Outcome
| Type |
Measure |
Description |
Time frame |
Safety issue |
| Primary |
Percentage of Participants With at Least One Event of New York Heart Association (NYHA) Class III or IV Heart Failure During the Neoadjuvant Treatment Period |
Symptomatic left ventricular systolic dysfunction (otherwise referred to as heart failure) is a serious adverse event. The NYHA Functional Classification System for Heart Failure considers the patient's symptoms: Class III: Marked limitation of physical activity; Comfortable at rest, but less than ordinary activity causes fatigue, palpitation, or dyspnea. Class IV: Unable to carry on any physical activity without discomfort; Symptoms of heart failure at rest; If any physical activity is undertaken, discomfort increases. The 95% CIs were calculated with the Clopper-Pearson method. Results included events with onset from first dose of pertuzumab/trastuzumab prior to surgery through the day before the first dose of any study drug after surgery. If participant withdrew without entering adjuvant period, results included all events with onset from first dose of pertuzumab/trastuzumab through 42 days after last dose of any study drug or on the day of target surgery whichever was later. |
From day of first dose of pertuzumab or trastuzumab until the end of the neoadjuvant treatment period (as defined in the description; up to 25 weeks) |
|
| Primary |
Percentage of Participants With at Least One Left Ventricular Ejection Fraction (LVEF) Significant Decline, Defined as a Drop in LVEF of at Least 10 Percentage Points From Baseline and to Below 50%, During the Neoadjuvant Treatment Period |
LVEF significant decline was defined as the decline in LVEF of >/= 10%-points from baseline to an LVEF of < 50%. A Confirmed LVEF Significant Decline was defined as at least two consecutive readings of significant declines in LVEF. A Single LVEF Significant Decline was defined as only one reading of a significant decline (no consecutive readings) in LVEF. The category of 'At Least one LVEF Significant Decline Event' was defined as the total of confirmed and single LVEF significant declines. The 95% confidence intervals (CIs) were calculated using the Clopper-Pearson method. Results include events with onset from the first dose of pertuzumab or trastuzumab prior to surgery through the day before the first dose of any study drug after surgery. If participant withdrew without entering adjuvant period, results included all events with onset from first dose of pertuzumab or trastuzumab through 42 days after last dose of any study drug or on the day of target surgery whichever is later. |
From day of first dose of pertuzumab or trastuzumab until the end of the neoadjuvant treatment period (as defined in the description; up to 25 weeks) |
|
| Secondary |
Percentage of Participants With at Least One Event of New York Heart Association (NYHA) Class III or IV Heart Failure During the Adjuvant Treatment Period |
Symptomatic left ventricular systolic dysfunction (otherwise referred to as heart failure) is a serious adverse event. The NYHA Functional Classification System for Heart Failure considers the patient's symptoms: Class III: Marked limitation of physical activity; Comfortable at rest, but less than ordinary activity causes fatigue, palpitation, or dyspnea. Class IV: Unable to carry on any physical activity without discomfort; Symptoms of heart failure at rest; If any physical activity is undertaken, discomfort increases. The 95% CIs were calculated with the Clopper-Pearson method. Results included events with onset from the first dose of any study drug after surgery through 42 days after the last dose of any study drug. |
From the first dose of any study drug after surgery through 42 days after the last dose of any study drug (during the adjuvant treatment period; up to approximately 39 weeks) |
|
| Secondary |
Percentage of Participants With at Least One Left Ventricular Ejection Fraction (LVEF) Significant Decline, Defined as a Drop in LVEF of at Least 10 Percentage Points From Baseline and to Below 50%, During the Adjuvant Treatment Period |
LVEF significant decline was defined as the decline in LVEF of >/= 10%-points from baseline to an LVEF of < 50%. A Confirmed LVEF Significant Decline was defined as at least two consecutive readings of significant declines in LVEF. A Single LVEF Significant Decline was defined as only one reading of a significant decline (no consecutive readings) in LVEF. The category of 'At Least one LVEF Significant Decline Event' was defined as the total of confirmed and single LVEF significant declines. The 95% confidence intervals were calculated using the Clopper-Pearson method. Results included events with onset from the first dose of any study drug after surgery through 42 days after the last dose of any study drug. |
From the first dose of any study drug after surgery through 42 days after the last dose of any study drug (during the adjuvant treatment period; up to approximately 39 weeks) |
|
| Secondary |
Percentage of Participants With at Least One Event of New York Heart Association (NYHA) Class III or IV Heart Failure During the Treatment-Free Follow-Up Period |
