: ipsilateral invasive breast tumor recurrence; ipsilateral local-regional invasive breast cancer reccurrence; distant recurrence; contralateral invasive breast cancer; or death attributable to any cause. Ipsilateral or contralateral in situ disease and SPNBC (including in situ carcinomas and non-melanoma skin cancers) will not be counted as progressive disease or relapse.
Time frame: From date of surgery to iDFS (excluding SPNBC) event (up to 5 years)
Secondary
Number of Participants With a Primary Cardiac Event
A primary cardiac event is defined as either a symptomatic ejection fraction decrease (heart failure) of New York Heart Association (NYHA) Class III/IV and a drop in left ventricular ejection fraction (LVEF) of at least 10-percentage points from baseline and to below 50%, or a definite or probable cardiac death. NYHA Class III is defined as: marked limitation of physical activity; comfortable at rest, but less than ordinary activity causes fatigue, palpitation, or dyspnea. NYHA Class IV is defined as: Inability to carry on any physical activity without discomfort; symptoms of cardiac insufficiency at rest; if any physical activity is undertaken, discomfort is increased. Definite cardiac death is defined as death due to heart failure, myocardial infarction, or documented primary arrhythmia. Probable cardiac death is defined as sudden unexpected death within 24 hours of a definite or probable cardiac event (e.g., syncope, cardiac arrest, chest pain, etc.) without documented etiology.
Time frame: From baseline until study completion (up to 5.5 years)
Secondary
Number of Participants With a Secondary Cardiac Event, Defined as an Asymptomatic or Mildly Symptomatic Left Ventricular Systolic Dysfunction (LVSD) of NYHA Class II
An LVSD (Ejection fraction decreased) of NYHA Class II is defined as a left ventricular ejection fraction (LVEF) decrease of ≥10-percentage points below the baseline measurement to an absolute LVEF value of \<50%, confirmed by a second LVEF assessment within approximately 3 weeks also showing a documented drop.
Time frame: From baseline until study completion (up to 5.5 years)
Secondary
Number of Participants With at Least One Adverse Event by Severity, Determined According to National Cancer Institute Common Terminology Criteria for Adverse Events Version 4 (NCI CTCAE v4)
Time frame: From baseline until study completion (up to 5.5 years)
Secondary
Percentage of Participants With Total Pathological Complete Response (tpCR), According to Local Pathologist Assessment
Total pathological complete response (tpCR) was defined as eradication of invasive disease in the breast and axilla; that is, ypT0/is ypN0, according to the local pathologists' assessment. Pathologic response to therapy was determined at the time of surgery. The tpCR rate is the percentage of participants in the ITT population who achieved a tpCR. Participants with missing data for tpCR (i.e., do not undergo surgery or have an invalid pCR assessment) were included in the analysis and classified as non-responders. Rates of tpCR were calculated in each treatment arm and were assessed using the difference between the Arm B: Pertuzumab and Trastuzumab FDC SC and the Arm A: Pertuzumab IV and Trastuzumab IV tpCR rates and corresponding 95% Clopper-Pearson confidence intervals (CIs). The difference between the tpCR rates along with corresponding 95% Hauck-Anderson CIs were calculated.
Time frame: Following completion of surgery (up to 33 weeks)
Population: ITT Population: includes all enrolled participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A: Pertuzumab IV + Trastuzumab IV + Chemotherapy | Percentage of Participants With Total Pathological Complete Response (tpCR), According to Local Pathologist Assessment | 56.4 percentage of participants |
| Arm B: Pertuzumab and Trastuzumab FDC SC + Chemotherapy | Percentage of Participants With Total Pathological Complete Response (tpCR), According to Local Pathologist Assessment | 55.6 percentage of participants |
95% CI: [-15.21, 13.45]