A Study of Pertuzumab With High-Dose Trastuzumab for the Treatment of Human Epidermal Growth Factor Receptor 2 (HER2)-Positive Metastatic Breast Cancer (MBC) With Central Nervous System (CNS) Progression Post-Radiotherapy

Responses were assessed by the investigator, based on magnetic resonance imaging (MRI) of the brain, physical examinations, routine neurological examinations, and corticosteroid dosing. An objective response in the central nervous system (CNS) was a complete response (CR) or partial response (PR) confirmed by repeat assessment, according to RANO-BM criteria. Among participants who achieved an objective response, duration of response in the CNS was defined as the time from documentation of the first CR or PR to the time of disease progression, relapse, or death from any cause. If a participant did not experience death or disease progression in the CNS before the end of the study, duration of response was censored on the last date the participant was known to be progression free. Duration of response was estimated by the Kaplan-Meier method.

Responses were assessed by the investigator, based on magnetic resonance imaging (MRI) of the brain, physical examinations, routine neurological examinations, and corticosteroid dosing. Clinical benefit in the central nervous system (CNS) was defined here as a complete response (CR), partial response (PR), or stable disease (SD) for at least 4 months, confirmed by repeat assessment according to RANO-BM criteria. A CR or PR were defined in the same way as for objective response in the CNS. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum longest diameter (LD) while on study. The 95% Clopper-Pearson exact confidence intervals were calculated for responses.

Responses were assessed by the investigator, based on magnetic resonance imaging (MRI) of the brain, physical examinations, routine neurological examinations, and corticosteroid dosing. Clinical benefit in the central nervous system (CNS) was defined here as a complete response (CR), partial response (PR), or stable disease (SD) for at least 4 months, confirmed by repeat assessment according to RANO-BM criteria. Among participants who achieved clinical benefit, duration of clinical benefit in the CNS was defined as the time from documentation of the first CR, PR, or SD ≥4 months to the time of disease progression, relapse, or death from any cause. If a participant did not experience death or disease progression in the CNS before the end of the study, duration of clinical benefit was censored on the last date the participant was known to be progression free. Duration of clinical benefit was estimated by the Kaplan-Meier method.

Responses were assessed by the investigator, based on magnetic resonance imaging (MRI) of the brain, physical examinations, routine neurological examinations, and corticosteroid dosing. Clinical benefit in the central nervous system (CNS) was defined here as a complete response (CR), partial response (PR), or stable disease (SD) for at least 6 months, confirmed by repeat assessment according to RANO-BM criteria. A CR or PR were defined in the same way as for objective response in the CNS. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum longest diameter (LD) while on study. The 95% Clopper-Pearson exact confidence intervals were calculated for responses.

Responses were assessed by the investigator, based on magnetic resonance imaging (MRI) of the brain, physical examinations, routine neurological examinations, and corticosteroid dosing. Clinical benefit in the central nervous system (CNS) was defined here as a complete response (CR), partial response (PR), or stable disease (SD) for at least 6 months, confirmed by repeat assessment according to RANO-BM criteria. Among participants who achieved clinical benefit, duration of clinical benefit in the CNS was defined as the time from documentation of the first CR, PR, or SD ≥6 months to the time of disease progression, relapse, or death from any cause. If a participant did not experience death or disease progression in the CNS before the end of the study, duration of clinical benefit was censored on the last date the participant was known to be progression free. Duration of clinical benefit was estimated by the Kaplan-Meier method.

Progression-free survival (CNS) was defined as the time from the date of first dose to disease progression in the CNS or death from any cause. If no progressive disease in the CNS and no death occurred, progression-free survival (CNS) was censored on the date of the last CNS tumor assessment. If a post-baseline assessment was not available, progression-free survival (CNS) was censored on Day 1.

Progression-free survival (systemic) was defined as the time from the date of first dose to systemic disease progression or death from any cause. If no systemic disease progression and no death occurred, progression-free survival (systemic) was censored on the date of the last systemic tumor assessment. If a post-baseline assessment was not available, progression-free survival (systemic) was censored on Day 1.

Progression-free survival (CNS or systemic) was defined as the time from the date of first dose to CNS or systemic disease progression or death from any cause. If no CNS or systemic disease progression and no death occurred, data was censored on the date of the last CNS or systemic tumor assessment, whichever occurred first. If a post-baseline assessment was not available, data was censored on Day 1.

