PERTAIN: A Study of Pertuzumab in Combination With Trastuzumab Plus an Aromatase Inhibitor in Participants With Metastatic Human Epidermal Growth Factor Receptor 2 (HER2)-Positive and Hormone Receptor-Positive Advanced Breast Cancer
Sponsor
Hoffmann-La Roche (Industry)
Overall Status
Completed
CT.gov ID
NCT01491737
Collaborator
(none)
258
82
2
92.9
3.1
0
Study Details
Study Description
Brief Summary
This randomized, open-label, two-arm, multi-center, Phase II study will evaluate the efficacy and safety of pertuzumab in combination with trastuzumab plus an aromatase inhibitor (AI) in first-line participants with HER2-positive and hormone receptor-positive advanced breast cancer. Participants will be randomized to one of two treatment arms; Arm A (pertuzumab in combination with trastuzumab plus an AI) or Arm B (trastuzumab plus an AI). Participants may also receive induction chemotherapy (a taxane, either docetaxel or paclitaxel) at the investigator's discretion in combination with the assigned treatment arm. The anticipated time on study treatment is until disease progression, unacceptable toxicity, withdrawal of consent, or death whichever occurs first.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2 |
Study Design
Study Type:
Interventional
Actual Enrollment
:
258 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Randomized, Two-Arm, Open-Label, Multicenter Phase II Trial Assessing the Efficacy and Safety of Pertuzumab Given in Combination With Trastuzumab Plus an Aromatase Inhibitor in First Line Patients With HER2-Positive and Hormone Receptor-Positive Advanced (Metastatic or Locally Advanced) Breast Cancer
Actual Study Start Date
:
Feb 17, 2012
Actual Primary Completion Date
:
Mar 17, 2016
Actual Study Completion Date
:
Nov 14, 2019
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Arm A: Pertuzumab + Trastuzumab + AI +/- Chemotherapy 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. |
Drug: Pertuzumab
Participants will receive a loading dose of 840 milligrams (mg) as an intravenous infusion on Day 1 of first treatment cycle, followed by 420 mg on Day 1 or Day 2 of each subsequent 3-week cycle until disease progression or unacceptable toxicity.
Other Names:
Drug: Trastuzumab
Participants will receive a loading dose of 8 milligrams per kilogram (mg/kg) as an intravenous infusion on Day 1 or 2 of first treatment cycle, followed by 6 mg/kg on Day 1 or Day 2 of each subsequent treatment 3-week cycles until disease progression or unacceptable toxicity.
Other Names:
Drug: Aromatase Inhibitor
Participants will receive 1 mg anastrozole or 2.5 mg letrozole orally once daily.
Drug: Induction Chemotherapy
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.
|
| Active Comparator: Arm B: Trastuzumab + AI +/- Chemotherapy 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. |
Drug: Trastuzumab
Participants will receive a loading dose of 8 milligrams per kilogram (mg/kg) as an intravenous infusion on Day 1 or 2 of first treatment cycle, followed by 6 mg/kg on Day 1 or Day 2 of each subsequent treatment 3-week cycles until disease progression or unacceptable toxicity.
Other Names:
Drug: Aromatase Inhibitor
Participants will receive 1 mg anastrozole or 2.5 mg letrozole orally once daily.
Drug: Induction Chemotherapy
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.
|
Outcome Measures
Primary Outcome Measures
- Progression-Free Survival (PFS) [Median [full range] of follow-up time on study for: Primary Analysis: 31.7 [0.0-44.3] months vs. 30.4 [0.0-45.8] months in Arm A vs. Arm B; Final Analysis: 73.20 [0.03-88.34] months vs. 71.06 [0.03-88.97] months in Arm A vs. Arm B]
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.
Secondary Outcome Measures
- Overall Survival (OS) [Median [full range] of follow-up time on study for: Primary Analysis: 31.7 [0.0-44.3] months vs. 30.4 [0.0-45.8] months in Arm A vs. Arm B; Final Analysis: 73.20 [0.03-88.34] months vs. 71.06 [0.03-88.97] months in Arm A vs. Arm B]
Overall survival (OS) was defined as the time from the date of randomization to the date of death, regardless of the cause of death. Participants who were alive at the time of the analysis were censored at the date of the last follow-up assessment. Participants without follow-up assessment were censored at the day of last study medication (pertuzumab, trastuzumab, AI or induction chemotherapy), and participants with no post-baseline information were censored at the date of randomization. The primary analysis of OS was planned to be performed at the same time as for PFS (when a total of 165 PFS events had occurred), and the final analysis was planned after at least 60 months follow-up for all participants.
- Overall Response Rate (ORR) [Median [full range] of follow-up time on study for Primary Analysis: 31.7 [0.0-44.3] months vs. 30.4 [0.0-45.8] months in Arm A vs. Arm B]
The overall response rate (ORR) was defined as the percentage of participants with best (confirmed) overall response (BOR) of either complete response (CR) or partial response (PR) from start of study treatment until progressive disease (PD)/recurrence or death, as assessed by the investigator according to RECIST version 1.1. CR: disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm; PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference baseline sum diameters; stable disease (SD): neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. Participants needed to have two consecutive assessments of PR or CR at least 4 weeks apart to be a responder. Analysis of this outcome measure was only planned to occur at the time of primary analysis.
- Clinical Benefit Rate (CBR) [Median [full range] of follow-up time on study for Primary Analysis: 31.7 [0.0-44.3] months vs. 30.4 [0.0-45.8] months in Arm A vs. Arm B]
Clinical Benefit Rate (CBR) was defined as the percentage of participants with best (confirmed) partial response (PR) or complete response (CR) or stable disease (SD) for at least 6 months. According to RECIST version 1.1, CR: disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm; PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters; SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. Analysis of this outcome measure was only planned to occur at the time of primary analysis.
- Duration of Response (DOR) [Median [full range] of follow-up time on study for: Primary Analysis: 31.7 [0.0-44.3] months vs. 30.4 [0.0-45.8] months in Arm A vs. Arm B; Final Analysis: 73.20 [0.03-88.34] months vs. 71.06 [0.03-88.97] months in Arm A vs. Arm B]
Duration of response (DOR) was defined as the period from the date of initial confirmed partial response (PR) or complete response (CR) until the date of progressive disease or death from any cause. According to RECIST version 1.1, CR: disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm; PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Participants with no documented progression after CR or PR were censored at the last date at which they were known to have had the CR or PR, respectively. The primary analysis of DOR was planned to be performed at the same time as for PFS (when a total of 165 PFS events had occurred), and the final analysis was planned after at least 60 months follow-up for all participants.
- Time to Response (TTR) [Median [full range] of follow-up time on study for Primary Analysis: 31.7 [0.0-44.3] months vs. 30.4 [0.0-45.8] months in Arm A vs. Arm B]
Time to Response (TTR) was defined as the time from the date of randomization to the date of first complete response (CR) or partial response (PR). According to RECIST version 1.1, CR: disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm; PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. For participants who did not have a confirmed response, a censored TTR was calculated at the date of the last adequate tumor assessment. If no tumor assessment is performed for the participant (or all post-baseline assessments are not evaluable or PD) the censoring day would be set to day 1 (date of randomization). Analysis of this outcome measure was only planned to occur at the time of primary analysis.
- Change From Baseline in Health-Related Quality of Life as Determined by European Quality of Life 5-Dimension (EQ-5D) Visual Analog Scale (VAS) Scores [Baseline and every 3 cycles until treatment discontinuation (up to Cycle 120; 1 cycle is 21 days)]
The EQ-5D VAS is a participant-rated questionnaire to assess health-related quality of life (QoL) in terms of a single index value. The VAS component rates current health state on a scale from 0 mm (worst imaginable health state) to 100 mm (best imaginable health state); higher scores indicate a better health state.
- Overview of the Number of Participants With Adverse Events, Severity Determined According to NCI-CTCAE Version 4.03 [From Baseline until the end of post-treatment follow-up (up to 89 months)]
All adverse events (AEs) occurring during the study and until the post-treatment safety follow-up visit approximately 28 days after last study medication were recorded; thereafter, only study drug-related serious adverse events (SAEs) continued to be collected. The investigator graded all AEs for severity per the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), Version 4.03; if not listed, the AE was assessed as follows: Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe; Grade 4 = life-threatening/disabling; Grade 5 = death. The investigator determined whether an AE was related to study drug and independently assessed severity and seriousness of each AE. AEs suggestive of congestive heart failure (CHF) were identified by the SMQ (wide) "Cardiac Failure" with a status of "serious", which included the preferred terms cardiac failure, left ventricular dysfunction, and pulmonary oedema.
- Number of Participants Who Died Over the Course of the Study by Reported Cause of Death and Time of Death Relative to First or Last Dose of Study Treatment [From Baseline until the end of post-treatment follow-up (up to 89 months)]
The causes of death over the course of the study, regardless of whether the death was related to study treatment, are listed by preferred term according to the Medical Dictionary for Regulatory Activities (MedDRA), version 22.1.
