Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
Pertuzumab · 35 trials · 19 indications
The PPQ was used to evaluate the participant preference for PH FDC SC compared to P+H IV. Participants completed the PPQ, where Question (Q) 1 was: "All things considered, which setting for your treatment did you prefer?" Participants were required to select one of the following options: home, hospital or no preference. The reported results show the percentage of participants who preferred receiving PH FDC SC at home setting over the hospital setting. Percentages were rounded off.
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.
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.
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 subcutaneous injection site other than thigh was used, if the Cycle 8 pre-dose and post-dose samples were switched, and an assay error impacting Ctrough measurement.
Progression-free survival (PFS) was defined as the time from randomization to first occurrence of progressive disease (PD), as determined by the investigator using RECIST v1.1, or death from any cause within 18 weeks after the last tumor assessment, whichever occurred first. As per RECIST v1.1, PD is defined as a 20% increase in the sum of the diameters of target lesions, an increase in size of measurable lesions by at least 5 millimeters (mm), and the appearance of new lesions. The Kaplan-Meier approach was used to estimate median PFS for each treatment arm. Data for participants who did not have a PFS event were censored at the time of the last tumor assessment (if no tumor assessments performed after baseline, at randomization plus 1 day).
Progression-free survival (PFS) was defined as the time from randomization to first occurrence of progressive disease (PD), as determined by the investigator using RECIST v1.1, or death from any cause within 18 weeks after the last tumor assessment, whichever occurred first. As per RECIST v1.1, PD is a 20% increase in the sum of the diameters of target lesions, an increase in size of measurable lesions by at least 5 mm, and the appearance of new lesions. The Kaplan-Meier approach was used to estimate the percentage of participants who were event-free for PFS at 1, 2, and 3 years. Data for participants who did not have a PFS event were censored at the time of the last tumor assessment (if no tumor assessments performed after baseline visit, at randomization plus 1 day). At final analysis, the median \[range\] time on study for Arm A vs. Arm B was 145.29 \[3.3-225.3\] weeks vs. 174.79 \[0.9-226.1\] weeks.
Non-serious AESIs for this study include the following: Cases of potential drug-induced liver injury that include an elevated alanine aminotransferase (ALT) or aspartate aminotransferase (AST) in combination with either an elevated bilirubin or clinical jaundice, as defined by Hy's law; Suspected transmission of an infectious agent by the study drug; or, An asymptomatic decline in left ventricular ejection fraction (LVEF) requiring treatment or leading to discontinuation of human epidermal growth factor receptor 2 (HER2)-targeted therapies.
tpCR was assessed by local pathology review on samples taken at surgery following completion of neoadjuvant therapy. tpCR was defined as the absence of any residual invasive cancer on hematoxylin and eosin evaluation of the resected breast specimen and all sampled ipsilateral lymph nodes ( that is \[i.e.\], ypT0/is, ypN0 in the American Joint Committee on Cancer \[AJCC\] staging system, 7th edition). Percentage of participants with tpCR was reported.
IDFS event was defined as the time from randomization until the date of first occurrence of one of the following: Ipsilateral invasive breast tumor recurrence (an invasive breast cancer \[bc\] involving the same breast parenchyma as the original primary lesion); Ipsilateral local-regional invasive bc recurrence (an invasive bc in the axilla, regional lymph nodes, chest wall, and/or skin of the ipsilateral breast); Contralateral or ipsilateral second primary invasive bc; Distant recurrence (evidence of bc in any anatomic site \[other than the three sites mentioned above\]) that has either been histologically confirmed or clinically/radiographically diagnosed as recurrent invasive bc; Death attributable to any cause, including bc, non-bc, or unknown cause. 3-year IDFS event-free rate per randomized treatment arms in the ITT population was estimated using the Kaplan-Meier method and estimated the probability of a participant being event-free after 3 years after randomization.
IDFS event was defined as the time from randomization until the date of first occurrence of one of the following: Ipsilateral invasive breast tumor recurrence (an invasive breast cancer \[bc\] involving the same breast parenchyma as the original primary lesion); Ipsilateral local-regional invasive bc recurrence (an invasive bc in the axilla, regional lymph nodes, chest wall, and/or skin of the ipsilateral breast); Contralateral or ipsilateral second primary invasive bc; Distant recurrence (evidence of bc in any anatomic site \[other than the three sites mentioned above\]) that has either been histologically confirmed or clinically/radiographically diagnosed as recurrent invasive bc; Death attributable to any cause, including bc, non-bc, or unknown cause. 3-year IDFS event-free rate per randomized treatment arms in the ITT population were estimated using the Kaplan-Meier method and estimated the probability of a patient being event-free after 3 years after randomization.
An AE can be any unfavorable and unintended sign (including an abnormality laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.
PFS (IRC-Assessed) was defined as the time from randomization into Part 2 of the trial until progressive disease (PD), MBO or death from any cause, whichever occurred first per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. PD could base on symptom deterioration or was defined as at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since treatment started or the appearance of one or more new lesions and/or the unequivocal progression of existing non-target lesions.
Tumor assessments were performed according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, using radiographic images submitted to the IRF up to and including the confirmatory tumor assessment 4 to 6 weeks after study drug discontinuation. Disease progression was defined as a greater than or equal to (≥) 20 percent (%) and 5-millimeter (mm) increase in sum of diameters of target lesions, taking as reference the smallest sum obtained during the study, or appearance of new lesion(s). The percentage of participants with death or disease progression was calculated as \[number of participants with event divided by the number analyzed\] multiplied by 100.
Tumor assessments were performed according to RECIST version 1.1, using radiographic images submitted to the IRF up to and including the confirmatory tumor assessment 4 to 6 weeks after study drug discontinuation. PFS was defined as the time from randomization to first documented disease progression or death from any cause. Disease progression was defined as a ≥20% and 5-mm increase in sum of diameters of target lesions, taking as reference the smallest sum obtained during the study, or appearance of new lesion(s). Median duration of PFS was estimated using Kaplan-Meier analysis, and corresponding confidence intervals (CIs) were computed using the Brookmeyer-Crowley method.
Progression Free Survival (PFS) was defined as the time from randomization to first documented disease progression (PD), as determined by an Independent Review Facility (IRF) using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0, or death from any cause, whichever occurred first. PD was defined as at least a 20% increase in the sum of the longest diameter (LD) of target lesions taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions; or the appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. IRF review of tumor assessment ceased after the primary PFS analysis. The primary endpoint was analyzed after approximately 337 IRF-assessed PFS events were observed.
PFS was defined as the time from randomization to first documented radiographical progressive disease (PD), as determined by an independent review facility (IRF) using RECIST version 1.0, or death from any cause (within 18 weeks of last tumor assessment), whichever occurred first (Kaplan-Meier method). For target lesions, PD was defined as at least a 20% increase in the sum of the longest diameter (LD) of target lesions, taking as reference the smallest sum of the LD recorded since treatment started or the appearance of ≥1 new lesion. For non-target lesions, PD was defined as the appearance of ≥1 new lesion or unequivocal progression of existing lesions. Participants without IRF-determined PD or who had not died within 18 weeks of their last IRF-determined, progression-free tumor assessment were censored at the date of the last IRF-reviewed, evaluable tumor assessment; those with no post-baseline tumor assessment and who had not died within 18 weeks of baseline were censored at 1 day.
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. A CR was defined as the disappearance of all CNS target lesions sustained for at least 4 weeks; no new lesions; no corticosteroids; and stable or improved clinically; for non-target lesions, a CR was the disappearance of all enhancing CNS non-target lesions and no new CNS lesions. A PR was defined as at least a 30% decrease in the sum longest diameter (LD) of CNS target lesions, taking as reference the baseline sum LD sustained for at least 4 weeks; no new lesions; stable to decreased corticosteroid dose; and stable or improved clinically. The 95% Clopper-Pearson exact confidence intervals were calculated for responses.
The Objective Response Rate (ORR) is defined as the percentage of patients whose best response on or before the first occurrence of disease progression is a complete response (CR) or partial response (PR). Tumor responses were assessed by investigators using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 for all arms.