Overall survival was defined as the period from the date of first dose until the date of death from any cause. If no death occurred, overall survival was censored on the last date the participant was known to be alive.

Treatment-emergent adverse events (TEAEs) were defined as all adverse events occurring on or after Day 1 of study treatment until 30 days after the last dose of study treatment. All TEAEs were graded for severity using the NCI-CTCAE v4.0; any TEAE not specifically listed was assessed per the following 5 grades: Grade 1 = mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; or intervention not indicated. Grade 2 = moderate; minimal, local, or non-invasive intervention indicated; or limiting age-appropriate instrumental activities of daily living. Grade 3 = severe or medically significant, but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; or limiting self-care activities of daily living. Grade 4 = life-threatening consequences or urgent intervention indicated. Grade 5 = death related to adverse event. Multiple occurrences of TEAEs were counted only once per participant at the highest (worst) grade.

Treatment-emergent serious adverse events (SAEs) were defined as all adverse events that met seriousness criteria (as defined in the protocol; same as the ClinicalTrials.gov definition) occurring on or after Day 1 of study treatment until 30 days after the last dose of study treatment. All SAEs were graded for severity using the NCI-CTCAE v4.0; any SAE not specifically listed was assessed per the following 5 grades: Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe or medically significant, but not immediately life-threatening; Grade 4 = life-threatening consequences or urgent intervention indicated; and Grade 5 = death related to adverse event. The terms "severe" and "serious" are not synonymous and are independently assessed for each adverse event. Multiple occurrences of SAEs were counted only once per participant at the highest (worst) grade.

Treatment-emergent adverse events (TEAEs) were defined as all adverse events occurring on or after Day 1 of study treatment until 30 days after the last dose of study treatment. All TEAEs were graded for severity using the NCI-CTCAE v4.0; any TEAE not specifically listed was assessed per the following 5 grades: Grade 1 = mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; or intervention not indicated. Grade 2 = moderate; minimal, local, or non-invasive intervention indicated; or limiting age-appropriate instrumental activities of daily living. Grade 3 = severe or medically significant, but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; or limiting self-care activities of daily living. Grade 4 = life-threatening consequences or urgent intervention indicated. Grade 5 = death related to adverse event. Multiple occurrences of TEAEs were counted only once per participant at the highest (worst) grade.

Treatment-emergent adverse events (TEAEs) were defined as all adverse events occurring on or after Day 1 of study treatment until 30 days after the last dose of study treatment. All TEAEs were graded for severity using the NCI-CTCAE v4.0; any TEAE not specifically listed was assessed per the following 5 grades: Grade 1 = mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; or intervention not indicated. Grade 2 = moderate; minimal, local, or non-invasive intervention indicated; or limiting age-appropriate instrumental activities of daily living. Grade 3 = severe or medically significant, but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; or limiting self-care activities of daily living. Grade 4 = life-threatening consequences or urgent intervention indicated. Grade 5 = death related to adverse event. Multiple occurrences of TEAEs were counted only once per participant at the highest (worst) grade.

Treatment-emergent adverse events (TEAEs) were defined as all adverse events occurring on or after Day 1 of study treatment until 30 days after the last dose of study treatment. All TEAEs were graded for severity using the NCI-CTCAE v4.0; any TEAE not specifically listed was assessed per the following 5 grades: Grade 1 = mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; or intervention not indicated. Grade 2 = moderate; minimal, local, or non-invasive intervention indicated; or limiting age-appropriate instrumental activities of daily living. Grade 3 = severe or medically significant, but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; or limiting self-care activities of daily living. Grade 4 = life-threatening consequences or urgent intervention indicated. Grade 5 = death related to adverse event. Multiple occurrences of TEAEs were counted only once per participant at the highest (worst) grade.

Protocol-defined TEAEs of special interest, occurring on or after Day 1 of study treatment until 30 days after the last dose of study treatment, included the following: An elevated ALT or AST (>3 times baseline value) in combination with either an elevated total bilirubin (>2 times the upper limit of normal) or clinical jaundice; Suspected transmission of an infectious agent by the study treatment; Congestive heart failure; An asymptomatic decline in LVEF (a value 10 percentage points below baseline or lower, and <45%) that requires treatment or that leads to discontinuation of study treatment. All TEAEs of special interest were graded for severity using the NCI-CTCAE v4.0. Multiple occurrences of TEAEs of special interest were counted only once per participant at the highest (worst) grade.