- Change From Baseline in Left Ventricular Ejection Fraction (LVEF) Values Over the Course of the Study [Baseline and every 3 cycles until treatment discontinuation (up to Cycle 120; 1 cycle is 21 days)]
Left ventricular ejection fraction (LVEF) is the measurement of how much blood is being pumped out of the left ventricle of the heart (the main pumping chamber) with each contraction. A normal LVEF ranges from 55% to 70%, as measured by echocardiogram or multiple-gated acquisition (MUGA) scan. All participants must have had a baseline LVEF of at least (≥)50% to enroll in the study; patients with clinically significant cardiovascular disease or baseline LVEF below 50% were not eligible for this study.
Eligibility Criteria
Criteria
Ages Eligible for Study:
18 Years
and Older
Sexes Eligible for Study:
Female
Accepts Healthy Volunteers:
No
Inclusion Criteria:
-
Participants with HER2-positive and hormone receptor-positive advanced metastatic or locally advanced breast cancer
-
Post-menopausal status over 1 year
-
HER2-positive as assessed by local laboratory on primary or metastatic tumor
-
Hormone-receptor positive defined as estrogen receptor-positive and/or progesterone receptor-positive
-
At least one measurable lesion and/or non-measurable disease evaluable according to Response Evaluation Criteria In Solid Tumors Version 1.1
Exclusion Criteria:
-
Previous systemic non-hormonal anticancer therapy in the metastatic or locally advanced breast cancer setting
-
Previous treatment with anti-HER2 agents for breast cancer, except trastuzumab and/or lapatinib in the neoadjuvant or adjuvant setting
-
Disease progression while receiving adjuvant trastuzumab and/or lapatinib treatment
-
History of persistent Grade 2 or higher hematological toxicity according to National Cancer Institute-Common Toxicity Criteria Version 4.0
-
Disease-free interval from completion of adjuvant/neo-adjuvant systemic non-hormonal treatment to recurrence of within 6 months
-
Other malignancies within the last 5 years, except for carcinoma in situ of the cervix or basal cell carcinoma
-
Clinical or radiographic evidence of central nervous system metastases or significant cardiovascular disease
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | University of Alabama at Birmingham | Birmingham | Alabama | United States | 35249 |
| 2 | Ironwood Cancer TX & Rsch Ctrs | Chandler | Arizona | United States | 85224 |
| 3 | Genesis Cancer Center | Hot Springs | Arkansas | United States | 71913 |
| 4 | Comprehensive Blood & CA Ctr; Research | Bakersfield | California | United States | 93309 |
| 5 | Rocky Mountain Cancer Center - Denver | Denver | Colorado | United States | 80220 |
| 6 | Norwalk Hospital | Norwalk | Connecticut | United States | 06856 |
| 7 | Advanced Medical Specialties | Miami | Florida | United States | 33176 |
| 8 | Georgia Cancer Specialists - Northside | Atlanta | Georgia | United States | 30341 |
| 9 | Northwest Georgia Oncology Centers, a Service of WellStar Cobb Hospital | Marietta | Georgia | United States | 30060 |
| 10 | Cancer Center of Kansas | Wichita | Kansas | United States | 67214-3728 |
| 11 | Crescent City Rsrch Cnsrtm, LLC | Marrero | Louisiana | United States | 70072 |
| 12 | Weinberg CA Inst Franklin Sq | Baltimore | Maryland | United States | 21237 |
| 13 | Center For Cancer and Blood Disorders | Bethesda | Maryland | United States | 20817 |
| 14 | Washington University School of Medicine; Internal Medicine - Renal | Saint Louis | Missouri | United States | 63110 |
| 15 | Hematology Oncology Associates; Carol G. Simon Ctr | Morristown | New Jersey | United States | 07960 |
| 16 | Cooper Hospital; Hematology & Oncology | Voorhees | New Jersey | United States | 08043 |
| 17 | NS-Long Island Jewish Hlth Sys | Lake Success | New York | United States | 11042 |
| 18 | ProHEALTH Care Associates LLP | Lake Success | New York | United States | 11042 |
| 19 | UPMC Cancer Centers | Pittsburgh | Pennsylvania | United States | 15232 |
| 20 | Baylor College of Medicine; Lester & Sue Smith Breast Ctr | Houston | Texas | United States | 77030 |
| 21 | Scott and White Hospital; Cancer Center | Temple | Texas | United States | 76508 |
| 22 | Instituto do Cancer do Estado de Sao Paulo - ICESP | Sao Paulo | SP | Brazil | 01246-000 |
| 23 | Hospital Perola Byington | Sao Paulo | SP | Brazil | 01317-904 |
| 24 | Inst. Brasileiro de Controle Ao Cancer; Oncologia Clinica / Quimioterapia | Sao Paulo | SP | Brazil | 03102-002 |
| 25 | Hospital Sao Jose | São Paulo | SP | Brazil | CEP 01321-001 |
| 26 | HOPITAL JEAN MINJOZ; Oncologie | Besancon | France | 25030 | |
| 27 | Clinique Tivoli; Sce Radiotherapie | Bordeaux | France | 33000 | |
| 28 | Hopital Morvan; Oncologie - Radiotherapie | Brest | France | 29609 | |
| 29 | Centre Jean Perrin; Oncologie | Clermont Ferrand | France | 63011 | |
| 30 | Clinique De La Sauvegarde; Chimiotherapie | Lyon | France | 69337 | |
| 31 | Centre Catherine de Sienne; Chimiotherapie | Nantes | France | 44202 | |
| 32 | Centre Antoine Lacassagne; Hopital De Jour A2 | Nice | France | 06189 | |
| 33 | CH De Senlis; Medecine 2 | Senlis | France | 60309 | |
| 34 | Clinique Pasteur; Oncologie Medicale | Toulouse | France | 31076 | |
| 35 | Centre Alexis Vautrin; Oncologie Medicale | Vandoeuvre-les-nancy | France | 54519 | |
| 36 | Indraprastha Apollo Hospitals | New Delhi | Delhi | India | 110076 |
| 37 | Bangalore Institute of Oncology | Bangalore | Karnataka | India | 560027 |
| 38 | Jaslok Hospital & Research Centre; Medical Oncology | Mumbai | Maharashtra | India | 400026 |
| 39 | Apollo Speciality Hospital | Chennai | India | 600035 | |
| 40 | Ruby Hall Clinic | Pune | India | 411 001 | |
| 41 | Istituto Nazionale Tumori Fondazione G. Pascale | Napoli | Campania | Italy | 80131 |
| 42 | Università degli Studi Federico II; Clinica di Oncologia Medica | Napoli | Campania | Italy | 80131 |
| 43 | Azienda Ospedaliero-Universitaria S.Orsola-Malpighi; Unità Operativa Oncologia Medica | Bologna | Emilia-Romagna | Italy | 40138 |
| 44 | Ospedale Regionale Di Parma; Divisione Di Oncologia Medica | Parma | Emilia-Romagna | Italy | 43100 |
| 45 | A.O. Santa Maria Degli Angeli; U.O Di Oncologia Medica | Pordenone | Friuli-Venezia Giulia | Italy | 33170 |
| 46 | Ospedale S.S. Trinità Nuovo; Divisione Oncologia | Sora | Lazio | Italy | 03039 |
| 47 | Casa di Cura MultiMedica Ospedale di Castellanza; UO Senologia Medica | Castellanza | Lombardia | Italy | 21053 |
| 48 | Irccs Istituto Nazionale Dei Tumori (Int);S.C. Medicina Oncologica 1 | Milano | Lombardia | Italy | 20133 |
| 49 | IRCCS Fondazione Maugeri; Oncologia Medica I | Pavia | Lombardia | Italy | 27100 |
| 50 | Irccs Ist. Tumori Giovanni Paolo Ii; Dipartimento Oncologia Medica | Bari | Puglia | Italy | 70124 |
| 51 | Ospedale Antonio Perrino; Oncologia Medica | Brindisi | Puglia | Italy | 72100 |
| 52 | Ospedale Vito Fazzi; Div. Oncoematologia | Lecce | Puglia | Italy | 73100 |
| 53 | Az Ospedaliera Nuovo Garibaldi Quartiere Nesima; Oncologia Medica | Catania | Sicilia | Italy | 95122 |
| 54 | A.O. Careggi; Radioterapia | Firenze | Toscana | Italy | 50139 |
| 55 | Ospedale Misericordia E Dolce; Oncologia Medica | Prato | Toscana | Italy | 59100 |
| 56 | Hospital Universitari Germans Trias i Pujol; Servicio de Oncologia | Badalona | Barcelona | Spain | 08916 |
| 57 | Hospital Provincial de Castellon; Servicio de Oncologia | Castellon de La Plana | Castellon | Spain | 12002 |
| 58 | Hospital Universitario Reina Sofia; Servicio de Oncologia | Córdoba | Cordoba | Spain | 14004 |
| 59 | IInstituto Oncologico de San Sebastian, Oncologikoa; Servicio de Oncologia | San Sebastian | Guipuzcoa | Spain | 20014 |
| 60 | Hospital de Donostia; Servicio de Oncologia Medica | San Sebastian | Guipuzcoa | Spain | 20080 |
| 61 | Hospital del Mar; Servicio de Oncologia | Barcelona | Spain | 08003 | |
| 62 | Hospital de San Pedro de Alcantara | Caceres | Spain | 10003 | |
| 63 | Complejo Hospitalario Universitario A Coruña (CHUAC, Materno Infantil), Oncología | La Coruña | Spain | 15006 | |
| 64 | Centro Oncológico Gallego José Antonio Quiroga y Piñeiro, Servicio de Oncologia | La Coruña | Spain | 15009 | |