The Objective Response Rate (ORR) is defined as the proportion of patients whose best response on or before the first occurrence of disease progression is a complete response (CR) or partial response (PR). Tumor responses were assessed by Independent Review Committee (IRC) using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.
pCR will be measured after 12 weeks of randomized treatment.
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.
Progression-free survival (PFS) was defined as the time from randomization until the first radiographically documented progression of disease or death from any cause, whichever occurred first (either during study treatment or during follow-up). Progression of disease was evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1 and is defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). The sum of target lesion diameters must also demonstrate an absolute increase of at least 5 mm (Note: the appearance of one or more new lesions is also considered progression). Participants with no PFS events were censored at the time of the last evaluable tumor assessment. The primary analysis of PFS was planned to be performed when a total of 165 PFS events had occurred, and the final analysis after at least 60 months follow-up.
An adverse event (AE) was defined as any untoward medical occurrence in a participant administered the investigational product which does not necessarily have a causal relationship with this treatment.
Left ventricular systolic dysfunction (LVSD) as assessed by the Investigator, including Grade 3, 4 or 5 symptomatic LVSD with symptomatic cardiac events.
Percentage of participants with LVEF measures decline of ≥ 10% from baseline and to a value of \<50% during the pre-operative (neoadjuvant) period.
The QT interval is a measure of time between the start of the Q wave and the end of the T wave in the heart's electrical cycle. The corrected QT interval was calculated using Fridericia's correction (QTcF) from electrocardiogram (ECG) data. Each participant had triplicate QTcF intervals measured at each timepoint and the average was calculated for each patient at each timepoint. For each timepoint, a participant's corresponding baseline QTcF interval was subtracted from the average QTcF intervals to create a baseline-adjusted average QTcF interval.
The assessment of FDG-PET response was performed by a central reading site. PET response was based on the maximum standard uptake value (SUVmax) of up to 5 regions of interest (ROI). The tumor ROIs were identified for each patient on pretreatment FDG-PET scans and corresponded to a subset of the target lesions identified for Response Evaluation Criteria for Solid Tumors (RECIST) analysis. Specifically, the SUVmax of each ROI on the on-treatment scans was compared with the SUVmax on the corresponding pretreatment scan and the percent change was calculated. When there was more than 1 ROI, the overall percent change in SUVmax was the arithmetic mean of the percent changes in SUVmax for each of the ROIs (mSUVmax). An PET response is defined as a decrease of ≥ 20% in mSUVmax. EGFR mutation status was assessed in tumor tissue samples taken from each patient.
Tumor response was assessed using RECIST version 1.0 to determine the objective response (OR) rate, or the percentage of participants with either confirmed CR or PR. CR was defined as the disappearance of all target lesions, and PR was defined as at least a 30 percent (%) decrease in the sum of the longest diameter compared to Baseline. Response was to be confirmed a minimum of 4 weeks after the initial response was documented. The OR rate was calculated as \[number of participants meeting the above criteria divided by the number analyzed\] multiplied by 100.
Tumor response was assessed using RECIST version 1.0 to determine the clinical benefit response (CBR) rate, or the percentage of participants with either confirmed CR or PR, or SD lasting at least 6 months. CR was defined as the disappearance of all target lesions, and PR was defined as at least a 30% decrease in the sum of the longest diameter compared to Baseline. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient (20%) increase to qualify for disease progression, in addition to no new target lesions. Response was to be confirmed a minimum of 4 weeks after the initial response was documented. The CBR rate was calculated as \[number of participants meeting the above criteria divided by the number analyzed\] multiplied by 100.
Disease progression was assessed according to RECIST (Response Evaluation Criteria In Solid Tumors), for participants with measurable disease, or by changes in CA 125 (Cancer Antigen 125) according to GCIG (Gynecologic Cancer Inter Group) for all participants. Participants who did not progress or died while being followed were censored at the time of the last valid tumor assessment or valid CA 125 assessment.
The probability of being event free (no disease progression or death events) at 1 year in participants remaining at risk.
A best overall response could occur at any time during the study and was determined by Response Evaluation Criteria in Solid Tumors (RECIST). A CR was defined as the disappearance of all target lesions (TL) or the disappearance of all non-TLs and normalization of tumor marker level. A PR was defined as at least a 30% decrease in the sum of the longest diameter (SLD) of TLs, taking as reference the baseline SLD. SD was defined as neither sufficient shrinkage to qualify for a PR nor sufficient increase to qualify for PD, taking as reference the smallest SLD since the treatment started for TLs and the persistence of 1 or more non-TL(s) and/or the maintenance of tumor marker level above normal limits. PD was defined as at least a 20% increase in the SLD of TLs, taking as reference the smallest SLD recorded since the treatment started or the appearance of one or more new lesions or the appearance of 1 or more new lesions and/or unequivocal progression of existing non-TLs.
Response by tumor measurement occurred if there was documented and confirmed CR or PR determined by 2 consecutive investigator assessments that were at least 28 days apart. Response was assessed by either the RECIST v 1.1 or by CA-125 changes, based on measurable or non-measurable disease at baseline. Per RECIST v 1.1 (for measurable disease), CR: disappearance of all target and non-target lesions and normalization of tumor marker level; PR: at least a 30 percent (%) decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum longest diameter. Per CA-125 changes (for non-measurable disease), CR: decrease in the CA-125 to within the normal limits and less than (\<) 40 international units per milliliter (IU/mL) and no clinical or radiological evidence of disease, PR: a greater than (\>) 50 percent (%) decrease in CA-125 values from baseline, and no clinical or radiological evidence of new lesions.
Objective tumor response was assessed using Response Evaluation Criteria in Solid Tumors (RECIST). Confirmed CR was defined as the disappearance of all target lesions, and confirmed PR was defined as at least at 30 percent (%) decrease in the sum of the longest diameters of target lesions. Response was to be confirmed at follow-up assessment completed within 4 weeks of the first documented response. The percentage of participants achieving a best overall response of CR or PR was calculated as \[number of participants meeting the above criteria divided by the number analyzed\] multiplied by 100.
An AE is defined as any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered to be related to the medicinal product. An SAE is any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or results in a congenital anomaly/birth defect.
DLT is defined as one of the following toxicities related to study drug during Cycle 1, according to the NCI CTCAE, Version 3: Grade 3 or higher non-hematologic AEs; Grade 3 or higher elevation of serum bilirubin, hepatic transaminases, or alkaline phosphatase; Grade 4 or higher thrombocytopenia; Grade 4 or higher neutropenia; any subjectively intolerable toxicity related to T-DM1, paclitaxel, or pertuzumab; any treatment-related toxicity prohibiting the start of the second cycle of treatment and/or prompting to a dose delay or modification during the DLT observation period, such as prompting a dose reduction at Cycle 2 Day1.
The MTD was defined as the highest dose of T-DM1 and paclitaxel at which 0 of 3 participants or 1 of 6 experienced a DLT, when T-DM1 (Q3W or QW) and paclitaxel (QW) was administered with and without pertuzumab treatment.
The MTD was defined as the highest dose of paclitaxel at which 0 of 3 participants or 1 of 6 experienced a DLT, when paclitaxel (QW) and T-DM1 (Q3W or QW) was administered with and without pertuzumab treatment.
Participants in Phase IIa received T-DM1 Q3W and paclitaxel in Group A and T-DM1, paclitaxel, and pertuzumab in Group B.
Participants were assessed for toxicity prior to each dose of T-DM1 and paclitaxel; dosing occurred only if the clinical assessment and laboratory test values were acceptable. Dose modifications included dose delayed or any dose reduction. Participants in whom significant toxicities had not recovered to the treatment range defined by the dose modification guidelines at the time of their next scheduled dose, had their dose of T-DM1 and/or paclitaxel delayed or reduced for up to 21 days.
Cmax of serum T-DM1 and total trastuzumab (sum of conjugated and unconjugated trastuzumab) in Cycle 1 was estimated by non-compartmental analysis for Phase Ib when T-DM1 was administered Q3W.
Cmax of plasma DM1 in Cycle 1 was estimated by non-compartmental analysis for Phase Ib when T-DM1 was administered Q3W.
AUC0-21 for serum T-DM1 and total trastuzumab (sum of conjugated and unconjugated trastuzumab) in Cycle 1 was estimated by non-compartmental analysis for Phase Ib when T-DM1 was administered Q3W.