Symptomatic left ventricular systolic dysfunction (otherwise referred to as heart failure) is a serious adverse event. The NYHA Functional Classification System for Heart Failure considers the patient's symptoms: Class III: Marked limitation of physical activity; Comfortable at rest, but less than ordinary activity causes fatigue, palpitation, or dyspnea. Class IV: Unable to carry on any physical activity without discomfort; Symptoms of heart failure at rest; If any physical activity is undertaken, discomfort increases. The 95% CIs were calculated with the Clopper-Pearson method. |
From 42 days after the last dose of study treatment until the end of treatment-free follow-up (up to 5 years) |
|
| Secondary |
Percentage of Participants With at Least One Left Ventricular Ejection Fraction (LVEF) Significant Decline, Defined as a Drop in LVEF of at Least 10 Percentage Points From Baseline and to Below 50%, During the Treatment-Free Follow-Up Period |
LVEF significant decline was defined as the decline in LVEF of >/= 10%-points from baseline to an LVEF of < 50%. A Confirmed LVEF Significant Decline was defined as at least two consecutive readings of significant declines in LVEF. A Single LVEF Significant Decline was defined as only one reading of a significant decline (no consecutive readings) in LVEF. The category of 'At Least one LVEF Significant Decline Event' was defined as the total of confirmed and single LVEF significant declines. The 95% confidence intervals were calculated using the Clopper-Pearson method. |
From 42 days after the last dose of study treatment until the end of treatment-free follow-up (up to 5 years) |
|
| Secondary |
Overview of the Number of Participants With at Least One Adverse Event During the Neoadjuvant Period |
An adverse event (AE) is any untoward medical occurrence in a clinical investigation subject administered a pharmaceutical product, regardless of causal attribution. The terms "severe" and "serious" are not synonymous with respect to an AE. Severity refers to the intensity of an AE (rated according to NCI-CTCAE v4.0 criteria or, if not listed, the following scale: Grade 3 is severe, Grade 4 is life-threatening, and Grade 5 is death related to AE), whereas a serious AE (SAE) is a significant medical event (per standard criteria). Severity and seriousness needed to be independently assessed for each AE that was recorded. Selected AEs for reporting included heart failure (NYHA Class II/III/IV) and asymptomatic declines in LVEF (reported as an AE with the term of ejection fraction decreased). In the results table, multiple occurrences of the same AE in one individual were counted only once. Any AE includes all serious and non-serious AEs. |
From first dose of any study drug prior to surgery through the day before the first dose of study drug after surgery (up to 25 weeks) |
|
| Secondary |
Overview of the Number of Participants With at Least One Adverse Event During the Adjuvant Period |
An adverse event (AE) is any untoward medical occurrence in a clinical investigation subject administered a pharmaceutical product, regardless of causal attribution. The terms "severe" and "serious" are not synonymous with respect to an AE. Severity refers to the intensity of an AE (rated according to NCI-CTCAE v4.0 criteria or, if not listed, the following scale: Grade 3 is severe, Grade 4 is life-threatening, and Grade 5 is death related to AE), whereas a serious AE (SAE) is a significant medical event (per standard criteria). Severity and seriousness needed to be independently assessed for each AE that was recorded. Selected AEs for reporting included heart failure (NYHA Class II/III/IV) and asymptomatic declines in LVEF (reported as an AE with the term of ejection fraction decreased). In the results table, multiple occurrences of the same AE in one individual were counted only once. Any AE includes all serious and non-serious AEs. |
From the first dose of any study drug after surgery through 42 days after the last dose of any study drug (during the adjuvant treatment period; up to approximately 39 weeks) |
|
| Secondary |
Overview of the Number of Participants With at Least One Adverse Event During the Treatment-Free Follow-Up Period |
An adverse event (AE) is any untoward medical occurrence in a clinical investigation subject administered a pharmaceutical product, regardless of causal attribution. The terms "severe" and "serious" are not synonymous. Severity refers to the intensity of an AE (rated according to NCI-CTCAE v4.0 criteria or, if not listed, the following scale: Grade 3 is severe, Grade 4 is life-threatening, and Grade 5 is death related to AE), and a serious AE (SAE) is a significant medical event (per standard criteria). Severity and seriousness were independently assessed for each AE. Selected AEs for reporting included heart failure (NYHA Class II/III/IV) and asymptomatic declines in LVEF (reported as ejection fraction decreased). During TFFU, only heart failure, pregnancies, and non-breast-related second primary malignancies, irrespective of causal relationship with study treatment, and drug-related SAEs were reported. Multiple occurrences of the same AE in 1 subject were counted only once. |
From 42 days after the last dose of study treatment until the end of treatment-free follow-up (TFFU; up to 5 years) |
|
| Secondary |
Percentage of Participants Positive for Anti-Therapeutic Antibodies (ATAs) to Pertuzumab at Baseline and Anytime Post-Baseline |
ATAs to pertuzumab in serum samples were detected using a validated bridging enzyme-linked immunosorbent assay (ELISA) method. This analysis only included participants with an ATA assay result from a baseline sample and/or at least one post-baseline sample. |