| 65 | Hospital Universitari Arnau de Vilanova de Lleida; Servicio de Oncologia | Lerida | Spain | 25198 | |
| 66 | Hospital Ramon y Cajal; Servicio de Oncologia | Madrid | Spain | 28034 | |
| 67 | Hospital Universitario Clínico San Carlos; Servicio de Oncologia | Madrid | Spain | 28040 | |
| 68 | Hospital Universitario Virgen de Arrixaca; Servicio de Oncologia | Murcia | Spain | 30120 | |
| 69 | Hospital Universitario Virgen Macarena; Servicio de Oncologia | Sevilla | Spain | 41009 | |
| 70 | Hospital Clinico Universitario de Valencia; Servicio de Onco-hematologia | Valencia | Spain | 46010 | |
| 71 | Hospital Universitario Miguel Servet; Servicio Oncologia | Zaragoza | Spain | 50009 | |
| 72 | Hacettepe Uni Medical Faculty Hospital; Oncology Dept | Ankara | Turkey | 06100 | |
| 73 | Ankara City Hospital | Ankara | Turkey | 06490 | |
| 74 | Ege Uni Medical Faculty Hospital; Oncology Dept | Izmir | Turkey | 35100 | |
| 75 | Inonu University Medical Faculty Turgut Ozal Medical Center Medical Oncology Department | Malatya | Turkey | 44280 | |
| 76 | Brighton and Sussex Univ Hosp | Brighton | United Kingdom | BN2 5BE | |
| 77 | University Hospital coventry; Oncology Department | Coventry | United Kingdom | CV2 2DX | |
| 78 | Beatson West of Scotland Cancer Centre | Glasgow | United Kingdom | G12 0YN | |
| 79 | Queen Elizabeth Hospital | London | United Kingdom | SE18 4QH | |
| 80 | Queen Alexandra Hospital, Portsmouth | Portsmouth | United Kingdom | PO6 3LY | |
| 81 | Scarborough General Hospital | Scarborough | United Kingdom | YO12 6QL | |
| 82 | Weston Park Hospital; Cancer Clinical Trials Centre | Sheffield | United Kingdom | S10 2SJ |
Sponsors and Collaborators
- Hoffmann-La Roche
Investigators
- Study Director: Clinical Trials, Hoffmann-La Roche
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.Responsible Party:
Hoffmann-La Roche
ClinicalTrials.gov Identifier:
NCT01491737
Other Study ID Numbers:
- MO27775
- 2011-002132-10
First Posted:
Dec 14, 2011
Last Update Posted:
Oct 28, 2020
Last Verified:
Oct 1, 2020
Studies a U.S. FDA-regulated Drug Product:
Yes
Studies a U.S. FDA-regulated Device Product:
No
Additional relevant MeSH terms:
Study Results
Participant Flow
| Recruitment Details | |
|---|---|
| Pre-assignment Detail | A total of 258 participants were enrolled in the study. |
| Arm/Group Title | Arm A: Pertuzumab + Trastuzumab + AI +/- Chemotherapy | Arm B: Trastuzumab + AI +/- Chemotherapy |
|---|---|---|
| Arm/Group Description | Participants received pertuzumab at a loading dose of 840 mg followed by 420 mg along with trastuzumab at a loading dose of 8 mg/kg of body weight followed by 6 mg/kg of body weight on Day 1 or Day 2 of each 3-weekly cycle until disease progression, unacceptable toxicity, withdrawal of consent, or death, or the predefined end of study whichever occurred first. Participants also received an aromatase inhibitor (AI), orally as per product labeling (anastrozole: 1 mg once daily or letrozole: 2.5 mg once daily). Participants receiving induction chemotherapy up to the first 18-24 weeks of the treatment period were to receive a taxane (docetaxel every 3 weeks or paclitaxel weekly), administered in line with the respective product labeling. | Participants received trastuzumab at a loading dose of 8 mg/kg of body weight followed by 6 mg/kg of body weight on Day 1 or Day 2 of each 3-weekly cycle until disease progression, unacceptable toxicity, withdrawal of consent, or death, or the predefined end of study whichever occurred first. Participants also received an aromatase inhibitor (AI), orally as per product labeling (anastrozole: 1 mg once daily or letrozole: 2.5 mg once daily). Participants receiving induction chemotherapy up to the first 18-24 weeks of the treatment period were to receive a taxane (docetaxel every 3 weeks or paclitaxel weekly), administered in line with the respective product labeling. |
| Period Title: Overall Study | ||
| STARTED | 129 | 129 |
| Received at Least One Dose of Study Drug | 127 | 124 |
| Entered Follow-Up (Post-Treatment) | 120 | 116 |
| COMPLETED | 0 | 0 |
| NOT COMPLETED | 129 | 129 |
Baseline Characteristics
| Arm/Group Title | Arm A: Pertuzumab + Trastuzumab + AI +/- Chemotherapy | Arm B: Trastuzumab + AI +/- Chemotherapy | Total |
|---|---|---|---|
| Arm/Group Description | Participants received pertuzumab at a loading dose of 840 mg followed by 420 mg along with trastuzumab at a loading dose of 8 mg/kg of body weight followed by 6 mg/kg of body weight on Day 1 or Day 2 of each 3-weekly cycle until disease progression, unacceptable toxicity, withdrawal of consent, or death, or the predefined end of study whichever occurred first. Participants also received an aromatase inhibitor (AI), orally as per product labeling (anastrozole: 1 mg once daily or letrozole: 2.5 mg once daily). Participants receiving induction chemotherapy up to the first 18-24 weeks of the treatment period were to receive a taxane (docetaxel every 3 weeks or paclitaxel weekly), administered in line with the respective product labeling. | Participants received trastuzumab at a loading dose of 8 mg/kg of body weight followed by 6 mg/kg of body weight on Day 1 or Day 2 of each 3-weekly cycle until disease progression, unacceptable toxicity, withdrawal of consent, or death, or the predefined end of study whichever occurred first. Participants also received an aromatase inhibitor (AI), orally as per product labeling (anastrozole: 1 mg once daily or letrozole: 2.5 mg once daily). Participants receiving induction chemotherapy up to the first 18-24 weeks of the treatment period were to receive a taxane (docetaxel every 3 weeks or paclitaxel weekly), administered in line with the respective product labeling. | Total of all reporting groups |
| Overall Participants | 129 | 129 | 258 |
| Age (Years) [Mean (Standard Deviation) ] | |||
| Mean (Standard Deviation) [Years] |
60.9
(10.85)
|
62.3
(11.54)
|
61.6
(11.20)
|
| Sex: Female, Male (Count of Participants) | |||
| Female |
129
100%
|
129
100%
|
258
100%
|
| Male |
0
0%
|
0
0%
|
0
0%
|
| Race (NIH/OMB) (Count of Participants) | |||
| American Indian or Alaska Native |
0
0%
|
1
0.8%
|
1
0.4%
|
| Asian |
10
7.8%
|
18
14%
|
28
10.9%
|
| Native Hawaiian or Other Pacific Islander |
0
0%
|
0
0%
|
0
0%
|
| Black or African American |
4
3.1%
|
5
3.9%
|
9
3.5%
|
| White |
104
80.6%
|
93
72.1%
|
197
76.4%
|
| More than one race |
0
0%
|
0
0%
|
0
0%
|
| Unknown or Not Reported |
11
8.5%
|
12
9.3%
|
23
8.9%
|
| Race/Ethnicity, Customized (Count of Participants) | |||
| Hispanic/Latino |
45
34.9%
|
40
31%
|
85
32.9%
|
| Chinese |
0
0%
|
0
0%
|
0
0%
|
| Indian (Indian subcontinent) |
10
7.8%
|
16
12.4%
|
26
10.1%
|
| Japanese |
0
0%
|
1
0.8%
|
1
0.4%
|
| Mixed Ethnicity |
0
0%
|
0
0%
|
0
0%
|
| Other |
63
48.8%
|
60
46.5%
|
123
47.7%
|
| Missing |
11
8.5%
|
12
9.3%
|
23
8.9%
|
| Number of Participants by Induction Chemotherapy and Prior Adjuvant Hormone Therapy (Count of Participants) | |||
| <12 Months Since Hormone Therapy |
12
9.3%
|
12
9.3%
|
24
9.3%
|
| ≥12 Months Since Hormone Therapy |
24
18.6%
|
23
17.8%
|
47
18.2%
|
| No Prior Hormone Therapy |
39
30.2%
|
38
29.5%
|
77
29.8%
|
| <12 Months Since Hormone Therapy |
12
9.3%
|
12
9.3%
|
24
9.3%
|
| ≥12 Months Since Hormone Therapy |
18
14%
|
19
14.7%
|
37
14.3%
|
| No Prior Hormone Therapy |
24
18.6%
|
25
19.4%
|
49
19%
|
Outcome Measures
| Title | Progression-Free Survival (PFS) |
|---|---|
| Description | 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. |
| Time Frame | Median [full range] of follow-up time on study for: Primary Analysis: 31.7 [0.0-44.3] months vs. 30.4 [0.0-45.8] months in Arm A vs. Arm B; Final Analysis: 73.20 [0.03-88.34] months vs. 71.06 [0.03-88.97] months in Arm A vs. Arm B |
Outcome Measure Data
| Analysis Population Description |
|---|
| Intent-to-Treat (ITT) population included all randomized participants. |
| Arm/Group Title | Arm A: Pertuzumab + Trastuzumab + AI +/- Chemotherapy | Arm B: Trastuzumab + AI +/- Chemotherapy |
|---|---|---|