Cmax for serum T-DM1 and total trastuzumab (sum of conjugated and unconjugated trastuzumab) in Cycle 1 was estimated by non-compartmental analysis when T-DM1 was administered QW.
Cmax for plasma DM1 in Cycle 1 was estimated by non-compartmental analysis for Phase Ib when T-DM1 was administered QW
AUClast for serum T-DM1 and serum total trastuzumab (sum of conjugated and unconjugated trastuzumab) in Cycle 1 was estimated by non-compartmental analysis for Phase Ib when T-DM1 was administered QW
Plasma Cmax of paclitaxel (65 mg/m\^2 and 80 mg/m\^2) for Cycle 1 (in the absence T-DM1) and Cycle 2 (in the presence T-DM1) was estimated by non-compartmental analysis.
Plasma AUC0-inf of paclitaxel (65 mg/m\^2 and 80 mg/m\^2) was estimated by non-compartmental analysis in Cycle 1 (in the absence T-DM1) and Cycle 2 (in the presence T-DM1).
Plasma t1/2 of paclitaxel (65 mg/m\^2 and 80 mg/m\^2) was estimated by non-compartmental analysis in Cycle 1 (in the absence T-DM1) and Cycle 2 (in the presence T-DM1).
Plasma CL of paclitaxel (65 mg/m\^2 and 80 mg/m\^2) was estimated by non-compartmental analysis for in Cycle 1 (in the absence T-DM1) and Cycle 2 (in the presence T-DM1).
Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug. Vss is the apparent volume of distribution at steady-state which is estimated by (D/AUC\[0-inf\]) X (AUMC\[0-inf\])/AUC\[0-inf\]) where D is the dose of study drug, AUMC(0-inf) is the area under the first moment curve extrapolated to infinity and AUC(0-inf) is the area under the plasma concentration-time curve from time zero to infinite time. The Vss of paclitaxel (65 mg/m2 and 80 mg/m2) is observed in Cycle 1 (in the absence of T-DM1) and Cycle 2 (in the presence of T-DM1).
Change in cardiac functions i.e., left ventricular ejection fraction (LVEF) and segmental wall abnormalities were assessed by echocardiogram or multigated acquisition scans. LVEF was assessed as change from baseline as 0 to \<15%, \>=15 to \<25%, \>=25%, and missing values.
DLTs included (as per National Cancer Institute Common Terminology Criteria for Adverse Events \[NCI CTCAE\] grading): Grade 4 thrombocytopenia, thrombocytopenia of any grade with concurrent hemorrhage or requiring blood platelet transfusion, or thrombocytopenia not recovered by Day 21 to at least 100,000/microliter (mcL); Grade 4 neutropenia lasting for more than 7 days; Febrile neutropenia; Grade greater than or equal to (\>/=) 3 neurotoxicity in the form of peripheral neuropathy or peripheral neurotoxicity not improving to baseline or Grade less than or equal to (\</=) 1 by Day 21; Any non-hematological toxicity of Grade \>/= 3 except for alopecia, fever, and chills, not improving to baseline or Grade \</=1 by Day 21, despite adequate toxicity management; Any subjective intolerable toxicity felt by the investigator to be related to either study treatment; Any other treatment-related toxicity prohibiting the start of the Cycle 2 on Day 22; Fulminant skin rash.
An AE is any new untoward medical occurrence or worsening of a pre-existing medical condition which does not necessarily have a causal relationship with this treatment. SAE is any untoward medical occurrence that at any dose results in death, is life-threatening, requires in-patient hospitalization or causes prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, results in development of drug dependency or drug abuse, is an important medical event.
A patient had an objective response if they had a complete response or a partial response on 2 consecutive occasions ≥ 4 weeks apart. For target lesions, a complete response was defined as the disappearance of all target lesions; a partial response was defined as at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum longest diameter. For non-target lesions, a complete response was defined as the disappearance of all non-target lesions; a partial response was defined as the persistence of 1 or more non-target lesions.
A DLT was defined as: Any non-hematological toxicity ≥ Grade 3 according to the Common Terminology Criteria for Adverse Events, version 3.0, except for fever, chills, and flu-like symptoms, which occurred despite adequate participant management. The following Grade 1-3 toxicities were exempt: Grade 1-3 skin and/or epithelial toxicities consistent with erlotinib single agent therapy, unless they did not respond to treatment or dose reduction or interruption (Grade 4 skin and/or epithelial toxicities were considered to be a DLT); Grade 4 neutropenia occurring for \> 7 days; febrile neutropenia which occurred despite adequate participant management; Grade 4 thrombocytopenia or any thrombocytopenia requiring platelet transfusion; and any subjectively intolerable toxicity felt by the investigator to be related to either one of the compounds.
| Arm | Type | Description |
|---|---|---|
| Arm A: Pertuzumab IV and Trastuzumab IV Plus Investigator's Choice of Chemotherapy | OTHER | During the neoadjuvant phase, the enrolled participants randomized to this arm will receive treatment with pertuzumab and trastuzumab intravenously (PH IV) plus investigator's choice of chemotherapy (Option 1, 2, or 3). With chemotherapy Option 1, PH IV will be administered at each cycle from Cycles 1 to 6 (1 cycle is 3 weeks); with chemotherapy Options 2 and 3, PH IV will be administered once per cycle from Cycles 5 to 8 (1 cycle is 3 weeks). |
| Arm B: PH FDC SC Plus Investigator's Choice of Chemotherapy | OTHER | During the neoadjuvant phase, the enrolled participants randomized to this arm will receive treatment with the fixed dose combination of pertuzumab and trastuzumab for subcutaneous use (PH FDC SC) plus investigator's choice of chemotherapy (Option 1, 2, or 3). With chemotherapy Option 1, PH FDC SC will be administered at each cycle from Cycles 1 to 6 (1 cycle is 3 weeks); with chemotherapy Options 2 and 3, PH FDC SC will be administered once per cycle from Cycles 5 to 8 (1 cycle is 3 weeks). |
| Arm C: Adjuvant PH FDC SC in Hospital, Then at Home | EXPERIMENTAL | During the adjuvant phase, participants who have achieved pCR after surgery will be treated with 2 cycles of PH FDC SC in the hospital (run-in period). After completion of the last cycle of radiotherapy and the last cycle of PH FDC SC (run-in period), participants will then be randomized with a ratio of 1:1 into one of two treatment arms (Arm C or D) in a cross-over treatment period to receive the next 6 cycles of PH FDC SC treatment. Participants in Arm C will receive 3 cycles of PH FDC SC in the hospital and then 3 cycles of PH FDC SC in the home setting. After the cross-over treatment period, participants will receive the remaining PH FDC SC treatment cycles required to complete the planned 18 cycles of HER2-directed therapy, unless of disease recurrence, unacceptable toxicity, or withdrawal. Study treatment during this treatment continuation period will be administered either in the hospital or in the home setting as selected by the participant at the end of the crossover period. |
| Arm D: Adjuvant PH FDC SC at Home, Then in Hospital | EXPERIMENTAL | During the adjuvant phase, participants who have achieved pCR after surgery will be treated with 2 cycles of PH FDC SC in the hospital (run-in period). After completion of the last cycle of radiotherapy and the last cycle of PH FDC SC (run-in period), participants will then be randomized with a ratio of 1:1 into one of two treatment arms (Arm C or D) in a cross-over treatment period to receive the next 6 cycles of PH FDC SC treatment. Participants in Arm D will receive 3 cycles of PH FDC SC in the home setting and then 3 cycles of PH FDC SC in the hospital. After the cross-over treatment period, participants will receive the remaining PH FDC SC treatment cycles required to complete the planned 18 cycles of HER2-directed therapy, unless of disease recurrence, unacceptable toxicity, or withdrawal. Study treatment during this treatment continuation period will be administered either in the hospital or in the home setting as selected by the participant at the end of the crossover period. |