Left ventricular ejection fraction (LVEF) is the measurement of the percentage of blood that is being pumped out of the left ventricle of the heart (the main pumping chamber) with each contraction. All participants were required to have had a baseline LVEF of at least 50% to participate in this study. Measurements were done by either echocardiogram (ECHO) or mulitple-gated acquisition (MUGA) scan (with ECHO as the preferred method). Participants were to be reassessed with the same technique used for baseline cardiac evaluation throughout the study.

Left ventricular ejection fraction (LVEF) is the measurement of the percentage of blood that is being pumped out of the left ventricle of the heart (the main pumping chamber) with each contraction. All participants were required to have had a baseline LVEF of at least (≥)50% to participate in this study. Measurements were done by either echocardiogram (ECHO) or mulitple-gated acquisition (MUGA) scan (with ECHO as the preferred method). Participants were to be reassessed with the same technique used for baseline cardiac evaluation throughout the study. The following are definitions for the three categories of LVEF findings: 'Normal' was defined as LVEF >45% or LVEF 40-45% with less than (<)10% points drop below baseline; 'Abnormal' was defined as LVEF <40% or LVEF ≥10% points drop below baseline, and clinically significant versus non-clinically significant was subject to the investigator's assessment of whether symptoms were present or absent.

Clinical laboratory tests for hematology parameters were performed every 6 weeks and any abnormal values (High or Low) were based on NCI-CTCAE v4.0 grades. Laboratory abnormalities of NCI-CTCAE v4.0 Grades 3 and 4 are presented. Not every abnormal laboratory value qualified as an adverse event, only if it met any of the following criteria: clinically significant (per investigator); accompanied by clinical symptoms; resulted in a change in study treatment; or required a change in concomitant therapy. For the overall category, multiple occurrences of the same laboratory abnormality over time in one participant were only counted once.

Clinical laboratory tests for blood chemistry parameters were performed every 6 weeks and any abnormal values (High or Low) were based on NCI-CTCAE v4.0 grades. Laboratory abnormalities of NCI-CTCAE v4.0 Grades 3 and 4 are presented. Not every abnormal laboratory value qualified as an adverse event, only if it met any of the following criteria: clinically significant (per investigator); accompanied by clinical symptoms; resulted in a change in study treatment; or required a change in concomitant therapy. For the overall category, multiple occurrences of the same laboratory abnormality over time in one participant were only counted once.

Per protocol eligibility criteria, participants were not required to be pertuzumab naïve; therefore pertuzumab was detectable in some participants pre-dose at Week 1.

Per protocol eligibility criteria, participants were not required to be trastuzumab naïve; therefore trastuzumab was detectable in some participants pre-dose at Week 1.

The MDASI-BT consists of 28 items and is a multi-symptom measure of cancer-related symptoms (Cleeland et al. 2000) that are sensitive to disease and treatment changes. The MDASI-BT is composed of the symptom severity scale and the symptom interference scale. In the symptom severity scale, participants rate the severity of their symptoms in the last 24 hours on 0-10 numeric scales, ranging from 0 = "not present" to 10 = "as bad as you can imagine." The MDASI-BT symptom severity scale score will be calculated by (sum of total scores of non-missing items) divided by (total number of non-missing items), if participants answered at least 12 of the 22 severity scale items. The score will be considered missing if less than 12 items are completed.

The MDASI-BT consists of 28 items and is a multi-symptom measure of cancer-related symptoms that are sensitive to disease and treatment changes. The MDASI-BT is composed of the symptom severity scale and the symptom interference scale. In the symptom interference scale, participants rate interference with daily activities caused by their symptoms on 0-10 numeric scales ranging from 0 = "did not interfere" to 10 = "interfered completely." The MDASI-BT symptom interference scale score will be calculated by (sum of total scores of non-missing items) divided by (total number of non-missing items), if participants answered at least 4 of the 6 interference scale items. The score will be considered missing if less than 4 items are completed.