| Arm/Group Description | Participants received pertuzumab at a loading dose of 840 mg followed by 420 mg along with trastuzumab at a loading dose of 8 mg/kg of body weight followed by 6 mg/kg of body weight on Day 1 or Day 2 of each 3-weekly cycle until disease progression, unacceptable toxicity, withdrawal of consent, or death, or the predefined end of study whichever occurred first. Participants also received an aromatase inhibitor (AI), orally as per product labeling (anastrozole: 1 mg once daily or letrozole: 2.5 mg once daily). Participants receiving induction chemotherapy up to the first 18-24 weeks of the treatment period were to receive a taxane (docetaxel every 3 weeks or paclitaxel weekly), administered in line with the respective product labeling. | Participants received trastuzumab at a loading dose of 8 mg/kg of body weight followed by 6 mg/kg of body weight on Day 1 or Day 2 of each 3-weekly cycle until disease progression, unacceptable toxicity, withdrawal of consent, or death, or the predefined end of study whichever occurred first. Participants also received an aromatase inhibitor (AI), orally as per product labeling (anastrozole: 1 mg once daily or letrozole: 2.5 mg once daily). Participants receiving induction chemotherapy up to the first 18-24 weeks of the treatment period were to receive a taxane (docetaxel every 3 weeks or paclitaxel weekly), administered in line with the respective product labeling. |
| Measure Participants | 129 | 129 |
| Primary Analysis |
18.89
|
15.80
|
| Final Analysis |
20.63
|
15.80
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Arm A: Pertuzumab + Trastuzumab + AI +/- Chemotherapy, Arm B: Trastuzumab + AI +/- Chemotherapy |
|---|---|---|
| Comments | Primary Analysis. Log Rank tested the following: Null Hypothesis (H0): the distribution of the PFS time was the same in Arms A & B; The Alternative Hypothesis (H1): the distribution of the PFS time was different in Arms A & B. A Cox proportional hazards model tested the HR. If the HR of investigational arm (Arm A) compared with control arm (Arm B) with respect to PFS was assumed to be constant over time (λ) then the null (H0) and alternative hypotheses (H1) were: H0: λ =1; H1: λ ≠1. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.0070 |
| Comments | Test was performed at 2-sided alpha of 5%. | |
| Method | Log Rank | |
| Comments | Stratified log-rank test based upon Kaplan-Meier including induction chemotherapy and prior adjuvant hormone therapy stratification factors. | |
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.65 | |
| Confidence Interval |
(2-Sided) 95% 0.48 to 0.89 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Hazard ratio comparing Arm A vs. B from stratified Cox proportional hazards model including stratification factors. | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Arm A: Pertuzumab + Trastuzumab + AI +/- Chemotherapy, Arm B: Trastuzumab + AI +/- Chemotherapy |
|---|---|---|
| Comments | Final Analysis | |
| Type of Statistical Test | Other | |
| Comments | Exploratory | |
| Statistical Test of Hypothesis | p-Value | 0.0059 |
| Comments | ||
| Method | Log Rank | |
| Comments | Stratified log-rank test based upon Kaplan-Meier including induction chemotherapy and prior adjuvant hormone therapy stratification factors. | |
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.67 | |
| Confidence Interval |
(2-Sided) 95% 0.50 to 0.89 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Hazard ratio comparing Arm A vs. B from stratified Cox proportional hazards model including stratification factors. | |
| Title | Overall Survival (OS) |
|---|---|
| Description | Overall survival (OS) was defined as the time from the date of randomization to the date of death, regardless of the cause of death. Participants who were alive at the time of the analysis were censored at the date of the last follow-up assessment. Participants without follow-up assessment were censored at the day of last study medication (pertuzumab, trastuzumab, AI or induction chemotherapy), and participants with no post-baseline information were censored at the date of randomization. The primary analysis of OS was planned to be performed at the same time as for PFS (when a total of 165 PFS events had occurred), and the final analysis was planned after at least 60 months follow-up for all participants. |
| Time Frame | Median [full range] of follow-up time on study for: Primary Analysis: 31.7 [0.0-44.3] months vs. 30.4 [0.0-45.8] months in Arm A vs. Arm B; Final Analysis: 73.20 [0.03-88.34] months vs. 71.06 [0.03-88.97] months in Arm A vs. Arm B |
Outcome Measure Data
| Analysis Population Description |
|---|
| ITT population included all randomized participants. |
| Arm/Group Title | Arm A: Pertuzumab + Trastuzumab + AI +/- Chemotherapy | Arm B: Trastuzumab + AI +/- Chemotherapy |
|---|---|---|
| Arm/Group Description | Participants received pertuzumab at a loading dose of 840 mg followed by 420 mg along with trastuzumab at a loading dose of 8 mg/kg of body weight followed by 6 mg/kg of body weight on Day 1 or Day 2 of each 3-weekly cycle until disease progression, unacceptable toxicity, withdrawal of consent, or death, or the predefined end of study whichever occurred first. Participants also received an aromatase inhibitor (AI), orally as per product labeling (anastrozole: 1 mg once daily or letrozole: 2.5 mg once daily). Participants receiving induction chemotherapy up to the first 18-24 weeks of the treatment period were to receive a taxane (docetaxel every 3 weeks or paclitaxel weekly), administered in line with the respective product labeling. | Participants received trastuzumab at a loading dose of 8 mg/kg of body weight followed by 6 mg/kg of body weight on Day 1 or Day 2 of each 3-weekly cycle until disease progression, unacceptable toxicity, withdrawal of consent, or death, or the predefined end of study whichever occurred first. Participants also received an aromatase inhibitor (AI), orally as per product labeling (anastrozole: 1 mg once daily or letrozole: 2.5 mg once daily). Participants receiving induction chemotherapy up to the first 18-24 weeks of the treatment period were to receive a taxane (docetaxel every 3 weeks or paclitaxel weekly), administered in line with the respective product labeling. |
| Measure Participants | 129 | 129 |
| Primary Analysis |
NA
|
NA
|
| Final Analysis |
60.16
|
57.17
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Arm A: Pertuzumab + Trastuzumab + AI +/- Chemotherapy, Arm B: Trastuzumab + AI +/- Chemotherapy |
|---|---|---|
| Comments | Primary Analysis. This study was not powered for overall survival (OS), so adequately powered statistical testing for this outcome measure was not possible. | |
| Type of Statistical Test | Other | |
| Comments | Exploratory | |
| Statistical Test of Hypothesis | p-Value | 0.5850 |
| Comments | ||
| Method | Log Rank | |
| Comments | Stratified log-rank test based upon Kaplan-Meier including induction chemotherapy and prior adjuvant hormone therapy stratification factors. | |
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 1.15 | |
| Confidence Interval |
(2-Sided) 95% 0.69 to 1.91 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Hazard ratio comparing Arm A vs. B from stratified Cox proportional hazards model including stratification factors. | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Arm A: Pertuzumab + Trastuzumab + AI +/- Chemotherapy, Arm B: Trastuzumab + AI +/- Chemotherapy |
|---|---|---|
| Comments | Final Analysis. This study was not powered for overall survival (OS), so adequately powered statistical testing for this outcome measure was not possible. | |
| Type of Statistical Test | Other | |
| Comments | Exploratory | |
| Statistical Test of Hypothesis | p-Value | 0.7833 |
| Comments | ||
| Method | Log Rank | |
| Comments | Stratified log-rank test based upon Kaplan-Meier including induction chemotherapy and prior adjuvant hormone therapy stratification factors. | |
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 1.05 | |
| Confidence Interval |
(2-Sided) 95% 0.73 to 1.52 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Hazard ratio comparing Arm A vs. B from stratified Cox proportional hazards model including stratification factors. | |
| Title | Overall Response Rate (ORR) |
|---|---|