| Arm E: Adjuvant Trastuzumab Emtansine | OTHER | Participants with pathological evidence of residual invasive carcinoma in the breast or axillary lymph nodes following completion of preoperative therapy and surgery will enter Arm E to receive trastuzumab emtansine for 14 cycles. Trastuzumab emtansine will be administered IV in the hospital as per prescribing information. |
| Arm A: Pertuzumab IV + Trastuzumab IV + Chemotherapy | ACTIVE_COMPARATOR | Participants will receive 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 will be given intravenously (IV) for 4 cycles Q3W concurrently with the taxane component of chemotherapy. After completing their neoadjuvant therapy, participants will undergo surgery. Thereafter, participants will receive an additional 14 cycles of pertuzumab IV and trastuzumab IV for a total of 18 cycles. |
| Arm B: Pertuzumab and Trastuzumab FDC SC + Chemotherapy | EXPERIMENTAL | Participants will receive 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) will be given subcutaneously (SC) for 4 cycles (Q3W) concurrently with the taxane component of chemotherapy. After completing their neoadjuvant therapy, participants will undergo surgery. Thereafter, participants will receive an additional 14 cycles of the PH FDC SC for a total of 18 cycles. |
| Arm B: FDC of Pertuzumab and Trastuzumab SC + Chemotherapy | EXPERIMENTAL | Participants will receive 8 cycles of investigator's choice of neoadjuvant chemotherapy. This will include either: 1) 4 cycles of ddAC Q2W (given with G-CSF support as needed according to local guidelines) followed by paclitaxel once every week (QW) for 12 weeks; or 2) 4 cycles of AC Q3W followed by docetaxel Q3W for 4 cycles. The fixed-dose combination (FDC) of pertuzumab and trastuzumab will be given subcutaneously (SC) for 4 cycles (Q3W) concurrently with the taxane component of chemotherapy. After completing their neoadjuvant therapy, participants will undergo surgery. Thereafter, participants will receive an additional 14 cycles of the FDC of pertuzumab and trastuzumab SC for a total of 18 cycles. |
| Arm A: Placebo + Trastuzumab + Docetaxel | ACTIVE_COMPARATOR | Placebo matched to pertuzumab, trastuzumab (8-milligrams per kilogram \[mg/kg\] loading dose for Cycle 1, followed by 6 mg/kg for subsequent cycles), and docetaxel (75-milligrams per square meter \[mg/m\^2\]) were administered by intravenous (IV) infusion every 3 weeks until disease progression or unacceptable toxicity. |
| Arm B: Pertuzumab + Trastuzumab + Docetaxel | EXPERIMENTAL | Pertuzumab (840-mg loading dose for Cycle 1, followed by 420 mg for subsequent cycles), trastuzumab (8-mg/kg loading dose for Cycle 1, followed by 6 mg/kg for subsequent cycles), and docetaxel (75-mg/m\^2) were administered by IV infusion every 3 weeks until disease progression or unacceptable toxicity. |
| Herceptin SC + Perjeta IV + docetaxel IV | EXPERIMENTAL | Single arm |
| Pertuzumab (Single-Agent or Combination Therapy) | EXPERIMENTAL | Pertuzumab will continue to be administered as a single agent or in combination with other anti-cancer therapies at the same dose, schedule, and guidelines that were in effect at the end of the Parent study. |
| Trastuzumab (TCH) + Pertuzumab | ACTIVE_COMPARATOR | Participants will receive pertuzumab 840 milligrams (mg) (loading dose) and 420 mg (maintenance dose) intravenous (IV) infusion followed by trastuzumab 8 milligrams per kilogram (mg/kg) (loading dose) and 6 mg/kg (maintenance dose) IV infusion followed by docetaxel 75 milligrams per square meter (mg/m\^2) IV infusion and carboplatin at a dose to achieve an area under the curve (AUC) of 6 milligrams per milliliter\* minute (mg/mL\*min) IV infusion every 3 weeks (q3w) for 6 cycles in neoadjuvant period. Participants will receive pertuzumab 840 mg (loading dose) and 420 mg (maintenance dose) IV infusion followed by trastuzumab 8 mg/kg (loading dose) and 6 mg/kg (maintenance dose) IV infusion q3w for rest of the cycles (12 cycles) in adjuvant period (up to a total of 18 cycles). |
| Trastuzumab Emtansine (T-DM1) + Pertuzumab | EXPERIMENTAL | Participants will receive pertuzumab 840 mg (loading dose) and 420 mg (maintenance dose) IV infusion followed by trastuzumab emtansine 3.6 mg/kg IV infusion q3w for a total of 18 cycles (6 cycles of neoadjuvant period and 12 cycles of adjuvant period). |
| Anthracycline Followed by Trastuzumab, Pertuzumab, and Taxane | ACTIVE_COMPARATOR | Trastuzumab and pertuzumab will be administered concurrently for up to a total duration of 1 year (up to 18 cycles \[1 Cycle = 21 days\]) with the taxane (docetaxel or paclitaxel) component of chemotherapy following anthracycline \[5 fluorouracil, epirubicin, and cyclophosphamide (FEC) or epirubicin and cyclophosphamide (EC) or doxorubicin and cyclophosphamide (AC)\] based chemotherapy. |
| Anthracycline Followed by Trastuzumab Emtansine and Pertuzumab | EXPERIMENTAL | Trastuzumab emtansine and pertuzumab will continue for up to a total duration of 1 year (up to 18 cycles \[1 Cycle = 21 days\]) following anthracycline \[5 fluorouracil, epirubicin, and cyclophosphamide (FEC) or epirubicin and cyclophosphamide (EC) or doxorubicin and cyclophosphamide (AC)\] based chemotherapy. |
| Part 1: Pertuzumab + Topotecan | EXPERIMENTAL | Participants received pertuzumab and topotecan in cycles of 3 weeks until progressive disease as per investigator's assessment, unacceptable toxicity, withdrawal of consent, or death. |
| Part 1: Pertuzumab + Paclitaxel | EXPERIMENTAL | Participants received pertuzumab and paclitaxel in cycles of 3 weeks until progressive disease as per investigator's assessment, unacceptable toxicity, withdrawal of consent, or death. |
| Part 2: Pertuzumab+Chemotherapy | EXPERIMENTAL | Participants received pertuzumab and chemotherapy (paclitaxel or topotecan or gemcitabine) in cycles of 3 weeks until progressive disease as per investigator's assessment, unacceptable toxicity, withdrawal of consent, or death. Chemotherapy was administered as per investigators discretion. |
| Part 2: Placebo+Chemotherapy | PLACEBO_COMPARATOR | Participants received pertuzumab matching placebo and chemotherapy (paclitaxel or topotecan or gemcitabine) in cycles of 3 weeks until progressive disease as per investigator's assessment, unacceptable toxicity, withdrawal of consent, or death. Chemotherapy was administered as per investigators discretion. |
| Trastuzumab + Taxane (docetaxel or paclitaxel) | EXPERIMENTAL | - |
| Trastuzumab emtansine + pertuzumab | EXPERIMENTAL | - |
| Trastuzumab emtansine + pertuzumab placebo | EXPERIMENTAL | - |
| A: Capecitabine + Trastuzumab | ACTIVE_COMPARATOR | - |
| B: Capecitabine + Trastuzumab + Pertuzumab | EXPERIMENTAL | - |
| Pertuzumab + Trastuzumab + Docetaxel | EXPERIMENTAL | Participants randomized to this arm received pertuzumab 420 milligrams (mg) intravenously (IV) once every 3 weeks (q3w) and trastuzumab 6 milligrams per kilogram (mg/kg) IV q3w, plus docetaxel 75 milligrams per square metre of body surface (mg/m\^2) IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination. |
| Placebo + Trastuzumab + Docetaxel | PLACEBO_COMPARATOR | Participants randomized to this arm received placebo IV q3w and trastuzumab 6 mg/kg IV q3w, plus docetaxel 75 mg/m\^2 IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination. |