Screening (baseline) then prior to pertuzumab infusion (Hour 0) in Cycles 5, 14, 18 thereafter anytime between Cycle 8 Day 21 and surgery, up to treatment completion visit (cycle length=2-3 weeks; up to approximately 1 year, 3 months) |
|
| Secondary |
Percentage of Participants With Total Pathologic Complete Response (tpCR), Evaluated After Surgery |
Total pathologic complete response (tpCR) was the pCR based on tumor and nodal staging (i.e., histological confirmation of pCR in breast and nodes at surgery) and was defined as the absence of any residual invasive cancer in the breast and the absence of any metastatic cells in the regional lymph nodes (i.e., ypT0/is ypN0 tpCR). Participants who did not undergo surgery or did not have a valid pCR assessment were considered non-responders in the analysis. The 95% CIs were calculated using the Clopper-Pearson method. |
After completion of neoadjuvant treatment and surgery (up to 25 weeks) |
|
| Secondary |
Percentage of Participants With Clinical Response as Determined by the Investigator According to Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1 During the Neoadjuvant Treatment Period |
The clinical response rate was defined as the percentage of participants in the ITT population who achieved a complete response (CR) or partial response (PR) prior to surgery, according to RECIST v1.1. CR: disappearance of all target lesions. PR: at least a 30% decrease in the sum of the longest diameter compared to Baseline. Stable Disease (SD): neither sufficient shrinkage to qualify for PR nor sufficient (20%) increase to qualify for disease progression, in addition to no new target lesions. Progressive Disease (PD): at least a 20% increase in the sum of the longest diameter, taking as reference the smallest sum of the longest diameter observed at previous tumor assessment, or the appearance of any new lesions. Participants were classified as missing or unevaluable if no assessments were measured prior to surgery on the ipsilateral breast. The 95% CIs were calculated using the Clopper-Pearson method; they were only calculated for responses (not for missing or unevaluable data). |
From Baseline until disease progression or death due to any cause up to 24 weeks (during the neoadjuvant treatment period; assessed on Day 1 of Cycles 1-8 [cycle length=2-3 weeks]) |
|
| Secondary |
Kaplan-Meier Estimate of the Percentage of Participants Event-Free for Event-Free Survival (EFS) at 1 to 5 Years, Determined by the Investigator According to RECIST v1.1 |
The Kaplan-Meier method was used to estimate the percentage of participants who were event-free at landmark timepoints. Event-free survival (EFS) was defined as the time from enrollment to the first occurrence of progressive disease (PD), relapse, or death from any cause, with tumor evaluations performed by the investigator according to RECIST v1.1. Ipsilateral or contralateral in situ disease and second primary non-breast cancers (including in situ carcinomas and non-melanoma skin cancers) were not counted as progressive disease or relapse. Participants who withdrew from the study without documented progression or relapse and for whom there existed evidence that evaluations had been made, were censored at the date of the last assessment at which the participant was known to be free from progressive disease or relapse. Participants with no tumor evaluations after baseline were censored at the date of enrollment plus 1 day. |
At 1, 2, 3, 4, and 5 years |
|
| Secondary |
Kaplan-Meier Estimate of the Percentage of Participants Event-Free for Invasive Disease-Free Survival (iDFS) at 1 to 4 Years, Determined by the Investigator According to RECIST v1.1 |
The Kaplan-Meier method was used to estimate the percentage of participants who were event-free at landmark timepoints. Invasive disease-free survival (iDFS) was defined as the time from the first date of no disease (the date of surgery) to the first documentation of progressive invasive disease, relapse, or death, with tumor evaluations performed by the investigator according to RECIST v1.1. Ipsilateral or contralateral in situ disease and second primary non-breast cancers (including in situ carcinomas and non-melanoma skin cancers) were not counted as progressive disease or relapse. Participants who withdrew from the study without documented progression or relapse and for whom there existed evidence that evaluations had been made, were censored at the date of the last assessment at which the participant was known to be alive and disease-free. Participants with no postbaseline information and participants who did not undergo surgery were excluded from the analysis. |
At 1, 2, 3, and 4 years |
|
| Secondary |
Kaplan-Meier Estimate of the Percentage of Participants Event-Free for Overall Survival (OS) at 1 to 5 Years |
The Kaplan-Meier method was used to estimate the percentage of participants who were event-free at landmark timepoints. Overall survival (OS) was defined as the time from enrollment to death from any cause. Participants who were alive or lost to follow-up were censored at their last known date in the study. Participants with no post-baseline assessments were censored at the date of enrollment plus 1 day. |
At 1, 2, 3, 4, and 5 years |
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