| Description | The overall response rate (ORR) was defined as the percentage of participants with best (confirmed) overall response (BOR) of either complete response (CR) or partial response (PR) from start of study treatment until progressive disease (PD)/recurrence or death, as assessed by the investigator according to RECIST version 1.1. CR: disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm; PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference baseline sum diameters; stable disease (SD): neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. Participants needed to have two consecutive assessments of PR or CR at least 4 weeks apart to be a responder. Analysis of this outcome measure was only planned to occur at the time of primary analysis. |
| Time Frame | Median [full range] of follow-up time on study for Primary Analysis: 31.7 [0.0-44.3] months vs. 30.4 [0.0-45.8] months in Arm A vs. Arm B |
Outcome Measure Data
| Analysis Population Description |
|---|
| ITT population included all randomized participants. Only participants with measurable disease at baseline were included in the analysis. |
| Arm/Group Title | Arm A: Pertuzumab + Trastuzumab + AI +/- Chemotherapy | Arm B: Trastuzumab + AI +/- Chemotherapy |
|---|---|---|
| Arm/Group Description | Participants received pertuzumab at a loading dose of 840 mg followed by 420 mg along with trastuzumab at a loading dose of 8 mg/kg of body weight followed by 6 mg/kg of body weight on Day 1 or Day 2 of each 3-weekly cycle until disease progression, unacceptable toxicity, withdrawal of consent, or death, or the predefined end of study whichever occurred first. Participants also received an aromatase inhibitor (AI), orally as per product labeling (anastrozole: 1 mg once daily or letrozole: 2.5 mg once daily). Participants receiving induction chemotherapy up to the first 18-24 weeks of the treatment period were to receive a taxane (docetaxel every 3 weeks or paclitaxel weekly), administered in line with the respective product labeling. | Participants received trastuzumab at a loading dose of 8 mg/kg of body weight followed by 6 mg/kg of body weight on Day 1 or Day 2 of each 3-weekly cycle until disease progression, unacceptable toxicity, withdrawal of consent, or death, or the predefined end of study whichever occurred first. Participants also received an aromatase inhibitor (AI), orally as per product labeling (anastrozole: 1 mg once daily or letrozole: 2.5 mg once daily). Participants receiving induction chemotherapy up to the first 18-24 weeks of the treatment period were to receive a taxane (docetaxel every 3 weeks or paclitaxel weekly), administered in line with the respective product labeling. |
| Measure Participants | 109 | 106 |
| ORR (CR + PR) |
63.3
49.1%
|
55.7
43.2%
|
| Non-responders (SD + PD + NE) |
36.7
28.4%
|
44.3
34.3%
|
| Complete Response (CR) |
7.3
5.7%
|
0.9
0.7%
|
| Partial Response (PR) |
56.0
43.4%
|
54.7
42.4%
|
| Stable Disease (SD) |
26.6
20.6%
|
27.4
21.2%
|
| Progressive Disease (PD) |
5.5
4.3%
|
12.3
9.5%
|
| Not Evaluable (NE) |
4.5
3.5%
|
4.7
3.6%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Arm A: Pertuzumab + Trastuzumab + AI +/- Chemotherapy, Arm B: Trastuzumab + AI +/- Chemotherapy |
|---|---|---|
| Comments | ORR for Arm A vs Arm B | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.2537 |
| Comments | Test was performed at 2-sided alpha of 5%. There was no multiplicity adjustment. | |
| Method | Chi-squared | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Difference in ORR |
| Estimated Value | 7.6 | |
| Confidence Interval |
(2-Sided) 95% -6.0 to 21.3 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Clinical Benefit Rate (CBR) |
|---|---|
| Description | Clinical Benefit Rate (CBR) was defined as the percentage of participants with best (confirmed) partial response (PR) or complete response (CR) or stable disease (SD) for at least 6 months. According to RECIST version 1.1, CR: disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm; PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters; SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. Analysis of this outcome measure was only planned to occur at the time of primary analysis. |
| Time Frame | Median [full range] of follow-up time on study for Primary Analysis: 31.7 [0.0-44.3] months vs. 30.4 [0.0-45.8] months in Arm A vs. Arm B |
Outcome Measure Data
| Analysis Population Description |
|---|
| ITT population included all randomized participants. Only participants with measurable disease at baseline were included in the analysis. |
| Arm/Group Title | Arm A: Pertuzumab + Trastuzumab + AI +/- Chemotherapy | Arm B: Trastuzumab + AI +/- Chemotherapy |
|---|---|---|
| Arm/Group Description | Participants received pertuzumab at a loading dose of 840 mg followed by 420 mg along with trastuzumab at a loading dose of 8 mg/kg of body weight followed by 6 mg/kg of body weight on Day 1 or Day 2 of each 3-weekly cycle until disease progression, unacceptable toxicity, withdrawal of consent, or death, or the predefined end of study whichever occurred first. Participants also received an aromatase inhibitor (AI), orally as per product labeling (anastrozole: 1 mg once daily or letrozole: 2.5 mg once daily). Participants receiving induction chemotherapy up to the first 18-24 weeks of the treatment period were to receive a taxane (docetaxel every 3 weeks or paclitaxel weekly), administered in line with the respective product labeling. | Participants received trastuzumab at a loading dose of 8 mg/kg of body weight followed by 6 mg/kg of body weight on Day 1 or Day 2 of each 3-weekly cycle until disease progression, unacceptable toxicity, withdrawal of consent, or death, or the predefined end of study whichever occurred first. Participants also received an aromatase inhibitor (AI), orally as per product labeling (anastrozole: 1 mg once daily or letrozole: 2.5 mg once daily). Participants receiving induction chemotherapy up to the first 18-24 weeks of the treatment period were to receive a taxane (docetaxel every 3 weeks or paclitaxel weekly), administered in line with the respective product labeling. |
| Measure Participants | 109 | 106 |
| CBR (CR + PR + SD for ≥6 Months) |
68.8
53.3%
|
67.0
51.9%
|
| Complete Response (CR) |
7.3
5.7%
|
0.9
0.7%
|
| Partial Response (PR) |
56.0
43.4%
|
54.7
42.4%
|
| Stable Disease (SD) for ≥6 Months |
5.5
4.3%
|
11.3
8.8%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Arm A: Pertuzumab + Trastuzumab + AI +/- Chemotherapy, Arm B: Trastuzumab + AI +/- Chemotherapy |
|---|---|---|
| Comments | CBR for Arm A vs. Arm B | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.7743 |
| Comments | Test was performed at 2-sided alpha of 5%. There was no multiplicity adjustment. | |
| Method | Chi-squared | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Difference in CBR |
| Estimated Value | 1.8 | |
| Confidence Interval |
(2-Sided) 95% -11.2 to 14.8 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Duration of Response (DOR) |
|---|---|
| Description | Duration of response (DOR) was defined as the period from the date of initial confirmed partial response (PR) or complete response (CR) until the date of progressive disease or death from any cause. According to RECIST version 1.1, CR: disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm; PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Participants with no documented progression after CR or PR were censored at the last date at which they were known to have had the CR or PR, respectively. The primary analysis of DOR was planned to be performed at the same time as for PFS (when a total of 165 PFS events had occurred), and the final analysis was planned after at least 60 months follow-up for all participants. |
| Time Frame | Median [full range] of follow-up time on study for: Primary Analysis: 31.7 [0.0-44.3] months vs. 30.4 [0.0-45.8] months in Arm A vs. Arm B; Final Analysis: 73.20 [0.03-88.34] months vs. 71.06 [0.03-88.97] months in Arm A vs. Arm B |
Outcome Measure Data
| Analysis Population Description |
|---|