| Pertuzumab + Trastuzumab | EXPERIMENTAL | Participants with CNS metastases secondary to HER2-positive MBC will receive pertuzumab in combination with high-dose trastuzumab until disease progression, unacceptable toxicity, withdrawal of consent, or study termination. |
| Trastuzumab Plus Pertuzumab | EXPERIMENTAL | Participants will receive trastuzumab 8 milligrams per kilogram (mg/kg) intravenous (IV) infusion as loading dose, followed by 6 mg/kg IV infusion every 3 weeks; and pertuzumab 840 mg IV infusion as loading dose, followed by 420 mg IV infusion every 3 weeks. |
| Atezolizumab | EXPERIMENTAL | Participants will receive atezolizumab 1200 mg IV infusion every 3 weeks. |
| Vemurafenib | EXPERIMENTAL | Participants will receive vemurafenib 960 mg orally twice daily (BID) in each 28-day cycle. |
| Vemurafenib Plus Cobimetinib | EXPERIMENTAL | Participants will receive vemurafenib 960 mg orally twice daily (BID) in each 28-day cycle; and cobimetinib 60 mg orally once daily for 21 days on and 7 days off in each 28-day cycle. |
| Vismodegib | EXPERIMENTAL | Participants will receive vismodegib 150 mg orally once daily in each 28-day cycle. |
| Alectinib | EXPERIMENTAL | Participants will receive alectinib 600 mg orally BID in each 28-day cycle. |
| Erlotinib | EXPERIMENTAL | Participants will receive erlotinib 150 mg orally once daily in each 28-day cycle. |
| Arm A | EXPERIMENTAL | Trastuzumab + Pertuzumab |
| Arm B | ACTIVE_COMPARATOR | Trastuzumab + Pertuzumab + Paclitaxel |
| Pertuzumab + Trastuzumab + Vinorelbine: Separate Infusion | EXPERIMENTAL | Pertuzumab will be administered as IV infusion on Day 1 of the first treatment cycle (1 cycle = 21 days) as a loading dose of 840 milligrams (mg), followed by 420 mg on Day 1 of each subsequent cycle. Trastuzumab will be administered as IV infusion on Day 2 of the first treatment cycle as a loading dose of 8 mg per kilogram (mg/kg), followed by 6 mg/kg on Day 2 of each subsequent cycle. Vinorelbine IV infusion (will be administered after trastuzumab) on Day 2 and Day 9 of the first treatment cycle at a dose of 25 mg per meter-squared (mg/m\^2) followed by 30-35 mg/m\^2 on Day 2 and Day 9 of each subsequent cycle. Pertuzumab and trastuzumab will be 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). |
| Pertuzumab + Trastuzumab + Vinorelbine: Single Infusion | EXPERIMENTAL | Pertuzumab will be administered as IV infusion on Day 1 of the first treatment cycle as a loading dose of 840 mg, followed by 420 mg on Day 1 of each subsequent cycle. Trastuzumab will be administered as IV infusion on Day 2 of the first treatment cycle as a loading dose of 8 mg/kg, followed by 6 mg/kg on Day 1 of each subsequent cycle. Vinorelbine IV infusion on Day 2 and Day 9 of the first treatment cycle at a dose of 25 mg/m\^2 followed by 30-35 mg/m\^2 on Day 1 and Day 8 of each subsequent cycle. If administration of all 3 drugs is well tolerated in Cycle 1, then on Day 1 of each subsequent cycle, pertuzumab 420 mg and trastuzumab 6 mg/kg will be 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). |
| Arm A: Pertuzumab + Trastuzumab + AI +/- Chemotherapy | EXPERIMENTAL | Participants will receive pertuzumab in combination with trastuzumab plus aromatase inhibitor (AI) until pre-defined study end, disease progression, unacceptable toxicity, withdrawal of consent or death, whichever occurs first. Participants may also receive induction chemotherapy (docetaxel every 3 weeks or paclitaxel weekly) up to the first 18-24 weeks of the treatment period at the investigator's discretion. |
| Arm B: Trastuzumab + AI +/- Chemotherapy | ACTIVE_COMPARATOR | Participants will receive trastuzumab plus aromatase inhibitor (AI) until predefined study end, disease progression, unacceptable toxicity, withdrawal of consent or death, whichever occurs first. Participants may also receive induction chemotherapy (docetaxel every 3 weeks or paclitaxel weekly) up to the first 18-24 weeks of the treatment period at the investigator's discretion. |
| Pertuzumab 840/420 mg | EXPERIMENTAL | Participants received pertuzumab as an intravenous (IV) infusion at a loading dose of 840 milligrams (mg) for cycle 1 and a dose of 420 mg every three weeks (Q3W) for cycles 2-6. Participants in both arms received trastuzumab, cisplatin, and capecitabine. Capecitabine 1000 milligram per meter squared (mg/m\^2) was administered orally twice daily, from the evening of Day 1 to the morning of Day 15 of each cycle. Cisplatin 80 mg/m\^2 was administered as an IV infusion on Day 1 of each cycle. Trastuzumab was administered as an IV infusion at a loading dose of 8 mg/kg for Cycle 1 and a dose of 6 milligram per kilogram (mg/kg) Q3W for subsequent cycles. |
| Pertuzumab 840/840 mg | EXPERIMENTAL | Participants received 840 mg as an IV infusion Q3W for cycles 1-6. Participants in both arms received trastuzumab, cisplatin, and capecitabine. Capecitabine 1000 mg/m\^2 was administered orally twice daily, from the evening of Day 1 to the morning of Day 15 of each cycle. Cisplatin 80 mg/m\^2 was administered as an IV infusion on Day 1 of each cycle. Trastuzumab was administered as an IV infusion at a loading dose of 8 mg/kg for Cycle 1 and a dose of 6 mg/kg Q3W for subsequent cycles. |
| T+P Concomitant Anthracycline-based chemotherapy | EXPERIMENTAL | 5-Fluorouracil, epirubicin with cyclophosphamide (FEC), trastuzumab (T) and pertuzumab (P) every three weeks for three cycles, followed by docetaxel, trastuzumab and pertuzumab every three weeks, for three cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 17 as adjuvant therapy post-surgery. |
| T+P Sequential Anthracycline-based chemotherapy | EXPERIMENTAL | FEC every three weeks for three cycles, followed by docetaxel, trastuzumab (T) and pertuzumab (P) every three weeks, for three cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 21 as adjuvant therapy post-surgery. |
| T+P Concomitant Non-Anthracycline chemotherapy | EXPERIMENTAL | Trastuzumab, carboplatin, docetaxel (TCH) and pertuzumab (P) every three weeks, for six cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 17 as adjuvant therapy post-surgery. |
| T-DM1 / T-DM1 + pertuzumab | EXPERIMENTAL | Trastuzumab emtansine (T-DM1) was administered to participants by intravenous (IV) infusion on Day 1 of every 3 week cycle at a dose of 3.6 mg/kg. From Cycle 4, participants with early progressive disease (demonstrated prior to the end of Cycle 6) could receive combined pertuzumab and trastuzumab emtansine. Pertuzumab was administered after trastuzumab emtansine by IV infusion at a loading dose of 840 mg on Day 1, starting at the cycle after tumor progression was determined, followed by 420 mg IV infusion every 3 weeks in subsequent cycles. Participants who met criteria for ongoing clinical benefit were allowed to continue study treatment in the absence of disease progression or unacceptable toxicity for up to 1 year. |
| Pertuzumab + erlotinib | EXPERIMENTAL | Patients received pertuzumab 840 mg intravenously (IV) 1 time (loading dose) followed by 420 mg IV (maintenance dose) every 3 weeks (q3w) plus erlotinib 150 mg orally once a day which was reduced to 100 mg orally once a day in a protocol amendment dated 19 May 2010. |
| Trastuzumab Emtansine | EXPERIMENTAL | Participants will receive trastuzumab emtansine either as a single agent or in combination with other anti-cancer therapy (atezolizumab, paclitaxel, trastuzumab and docetaxel). Participants will receive the same dose and schedule on Cycle 1, Day 1 at which it was given at the end of the parent study. Study drug will be administered in 21-day cycles or weekly, depending on the schedule used in the parent study. Participants will receive study treatment until disease progression or unacceptable toxicity. |