| ITT population included all randomized participants. Only participants who had measurable disease at baseline and were responders (CR or PR) were included in this analysis. |
| Arm/Group Title | Arm A: Pertuzumab + Trastuzumab + AI +/- Chemotherapy | Arm B: Trastuzumab + AI +/- Chemotherapy |
|---|---|---|
| Arm/Group Description | Participants received pertuzumab at a loading dose of 840 mg followed by 420 mg along with trastuzumab at a loading dose of 8 mg/kg of body weight followed by 6 mg/kg of body weight on Day 1 or Day 2 of each 3-weekly cycle until disease progression, unacceptable toxicity, withdrawal of consent, or death, or the predefined end of study whichever occurred first. Participants also received an aromatase inhibitor (AI), orally as per product labeling (anastrozole: 1 mg once daily or letrozole: 2.5 mg once daily). Participants receiving induction chemotherapy up to the first 18-24 weeks of the treatment period were to receive a taxane (docetaxel every 3 weeks or paclitaxel weekly), administered in line with the respective product labeling. | Participants received trastuzumab at a loading dose of 8 mg/kg of body weight followed by 6 mg/kg of body weight on Day 1 or Day 2 of each 3-weekly cycle until disease progression, unacceptable toxicity, withdrawal of consent, or death, or the predefined end of study whichever occurred first. Participants also received an aromatase inhibitor (AI), orally as per product labeling (anastrozole: 1 mg once daily or letrozole: 2.5 mg once daily). Participants receiving induction chemotherapy up to the first 18-24 weeks of the treatment period were to receive a taxane (docetaxel every 3 weeks or paclitaxel weekly), administered in line with the respective product labeling. |
| Measure Participants | 69 | 61 |
| Primary Analysis |
27.10
|
15.11
|
| Final Analysis |
27.40
|
16.36
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Arm A: Pertuzumab + Trastuzumab + AI +/- Chemotherapy, Arm B: Trastuzumab + AI +/- Chemotherapy |
|---|---|---|
| Comments | Primary Analysis. Log Rank tested the following: Null Hypothesis (H0): the distribution of the DOR time was the same in Arms A & B; The Alternative Hypothesis (H1): the distribution of the DOR time was different in Arms A & B. A Cox proportional hazards model tested the HR. If the HR of investigational arm (Arm A) compared with control arm (Arm B) with respect to DOR was assumed to be constant over time (λ) then the null (H0) and alternative hypotheses (H1) were: H0: λ =1; H1: λ ≠1. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.0181 |
| Comments | Test was performed at 2-sided alpha of 5%. | |
| Method | Log Rank | |
| Comments | Log-rank test from unstratified analysis based upon Kaplan-Meier approach. There was no multiplicity adjustment. | |
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.57 | |
| Confidence Interval |
(2-Sided) 95% 0.36 to 0.91 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Hazard ratio from stratified Cox proportional hazards model including stratification factors of induction chemotherapy and prior adjuvant hormone therapy. | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Arm A: Pertuzumab + Trastuzumab + AI +/- Chemotherapy, Arm B: Trastuzumab + AI +/- Chemotherapy |
|---|---|---|
| Comments | Final Analysis. | |
| Type of Statistical Test | Other | |
| Comments | Exploratory | |
| Statistical Test of Hypothesis | p-Value | 0.0205 |
| Comments | ||
| Method | Log Rank | |
| Comments | Log-rank test from unstratified analysis based upon Kaplan-Meier approach. There was no multiplicity adjustment. | |
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.62 | |
| Confidence Interval |
(2-Sided) 95% 0.41 to 0.93 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Hazard ratio from stratified Cox proportional hazards model including stratification factors of induction chemotherapy and prior adjuvant hormone therapy. | |
| Title | Time to Response (TTR) |
|---|---|
| Description | Time to Response (TTR) was defined as the time from the date of randomization to the date of first complete response (CR) or partial response (PR). According to RECIST version 1.1, CR: disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm; PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. For participants who did not have a confirmed response, a censored TTR was calculated at the date of the last adequate tumor assessment. If no tumor assessment is performed for the participant (or all post-baseline assessments are not evaluable or PD) the censoring day would be set to day 1 (date of randomization). Analysis of this outcome measure was only planned to occur at the time of primary analysis. |
| Time Frame | Median [full range] of follow-up time on study for Primary Analysis: 31.7 [0.0-44.3] months vs. 30.4 [0.0-45.8] months in Arm A vs. Arm B |
Outcome Measure Data
| Analysis Population Description |
|---|
| ITT population included all randomized participants. Only participants with measurable disease at baseline were included in this analysis. |
| Arm/Group Title | Arm A: Pertuzumab + Trastuzumab + AI +/- Chemotherapy | Arm B: Trastuzumab + AI +/- Chemotherapy |
|---|---|---|
| Arm/Group Description | Participants received pertuzumab at a loading dose of 840 mg followed by 420 mg along with trastuzumab at a loading dose of 8 mg/kg of body weight followed by 6 mg/kg of body weight on Day 1 or Day 2 of each 3-weekly cycle until disease progression, unacceptable toxicity, withdrawal of consent, or death, or the predefined end of study whichever occurred first. Participants also received an aromatase inhibitor (AI), orally as per product labeling (anastrozole: 1 mg once daily or letrozole: 2.5 mg once daily). Participants receiving induction chemotherapy up to the first 18-24 weeks of the treatment period were to receive a taxane (docetaxel every 3 weeks or paclitaxel weekly), administered in line with the respective product labeling. | Participants received trastuzumab at a loading dose of 8 mg/kg of body weight followed by 6 mg/kg of body weight on Day 1 or Day 2 of each 3-weekly cycle until disease progression, unacceptable toxicity, withdrawal of consent, or death, or the predefined end of study whichever occurred first. Participants also received an aromatase inhibitor (AI), orally as per product labeling (anastrozole: 1 mg once daily or letrozole: 2.5 mg once daily). Participants receiving induction chemotherapy up to the first 18-24 weeks of the treatment period were to receive a taxane (docetaxel every 3 weeks or paclitaxel weekly), administered in line with the respective product labeling. |
| Measure Participants | 109 | 106 |
| Median (95% Confidence Interval) [months] |
2.53
|
3.91
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Arm A: Pertuzumab + Trastuzumab + AI +/- Chemotherapy, Arm B: Trastuzumab + AI +/- Chemotherapy |
|---|---|---|
| Comments | Log Rank tested the following: Null Hypothesis (H0): the distribution of the TTR time was the same in Arms A & B; The Alternative Hypothesis (H1): the distribution of the TTR time was different in Arms A & B. A Cox proportional hazards model tested the HR. If the HR of investigational arm (Arm A) compared with control arm (Arm B) with respect to TTR was assumed to be constant over time (λ) then the null (H0) and alternative hypotheses (H1) were: H0: λ =1; H1: λ ≠1. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.5597 |
| Comments | Test was performed at 2-sided alpha of 5%. | |
| Method | Log Rank | |
| Comments | The log-rank test from unstratified analysis was based upon Kaplan-Meier approach. There was no multiplicity adjustment. | |
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 1.11 | |
| Confidence Interval |
(2-Sided) 95% 0.78 to 1.57 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Hazard ratio from stratified Cox proportional hazards model including the induction chemotherapy and prior adjuvant hormone therapy stratification factors. | |
| Title | Change From Baseline in Health-Related Quality of Life as Determined by European Quality of Life 5-Dimension (EQ-5D) Visual Analog Scale (VAS) Scores |
|---|---|