| Pertuzumab + Trastuzumab (Cohorts 1 and 2) | EXPERIMENTAL | Females with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer will receive dual-agent treatment with pertuzumab and trastuzumab. Trastuzumab will be administered IV as 2 milligrams per kilogram (mg/kg) once weekly, or as 6 mg/kg every 3 weeks, beginning on Day 1 of Cycle 1. Pertuzumab will be administered IV at a loading dose of 840 mg followed by a standard dose of 420 mg every 3 weeks, beginning on Day 2 of Cycle 1. Thereafter, both medications will be administered on Day 1 of each 3-week cycle. Treatment will continue for a minimum of 8 cycles and may be extended until disease progression, intolerable toxicity, or death. |
| Pertuzumab +/- Trastuzumab (Cohort 3) | EXPERIMENTAL | Females with HER2-positive metastatic breast cancer will receive single-agent treatment with pertuzumab. Pertuzumab will be administered IV at a loading dose of 840 mg followed by a standard dose of 420 mg every 3 weeks, administered on Day 1 of each 3-week cycle. Participants with documented disease progression may have trastuzumab added to the regimen, per the dosing schedule described for Cohorts 1 and 2, to receive dual-agent treatment until disease progression, intolerable toxicity, or death. |
| Chemotherapy + Pertuzumab | EXPERIMENTAL | - |
| Chemotherapy | ACTIVE_COMPARATOR | - |
| Pertuzumab | EXPERIMENTAL | Participants received the same dose of pertuzumab that they received in their parent Phase II trial, either 420 mg or 1050 mg, intravenously on Day 1 of every 3 week cycle until disease progression. |
| Placebo + gemcitabine | PLACEBO_COMPARATOR | Participants received placebo intravenously on Day 1 of every 3 week cycle for up to 1 year (up to 17 treatment cycles). In addition, participants received gemcitabine 800 mg/m\^2 intravenously on Days 1 and 8 of every 3 week cycle for up to 1 year (up to 17 treatment cycles). |
| Pertuzumab + gemcitabine | ACTIVE_COMPARATOR | Participants received pertuzumab intravenously on Day 1 of every 3 week cycle for up to 1 year (up to 17 treatment cycles). Participants received pertuzumab at a loading dose of 840 mg in Cycle 1 followed by a dose of 420 mg in Cycles 2 and beyond. In addition, participants received gemcitabine 800 mg/m\^2 intravenously on Days 1 and 8 of every 3 week cycle for up to 1 year (up to 17 treatment cycles |
| Pertuzumab 1050 mg | EXPERIMENTAL | Participants will not receive a loading dose, but will receive pertuzumab 1050 milligrams (mg) via intravenous (IV) infusion every 3 weeks until unacceptable toxicity or disease progression. |
| Pertuzumab 420 mg | EXPERIMENTAL | Participants will receive a loading dose of 840 mg via IV infusion at the first infusion of pertuzumab, followed by a maintenance dose of 420 mg every 3 weeks until unacceptable toxicity or disease progression. |
| Part 1-Cohort 1: Pertuzumab 420 Milligrams (mg) IV | ACTIVE_COMPARATOR | Part 1 includes healthy male participants. Participants will receive a single injection of pertuzumab 420 mg IV. |
| Part 1-Cohort 2: Pertuzumab 400 mg SC | EXPERIMENTAL | Part 1 includes healthy male participants. Participants will receive a single injection of pertuzumab 400 mg SC. |
| Part 1-Cohort 3: Pertuzumab 600 mg SC | EXPERIMENTAL | Part 1 includes healthy male participants. Participants will receive a single injection of pertuzumab 600 mg SC. |
| Part 1-Cohort 4: Pertuzumab 1200 mg SC | EXPERIMENTAL | Part 1 includes healthy male participants. Participants will receive a single injection of pertuzumab 1200 mg SC. |
| Part 1-Cohort 5: Trastuzumab 600 mg SC | ACTIVE_COMPARATOR | Part 1 includes healthy male participants. Participants will receive a single injection of trastuzumab 600 mg SC. |
| Part 1-Cohort 6: Pertuzumab 400 mg SC + Trastuzumab 600 mg SC | EXPERIMENTAL | Part 1 includes healthy male participants. Participants will receive a single injection of co-mixed pertuzumab 400 mg and trastuzumab 600 mg SC. |
| Part 1-Cohort 7: Pertuzumab 1200 mg SC + Trastuzumab 600 mg SC | EXPERIMENTAL | Part 1 includes healthy male participants. Participants will receive a single injection of co-mixed pertuzumab 1200 mg and trastuzumab 600 mg SC. |
| Part 1-Cohort 8: Pertuzumab 1200 mg SC + Trastuzumab 600 mg SC | EXPERIMENTAL | Part 1 includes healthy male participants. Participants will receive a single injection of co-mixed pertuzumab 1200 mg and trastuzumab 600 mg SC without recombinant human hyaluronidase (rHuPH20) excipient. |
| Part 2-Cohort A: Pertuzumab SC + Trastuzumab SC | EXPERIMENTAL | Part 2 includes women with early breast cancer. Cohort A will be enrolled only if FDC of pertuzumab and trastuzumab is not feasible. Participants will receive pertuzumab and trastuzumab (600 mg) SC administered separately. The dose of pertuzumab will be identified during Part 1. |
| Part 2-Cohort B: Pertuzumab SC + Trastuzumab SC | EXPERIMENTAL | Part 2 includes women with early breast cancer. Cohorts B and C will be enrolled if FDC of pertuzumab and trastuzumab is feasible. Participants will receive pertuzumab and trastuzumab (600 mg) SC; both agents administered in one injection (co-mixed). The dose of pertuzumab will be identified during Part 1. |
| Part 2-Cohort C: Pertuzumab SC + Trastuzumab SC | EXPERIMENTAL | Part 2 includes women with early breast cancer. Cohorts B and C will be enrolled if FDC of pertuzumab and trastuzumab is feasible. Participants will receive pertuzumab and trastuzumab (600 mg) SC; both agents formulated together and administered in one injection (FDC). The dose of pertuzumab will be identified during Part 1. |
| Lumretuzumab Dose Escalation | EXPERIMENTAL | Participants will receive escalating doses of lumretuzumab starting at 1000 mg IV (on Day 1, except Cycle 1 where lumretuzumab will be administered on Day 2) along with paclitaxel 80 mg/m\^2 IV (on Days 1, 8, and 15), and pertuzumab 840 mg IV (on Day 1) initial dose followed by 420 mg IV, in each 21-day cycle. Participants will be treated until disease progression, unacceptable toxicities, and withdrawal from treatment for other reasons or death. |
| EPC1: Lumretuzumab (Prior Chemotherapy) | EXPERIMENTAL | Extension phase Cohort 1 (EPC1): Participants will receive lumretuzumab 1000 mg IV (on Day 1) along with paclitaxel 80 mg/m\^2 IV (on Days 1, 8, and 15), and pertuzumab 840 mg IV (on Day 1) initial dose followed by 420 mg IV, in each 21-day cycle. Participants will be treated until disease progression, unacceptable toxicities, and withdrawal from treatment for other reasons or death. |
| EPC2: Lumretuzumab (Without Prior Chemotherapy) | EXPERIMENTAL | Extension phase Cohort 2 (EPC2): Participants will receive lumretuzumab 2000 mg IV (on Day 1) along with paclitaxel 80 mg/m\^2 IV (on Days 1, 8, and 15), and pertuzumab 420 mg IV (on Day 1), in each 21-day cycle. Participants will be treated until disease progression, unacceptable toxicities, and withdrawal from treatment for other reasons or death. Only participants with no prior chemotherapy for metastatic disease and/or a maximum of only one prior chemotherapy regimen in adjuvant or neoadjuvant setting will be enrolled in this cohort. |
| Phase lb Regimen 1 | EXPERIMENTAL | Participants received trastuzumab emtansine (T-DM1) every three weeks (Q3W) + paclitaxel weekly (QW) intravenously. |
| Phase Ib Regimen 2 | EXPERIMENTAL | Participants received T-DM1 Q3W + paclitaxel QW + pertuzumab Q3W intravenously. |
| Phase Ib Regimen 3 | EXPERIMENTAL | Participants received T-DM1 QW + paclitaxel QW intravenously. |
| Phase Ib Regimen 4 | EXPERIMENTAL | Participants received T-DM1 QW + paclitaxel QW + pertuzumab Q3W intravenously. |
| Phase IIa Group A | EXPERIMENTAL | Participants received maximum tolerated dose (MTD) from Phase 1b i.e. T-DM1 3.6mg/kg Q3W + paclitaxel 80mg/m\^2 QW intravenously. |
| Phase IIa Group B | EXPERIMENTAL | Participants received MTD from Phase 1b i.e. T-DM1 3.6mg/kg Q3W + paclitaxel 80mg/m\^2 QW + pertuzumab Q3W intravenously. |
| MBC: T-DM1 2.4 mg/kg + Doc 75 mg/m^2 (over 2 days) | EXPERIMENTAL | Participants with human epidermal growth factor receptor 2 (HER2)-positive MBC will receive docetaxel (Doc) 75 milligrams per square meter (mg/m\^2) intravenous (IV) infusion on Day 1 and T-DM1 2.4 milligrams per kilogram (mg/kg) IV infusion on Day 2 of Cycle 1 followed by T-DM1 75 mg/m\^2 and docetaxel 2.4 mg/kg IV infusion on Day 1 of each 3-week cycle for a minimum of 6 cycles. After 6 cycles, docetaxel 75 mg/m\^2 will be stopped and T-DM1 2.4 mg/kg will be continued until confirmed evidence of disease progression, unacceptable toxicity, or withdrawal of participant consent. |
| MBC: T-DM1 2.4 mg/kg + Doc 60 mg/m^2 (over 2 days) | EXPERIMENTAL | Participants with HER2-positive MBC will receive docetaxel 60 mg/m\^2 IV infusion on Day 1 and T-DM1 2.4 mg/kg IV infusion on Day 2 of Cycle 1 followed by T-DM1 60 mg/m\^2 and docetaxel 2.4 mg/kg IV infusion on Day 1 of each 3-week cycle for a minimum of 6 cycles. After 6 cycles, docetaxel 60 mg/m\^2 will be stopped and T-DM1 2.4 mg/kg will be continued until confirmed evidence of disease progression, unacceptable toxicity, or withdrawal of participant consent. |
| MBC: T-DM1 2.4 mg/kg + Doc 60 mg/m^2 (same day) | EXPERIMENTAL | Participants with HER2-positive MBC will receive docetaxel 60 mg/m\^2 IV infusion and T-DM1 2.4 mg/kg IV infusion on Day 1 of each 3-week cycle for a minimum of 6 cycles. After 6 cycles, docetaxel 60 mg/m\^2 will be stopped and T-DM1 2.4 mg/kg will be continued until confirmed evidence of disease progression, unacceptable toxicity, or withdrawal of participant consent. |
| MBC: T-DM1 3.6 mg/kg + Doc 60 mg/m^2 (same day) | EXPERIMENTAL | Participants with HER2-positive MBC will receive docetaxel 60 mg/m\^2 IV infusion and T-DM1 3.6 mg/kg IV infusion on Day 1 of each 3-week cycle for a minimum of 6 cycles. After 6 cycles, docetaxel 60 mg/m\^2 will be stopped and T-DM1 3.6 mg/kg will be continued until confirmed evidence of disease progression, unacceptable toxicity, or withdrawal of participant consent. |
| LABC: T-DM1 + Doc (Doublet Regimen) | EXPERIMENTAL | Participants with HER2-positive LABC will receive T-DM1 3.6 mg/kg IV infusion and docetaxel 60/75/100 mg/m\^2 IV infusion on Day 1 of each 3-week cycle, for 6 cycles. Study treatment will be administered for up to 6 cycles or until unacceptable toxicity, and prior to surgery. |
| LABC: T-DM1 + Doc + Pertuzumab (Triplet Regimen) | EXPERIMENTAL | Participants with HER2-positive LABC will receive T-DM1 3.6 mg/kg Iv infusion, docetaxel 60/75 mg/m\^2 IV infusion, and pertuzumab 840 mg (for Cycle 1) or 420 mg (for remaining cycles) IV infusion on Day 1 of each 3-week cycle, for 6 cycles. Study treatment will be administered for up to 6 cycles or until unacceptable toxicity, and prior to surgery. |
| Trastuzumab emtansine 3.0 mg/kg + pertuzumab 420 mg | EXPERIMENTAL | Patients received trastuzumab emtansine 3.0 mg/kg intravenously (IV) on Day 1 of every 3 week cycle until progressive disease, intolerable toxicity, initiation of another anti-cancer therapy, or patient discontinuation. Patients also received a loading dose of 840 mg of pertuzumab IV on Day 1 of Cycle 1 followed by pertuzumab 420 mg IV on Day 1 of every subsequent 3 week cycle. |
| Trastuzumab emtansine 3.6 mg/kg + pertuzumab 420 mg | EXPERIMENTAL | Patients received trastuzumab emtansine 3.6 mg/kg intravenously (IV) on Day 1 of every 3 week cycle until progressive disease, intolerable toxicity, initiation of another anti-cancer therapy, or patient discontinuation. Patients also received a loading dose of 840 mg of pertuzumab IV on Day 1 of Cycle 1 followed by pertuzumab 420 mg IV on Day 1 of every subsequent 3 week cycle. |
| Cohort 1 | EXPERIMENTAL | Participants will receive IV infusion of pertuzumab at a loading dose of 840 mg on Day 1, followed by a dose of 420 mg every 3 weeks. Erlotinib will be administered daily, at a dose level of 100 mg orally (PO). |
| Cohort 2 | EXPERIMENTAL | Participants will receive IV infusion of pertuzumab at a loading dose of 840 mg on Day 1, followed by a dose of 420 mg every 3 weeks. Erlotinib will be administered daily, at a dose level of 150 mg orally (PO). |
| Name | Type | Description |
|---|---|---|
| Fixed Dose Combination of Pertuzumab and Trastuzumab for Subcutaneous Use (PH FDC SC) | DRUG | PH FDC SC is administered subcutaneously (SC) as a fixed non-weight-based dose. A loading dose of 1200 milligram (mg) pertuzumab, 600 mg trastuzumab, and 30,000 units of recombinant human PH20 hyaluronidase (rHuPH20) is given in the first cycle (1 cycle is 21 days). In subsequent cycles, maintenance doses of 600 mg pertuzumab, 600 mg trastuzumab, and 20,000 units rHuPH20 are administered once every 3 weeks (Q3W). |
| Pertuzumab IV | DRUG | Pertuzumab is given as a fixed dose of 840 mg intravenous (IV) loading dose and then 420 mg IV for subsequent maintenance doses once every 3 weeks. |
| Trastuzumab IV | DRUG | Trastuzumab is given as an 8 milligram per kilogram (mg/kg) intravenous (IV) loading dose and then 6 mg/kg IV for subsequent maintenance doses once every 3 weeks. |
| Trastuzumab Emtansine | DRUG | Trastuzumab emtansine will be given at a dose of 3.6 mg/kg by intravenous (IV) infusion, once every 3 weeks. |
| Investigator's Choice of Chemotherapy | DRUG | Option 1: Docetaxel and carboplatin once every 3 weeks for 6 cycles; Option 2: Doxorubicin plus cyclophosphamide once every 3 weeks for 4 cycles, followed by a taxane (docetaxel once every 3 weeks for 4 cycles or paclitaxel once every week for 12 cycles); Option 3: Dose-dense doxorubicin plus cyclophosphamide (ddAC) once every 2 weeks for 4 cycles, followed by a taxane (docetaxel once every 3 weeks for 4 cycles or paclitaxel once every week for 12 cycles). |
| Surgery | PROCEDURE | After completing their neoadjuvant therapy, participants will undergo surgical resection for early or locally advanced HER2+ breast cancer (if eligible for surgery). Participants may undergo breast-conserving surgery or mastectomy according to routine clinical practice. The surgery cannot be performed ≤2 weeks from the last systemic neoadjuvant therapy and must be performed ≤6 weeks after the last systemic neoadjuvant therapy. |
| Radiotherapy | RADIATION | After surgery, radiotherapy is to be given as clinically indicated and as per local practice or institutional standards. The selected radiotherapy regimen should be initiated within 4 weeks after surgery. |
| Pertuzumab and Trastuzumab FDC SC | DRUG | 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. |
| Doxorubicin | DRUG | 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. |
| Cyclophosphamide | DRUG | 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. |
| Docetaxel | DRUG | 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. |
| Post-Operative Radiotherapy | RADIATION | If indicated, radiotherapy is given after chemotherapy and surgery, during adjuvant HER2-targeted therapy and hormone therapy (for hormone-receptor positive disease). |
| Hormone Therapy | DRUG | 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. |
| Paclitaxel | DRUG | As part of one of the two investigator's choices of chemotherapy (ddAC followed by paclitaxel), paclitaxel 80 mg/m2 will be administered IV QW for 12 weeks. |