| Description | The EQ-5D VAS is a participant-rated questionnaire to assess health-related quality of life (QoL) in terms of a single index value. The VAS component rates current health state on a scale from 0 mm (worst imaginable health state) to 100 mm (best imaginable health state); higher scores indicate a better health state. |
| Time Frame | Baseline and every 3 cycles until treatment discontinuation (up to Cycle 120; 1 cycle is 21 days) |
Outcome Measure Data
| Analysis Population Description |
|---|
| ITT population included all randomized participants. The number analyzed only included those who had a non-missing assessment for a specified time point. |
| Arm/Group Title | Arm A: Pertuzumab + Trastuzumab + AI +/- Chemotherapy | Arm B: Trastuzumab + AI +/- Chemotherapy |
|---|---|---|
| Arm/Group Description | Participants received pertuzumab at a loading dose of 840 mg followed by 420 mg along with trastuzumab at a loading dose of 8 mg/kg of body weight followed by 6 mg/kg of body weight on Day 1 or Day 2 of each 3-weekly cycle until disease progression, unacceptable toxicity, withdrawal of consent, or death, or the predefined end of study whichever occurred first. Participants also received an aromatase inhibitor (AI), orally as per product labeling (anastrozole: 1 mg once daily or letrozole: 2.5 mg once daily). Participants receiving induction chemotherapy up to the first 18-24 weeks of the treatment period were to receive a taxane (docetaxel every 3 weeks or paclitaxel weekly), administered in line with the respective product labeling. | Participants received trastuzumab at a loading dose of 8 mg/kg of body weight followed by 6 mg/kg of body weight on Day 1 or Day 2 of each 3-weekly cycle until disease progression, unacceptable toxicity, withdrawal of consent, or death, or the predefined end of study whichever occurred first. Participants also received an aromatase inhibitor (AI), orally as per product labeling (anastrozole: 1 mg once daily or letrozole: 2.5 mg once daily). Participants receiving induction chemotherapy up to the first 18-24 weeks of the treatment period were to receive a taxane (docetaxel every 3 weeks or paclitaxel weekly), administered in line with the respective product labeling. |
| Measure Participants | 129 | 129 |
| Baseline (BL) - Value at Visit |
73.0
(19.34)
|
72.8
(18.83)
|
| Change from BL at Cycle 3 |
3.3
(14.90)
|
1.9
(15.67)
|
| Change from BL at Cycle 6 |
3.5
(18.91)
|
0.5
(13.63)
|
| Change from BL at Cycle 9 |
5.3
(18.80)
|
2.1
(15.20)
|
| Change from BL at Cycle 12 |
10.7
(17.91)
|
4.0
(15.34)
|
| Change from BL at Cycle 15 |
9.1
(17.25)
|
1.4
(22.16)
|
| Change from BL at Cycle 18 |
7.5
(12.85)
|
3.5
(15.76)
|
| Change from BL at Cycle 21 |
5.8
(13.68)
|
3.5
(19.70)
|
| Change from BL at Cycle 24 |
6.2
(14.30)
|
3.2
(16.66)
|
| Change from BL at Cycle 27 |
7.5
(14.01)
|
3.9
(22.00)
|
| Change from BL at Cycle 30 |
8.3
(14.25)
|
4.9
(16.98)
|
| Change from BL at Cycle 33 |
5.1
(14.70)
|
4.3
(15.59)
|
| Change from BL at Cycle 36 |
7.3
(15.19)
|
5.9
(15.13)
|
| Change from BL at Cycle 39 |
8.1
(16.33)
|
2.4
(29.68)
|
| Change from BL at Cycle 42 |
6.4
(19.18)
|
9.0
(17.55)
|
| Change from BL at Cycle 45 |
9.7
(15.01)
|
9.9
(19.52)
|
| Change from BL at Cycle 48 |
8.8
(12.50)
|
6.8
(17.22)
|
| Change from BL at Cycle 51 |
7.2
(14.81)
|
9.1
(19.11)
|
| Change from BL at Cycle 54 |
4.7
(23.48)
|
7.6
(17.85)
|
| Change from BL at Cycle 57 |
6.8
(18.08)
|
10.5
(16.81)
|
| Change from BL at Cycle 60 |
8.2
(15.88)
|
10.9
(18.27)
|
| Change from BL at Cycle 63 |
4.0
(20.88)
|
8.8
(14.64)
|
| Change from BL at Cycle 66 |
10.4
(16.92)
|
4.1
(15.69)
|
| Change from BL at Cycle 69 |
7.5
(17.35)
|
5.0
(16.77)
|
| Change from BL at Cycle 72 |
6.2
(16.10)
|
5.8
(16.10)
|
| Change from BL at Cycle 75 |
8.6
(19.12)
|
5.1
(15.50)
|
| Change from BL at Cycle 78 |
12.8
(17.45)
|
6.9
(14.58)
|
| Change from BL at Cycle 81 |
11.5
(18.39)
|
8.0
(14.76)
|
| Change from BL at Cycle 84 |
11.2
(19.71)
|
1.3
(18.13)
|
| Change from BL at Cycle 87 |
11.2
(18.17)
|
-3.0
(11.22)
|
| Change from BL at Cycle 90 |
10.9
(18.28)
|
-3.0
(12.36)
|
| Change from BL at Cycle 93 |
7.1
(15.43)
|
6.6
(13.89)
|
| Change from BL at Cycle 96 |
7.5
(16.04)
|
8.6
(12.64)
|
| Change from BL at Cycle 99 |
4.4
(17.22)
|
5.6
(16.71)
|
| Change from BL at Cycle 102 |
5.6
(16.35)
|
10.0
(17.32)
|
| Change from BL at Cycle 105 |
4.4
(16.35)
|
0.0
(NA)
|
| Change from BL at Cycle 108 |
4.0
(14.39)
|
0.0
(NA)
|
| Change from BL at Cycle 111 |
3.3
(21.50)
|
|
| Change from BL at Cycle 114 |
-1.3
(17.97)
|
|
| Change from BL at Cycle 117 |
-5.0
(NA)
|
|
| Change from BL at Cycle 120 |
-5.0
(NA)
|
| Title | Overview of the Number of Participants With Adverse Events, Severity Determined According to NCI-CTCAE Version 4.03 |
|---|---|
| Description | All adverse events (AEs) occurring during the study and until the post-treatment safety follow-up visit approximately 28 days after last study medication were recorded; thereafter, only study drug-related serious adverse events (SAEs) continued to be collected. The investigator graded all AEs for severity per the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), Version 4.03; if not listed, the AE was assessed as follows: Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe; Grade 4 = life-threatening/disabling; Grade 5 = death. The investigator determined whether an AE was related to study drug and independently assessed severity and seriousness of each AE. AEs suggestive of congestive heart failure (CHF) were identified by the SMQ (wide) "Cardiac Failure" with a status of "serious", which included the preferred terms cardiac failure, left ventricular dysfunction, and pulmonary oedema. |
| Time Frame | From Baseline until the end of post-treatment follow-up (up to 89 months) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Safety population: included all participants who had received at least 1 dose of any study medication assigned to treatment arms as treated. |
| Arm/Group Title | Arm A: Pertuzumab + Trastuzumab + AI +/- Chemotherapy | Arm B: Trastuzumab + AI +/- Chemotherapy |
|---|---|---|
| Arm/Group Description | Participants received pertuzumab at a loading dose of 840 mg followed by 420 mg along with trastuzumab at a loading dose of 8 mg/kg of body weight followed by 6 mg/kg of body weight on Day 1 or Day 2 of each 3-weekly cycle until disease progression, unacceptable toxicity, withdrawal of consent, or death, or the predefined end of study whichever occurred first. Participants also received an aromatase inhibitor (AI), orally as per product labeling (anastrozole: 1 mg once daily or letrozole: 2.5 mg once daily). Participants receiving induction chemotherapy up to the first 18-24 weeks of the treatment period were to receive a taxane (docetaxel every 3 weeks or paclitaxel weekly), administered in line with the respective product labeling. | Participants received trastuzumab at a loading dose of 8 mg/kg of body weight followed by 6 mg/kg of body weight on Day 1 or Day 2 of each 3-weekly cycle until disease progression, unacceptable toxicity, withdrawal of consent, or death, or the predefined end of study whichever occurred first. Participants also received an aromatase inhibitor (AI), orally as per product labeling (anastrozole: 1 mg once daily or letrozole: 2.5 mg once daily). Participants receiving induction chemotherapy up to the first 18-24 weeks of the treatment period were to receive a taxane (docetaxel every 3 weeks or paclitaxel weekly), administered in line with the respective product labeling. |
| Measure Participants | 127 | 124 |
| Any Adverse Event (AE) |
122
94.6%
|
122
94.6%
|
| Any AE, Grade ≥3 |
72
55.8%
|
51
39.5%
|
| Any Serious Adverse Event (SAE), Grade ≥3 |
35
27.1%
|
22
17.1%
|
| Any AE, Grade 5 |
1
0.8%
|
1
0.8%
|
| Any SAE |
46
35.7%
|
28
21.7%
|
| SAE Related to Pertuzumab |
10
7.8%
|
NA
NaN
|
| SAE Related to Trastuzumab |
9
7%
|
2
1.6%
|
| SAE Related to Docetaxel |
6
4.7%
|
4
3.1%
|
| SAE Related to Paclitaxel |
3
2.3%
|
0
0%
|
| Any AE Leading to Discontinuation of Any Treatment |
20
15.5%
|
10
7.8%
|
| Any AE Leading to Pertuzumab Discontinuation |
16
12.4%
|
NA
NaN
|
| Any AE Leading to Trastuzumab Discontinuation |
16
12.4%
|
6
4.7%
|
| Any AE Leading to Interruption of Any Treatment |