| FDC of Pertuzumab and Trastuzumab SC | DRUG | The FDC of pertuzumab and trastuzumab 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. |
| Trastuzumab SC | DRUG | After surgery (from Cycle 9 onwards), participants in Arm A will be allowed to switch from trastuzumab IV to trastuzumab SC, at the discretion of the investigator, in the countries where trastuzumab SC is routinely used. For participants who switch, a fixed dose of 600 mg trastuzumab SC (irrespective of the patient's weight) will be administered in the adjuvant phase. |
| Pertuzumab | DRUG | Pertuzumab (840-mg loading dose for Cycle 1, followed by 420 mg for subsequent cycles) was administered by IV infusion every 3 weeks until disease progression or unacceptable toxicity. |
| Placebo | DRUG | Placebo matched to pertuzumab was administered by IV infusion every 3 weeks until disease progression or unacceptable toxicity. |
| Trastuzumab | DRUG | Trastuzumab (8-mg/kg loading dose for Cycle 1, followed by 6 mg/kg for subsequent cycles) was administered by IV infusion every 3 weeks until disease progression or unacceptable toxicity. |
| pertuzumab [Perjeta] | DRUG | Intravenous infusion every 3 weeks. First dose: 840 mg. Subsequent doses: 420 mg |
| trastuzumab [Herceptin] | DRUG | Subcutaneous administration of 600 mg/5 mL every 3 weeks |
| Other Combination Anti-Cancer Therapies | DRUG | If other anti-cancer therapies were given in combination with pertuzumab as part of the Parent study, patients will receive all treatments at the same dose, schedule and under the same administration guidelines which were in effect at the time of Parent study closure. |
| Carboplatin | DRUG | Carboplatin IV infusion at a dose to achieve an AUC of 6 mg\*min/mL q3w |
| Epirubicin | DRUG | 3 to 4 cycles (1 cycle = 21 days) of standard of care anthracycline-based chemotherapy using epirubicin may be administered in both Arms 1 and 2 as per discretion of the investigator and local prescribing information/institutional guidelines. |
| 5-Fluorouracil | DRUG | 3 to 4 cycles (1 cycle = 21 days) of standard of care anthracycline-based chemotherapy using 5-fluorouracil, may be administered in both Arms 1 and 2 as per discretion of the investigator and local prescribing information/institutional guidelines. |
| Gemcitabine (Chemotherapy) | DRUG | Participants administered gemcitabine at a dosage of 1000 milligrams per square meter (mg/m\^2) intravenous (IV) infusion on Days 1 and 8 every 3 weeks. |
| Paclitaxel (Chemotherapy) | DRUG | Participants administered paclitaxel at a dosage of 80 mg/m\^2 as 1 hour IV infusion on Days 1, 8 and 15 every 3 weeks. |
| Topotecan (Chemotherapy) | DRUG | Participants administered topotecan at a dosage of 1.25 mg/m\^2 as a 30 minute IV infusion daily on Days 1 to 5 every 3 weeks. |
| pertuzumab-placebo | DRUG | 840 mg intravenously on day 1 of cycle 1 followed by 420 mg intravenously every 3 weeks in subsequent cycles |
| Capecitabine | DRUG | 1000 mg/m2 po twice daily for 14 days every 3 weeks |
| Erlotinib | DRUG | Erlotinib will be administered as per the schedule specified in the respective arm, until tumor progression or occurrence of unacceptable toxicity. |
| Vemurafenib | DRUG | Vemurafenib will be administered as per the schedule specified in the respective arm, until tumor progression or occurrence of unacceptable toxicity. |
| Cobimetinib | DRUG | Cobimetinib will be administered as per the schedule specified in the respective arm, until tumor progression or occurrence of unacceptable toxicity. |
| Vismodegib | DRUG | Vismodegib will be administered as per the schedule specified in the respective arm, until tumor progression or occurrence of unacceptable toxicity. |
| Alectinib | DRUG | Alectinib will be administered as per the schedule specified in the respective arm, until tumor progression or occurrence of unacceptable toxicity. |
| Atezolizumab | DRUG | Atezolizumab will be administered as per the schedule specified in the respective arm, until tumor progression or occurrence of unacceptable toxicity. |
| Vinorelbine | DRUG | 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. |
| Aromatase Inhibitor | DRUG | Participants will receive 1 mg anastrozole or 2.5 mg letrozole orally once daily. |
| Induction Chemotherapy | DRUG | Participants receiving induction chemotherapy up to the first 18-24 weeks of the treatment period will receive a taxane (docetaxel every 3 weeks or paclitaxel weekly), administered in line with the respective pertuzumab and/or trastuzumab infusions at the investigator's discretion. |
| Cisplatin | DRUG | 80 mg/m2 on Day 1 of each cycle |
| FEC | DRUG | 5-fluorouracil 500 mg/m\^2, epirubicin 100 mg/m\^2 and cyclophosphamide 600 mg/m\^2. |
| TCH | DRUG | Trastuzumab followed by carboplatin at target area under the plasma concentration-time curve (AUC) 6 and docetaxel at a starting dose of 75 mg/m\^2. All treatments were given every three weeks by the IV route. |
| Trastuzumab emtansine [Kadcyla] | BIOLOGICAL | Intravenous repeating dose |
| gemcitabine | DRUG | 1000 mg/m2 IV Day 1 and 8 of each cycle for 6 cycles |
| Pertuzumab (rhuMAb 2C4) | DRUG | - |
| Lumretuzumab | DRUG | Lumretuzumab will be administered as per schedule described in individual arm. |
| Trastuzumab emtansine [Kadcyla] 3.0 mg/kg | DRUG | Trastuzumab emtansine was provided as a single-use lyophilized formulation. |
| Trastuzumab emtansine [Kadcyla] 3.6 mg/kg | DRUG | Trastuzumab emtansine was provided as a single-use lyophilized formulation. |
| Pertuzumab 420 mg | DRUG | Pertuzumab was provided as a single-use formulation. |
Inclusion Criteria: * Eastern Cooperative Oncology Group (ECOG) performance status 0-1 * Intact skin at planned site of subcutaneous (SC) injections * Left ventricular ejection fraction (LVEF) greater than or equal to (≥)55% by echocardiogram (ECHO) or multiple-gated acquisition scan (MUGA) * Negat...
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Pertuzumab is an investigational oncology drug being studied for solid tumors, breast neoplasms, HER2-positive early breast cancer, non-small cell lung cancer, and early breast cancer. It is a small molecule antibody being developed by Roche Holding AG (RHHBY) and is currently in Phase 3 clinical trials.
Pertuzumab is a monoclonal antibody (target class -mab) that targets HER2, a protein involved in cell growth. It is being studied in HER2-positive cancers, including breast cancer, where it is evaluated in combination with other therapies such as trastuzumab emtansine and paclitaxel.
Pertuzumab is being developed by Roche Holding AG, which trades under the ticker RHHBY. The company is conducting clinical trials to evaluate the drug's safety and efficacy in various oncology indications, including breast cancer and non-small cell lung cancer.
Pertuzumab is in Phase 3 clinical development. It is an investigational drug and has not been approved by regulatory authorities. The Phase 3 trial, NCT02131064, is evaluating pertuzumab in combination with trastuzumab emtansine compared to chemotherapy plus trastuzumab and pertuzumab in HER2-positive breast cancer.
Pertuzumab has been studied in 13 clinical trials, with one active trial and 13 completed trials. Notable trials include NCT02131064 (Phase 3, HER2-positive breast cancer), NCT02491892 (Phase 2, metastatic breast cancer), and NCT00934856 (Phase 1, advanced breast cancer). Total enrollment across trials is 5,308 participants.
No, Pertuzumab is not the same as trastuzumab emtansine (T-DM1). They are different drugs that are being studied in combination. For example, trial NCT02131064 compares trastuzumab emtansine plus pertuzumab against chemotherapy plus trastuzumab and pertuzumab in HER2-positive breast cancer.