59
45.7%
|
26
20.2%
|
| Any AE Leading to Pertuzumab Interruption |
44
34.1%
|
NA
NaN
|
| Any AE Leading to Trastuzumab Interruption |
48
37.2%
|
16
12.4%
|
| Any AE Related to Pertuzumab |
82
63.6%
|
NA
NaN
|
| Any AE Related to Trastuzumab |
81
62.8%
|
62
48.1%
|
| AE Suggestive of Congestive Heart Failure |
5
3.9%
|
1
0.8%
|
| Title | Number of Participants Who Died Over the Course of the Study by Reported Cause of Death and Time of Death Relative to First or Last Dose of Study Treatment |
|---|---|
| Description | The causes of death over the course of the study, regardless of whether the death was related to study treatment, are listed by preferred term according to the Medical Dictionary for Regulatory Activities (MedDRA), version 22.1. |
| Time Frame | From Baseline until the end of post-treatment follow-up (up to 89 months) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Safety Population: included all participants who had received at least 1 dose of any study medication assigned to treatment arms as treated. |
| Arm/Group Title | Arm A: Pertuzumab + Trastuzumab + AI +/- Chemotherapy | Arm B: Trastuzumab + AI +/- Chemotherapy |
|---|---|---|
| Arm/Group Description | Participants received pertuzumab at a loading dose of 840 mg followed by 420 mg along with trastuzumab at a loading dose of 8 mg/kg of body weight followed by 6 mg/kg of body weight on Day 1 or Day 2 of each 3-weekly cycle until disease progression, unacceptable toxicity, withdrawal of consent, or death, or the predefined end of study whichever occurred first. Participants also received an aromatase inhibitor (AI), orally as per product labeling (anastrozole: 1 mg once daily or letrozole: 2.5 mg once daily). Participants receiving induction chemotherapy up to the first 18-24 weeks of the treatment period were to receive a taxane (docetaxel every 3 weeks or paclitaxel weekly), administered in line with the respective product labeling. | Participants received trastuzumab at a loading dose of 8 mg/kg of body weight followed by 6 mg/kg of body weight on Day 1 or Day 2 of each 3-weekly cycle until disease progression, unacceptable toxicity, withdrawal of consent, or death, or the predefined end of study whichever occurred first. Participants also received an aromatase inhibitor (AI), orally as per product labeling (anastrozole: 1 mg once daily or letrozole: 2.5 mg once daily). Participants receiving induction chemotherapy up to the first 18-24 weeks of the treatment period were to receive a taxane (docetaxel every 3 weeks or paclitaxel weekly), administered in line with the respective product labeling. |
| Measure Participants | 127 | 124 |
| Total Number of Deaths |
62
48.1%
|
57
44.2%
|
| Deaths Related to Any Study Treatment |
0
0%
|
0
0%
|
| Cause of Death: Cardiac Arrest |
1
0.8%
|
0
0%
|
| Cause of Death: Craniocerebral Injury |
1
0.8%
|
0
0%
|
| Cause of Death: Dyspnoea |
1
0.8%
|
0
0%
|
| Cause of Death: High-grade B-cell Lymphoma |
1
0.8%
|
0
0%
|
| Cause of Death: Sudden Death |
0
0%
|
1
0.8%
|
| Cause of Death: Unevaluable Event |
2
1.6%
|
1
0.8%
|
| Cause of Death: Progressive Disease |
56
43.4%
|
55
42.6%
|
| Total Deaths Within 30 Days After First Dose |
0
0%
|
0
0%
|
| Total Deaths Within 28 Days After Last Dose |
1
0.8%
|
2
1.6%
|
| Total Deaths Within 60 Days After Last Dose |
2
1.6%
|
4
3.1%
|
| Title | Change From Baseline in Left Ventricular Ejection Fraction (LVEF) Values Over the Course of the Study |
|---|---|
| Description | Left ventricular ejection fraction (LVEF) is the measurement of how much blood is being pumped out of the left ventricle of the heart (the main pumping chamber) with each contraction. A normal LVEF ranges from 55% to 70%, as measured by echocardiogram or multiple-gated acquisition (MUGA) scan. All participants must have had a baseline LVEF of at least (≥)50% to enroll in the study; patients with clinically significant cardiovascular disease or baseline LVEF below 50% were not eligible for this study. |
| Time Frame | Baseline and every 3 cycles until treatment discontinuation (up to Cycle 120; 1 cycle is 21 days) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Safety Population: included all participants who had received at least 1 dose of any study medication assigned to treatment arms as treated. |
| Arm/Group Title | Arm A: Pertuzumab + Trastuzumab + AI +/- Chemotherapy | Arm B: Trastuzumab + AI +/- Chemotherapy |
|---|---|---|
| Arm/Group Description | Participants received pertuzumab at a loading dose of 840 mg followed by 420 mg along with trastuzumab at a loading dose of 8 mg/kg of body weight followed by 6 mg/kg of body weight on Day 1 or Day 2 of each 3-weekly cycle until disease progression, unacceptable toxicity, withdrawal of consent, or death, or the predefined end of study whichever occurred first. Participants also received an aromatase inhibitor (AI), orally as per product labeling (anastrozole: 1 mg once daily or letrozole: 2.5 mg once daily). Participants receiving induction chemotherapy up to the first 18-24 weeks of the treatment period were to receive a taxane (docetaxel every 3 weeks or paclitaxel weekly), administered in line with the respective product labeling. | Participants received trastuzumab at a loading dose of 8 mg/kg of body weight followed by 6 mg/kg of body weight on Day 1 or Day 2 of each 3-weekly cycle until disease progression, unacceptable toxicity, withdrawal of consent, or death, or the predefined end of study whichever occurred first. Participants also received an aromatase inhibitor (AI), orally as per product labeling (anastrozole: 1 mg once daily or letrozole: 2.5 mg once daily). Participants receiving induction chemotherapy up to the first 18-24 weeks of the treatment period were to receive a taxane (docetaxel every 3 weeks or paclitaxel weekly), administered in line with the respective product labeling. |
| Measure Participants | 127 | 124 |
| Baseline (BL) - Absolute LVEF at Visit |
63.8
(6.23)
|
63.9
(6.12)
|
| Change from BL at Cycle 3 |
-1.0
(6.25)
|
-1.4
(6.23)
|
| Change from BL at Cycle 6 |
-2.3
(6.66)
|
-1.3
(6.03)
|
| Change from BL at Cycle 9 |
-2.5
(6.80)
|
-2.2
(6.52)
|
| Change from BL at Cycle 12 |
-2.4
(8.05)
|
-2.8
(6.99)
|
| Change from BL at Cycle 15 |
-2.9
(8.67)
|
-2.5
(6.94)
|
| Change from BL at Cycle 18 |
-1.9
(6.42)
|
-1.3
(6.19)
|
| Change from BL at Cycle 21 |
-1.1
(6.01)
|
-1.1
(6.64)
|
| Change from BL at Cycle 24 |
-2.1
(6.82)
|
-0.6
(6.19)
|
| Change from BL at Cycle 27 |
-1.6
(5.05)
|
-1.3
(5.87)
|
| Change from BL at Cycle 30 |
-1.4
(5.20)
|
-0.3
(6.03)
|
| Change from BL at Cycle 33 |
-2.8
(5.60)
|
1.2
(6.71)
|
| Change from BL at Cycle 36 |
-2.5
(5.50)
|
-0.2
(5.41)
|
| Change from BL at Cycle 39 |
-2.6
(5.72)
|
1.4
(4.87)
|
| Change from BL at Cycle 42 |
-2.1
(5.91)
|
1.9
(6.12)
|
| Change from BL at Cycle 45 |
-1.0
(5.54)
|
3.0
(5.27)
|
| Change from BL at Cycle 48 |
-3.3
(6.56)
|
-0.2
(7.50)
|
| Change from BL at Cycle 51 |
-1.4
(5.82)
|
1.0
(4.19)
|
| Change from BL at Cycle 54 |
-1.3
(6.17)
|
-1.0
(6.23)
|
| Change from BL at Cycle 57 |
-1.7
(6.43)
|
0.8
(5.68)
|
| Change from BL at Cycle 60 |
-2.5
(5.54)
|
-0.9
(3.91)
|
| Change from BL at Cycle 63 |
-2.1
(6.10)
|
0.8
(5.99)
|
| Change from BL at Cycle 66 |
-2.9
(7.80)
|
-0.4
(5.17)
|
| Change from BL at Cycle 69 |
-2.1
(7.23)
|
-1.5
(7.68)
|
| Change from BL at Cycle 72 |
-3.0
(4.97)
|
-1.0
(5.75)
|
| Change from BL at Cycle 75 |
-3.3
(6.59)
|
-1.1
(6.97)
|
| Change from BL at Cycle 78 |
-3.3
(5.58)
|
-1.1
(7.82)
|
| Change from BL at Cycle 81 |
-2.9
(6.83)
|
-2.6
(6.00)
|
| Change from BL at Cycle 84 |
-2.5
(7.66)
|
-4.5
(3.59)
|
| Change from BL at Cycle 87 |
-3.8
(5.76)
|
-1.4
(5.12)
|
| Change from BL at Cycle 90 |
-2.4
(7.69)
|
0.4
(6.77)
|
| Change from BL at Cycle 93 |
-1.8
(6.57)
|
-3.9
(6.00)
|
| Change from BL at Cycle 96 |
-0.7
(7.45)
|
-3.2
(5.50)
|
| Change from BL at Cycle 99 |
-3.4
(5.78)
|
-2.8
(8.41)
|
| Change from BL at Cycle 102 |
-1.3
(6.12)
|
-1.6
(9.68)
|
| Change from BL at Cycle 105 |
-0.4
(7.05)
|
-2.0
(12.17)
|
| Change from BL at Cycle 108 |
-3.4
(5.32)
|
-3.3
(8.33)
|
| Change from BL at Cycle 111 |
-6.3
(5.91)
|
-5.5
(NA)
|
| Change from BL at Cycle 114 |
-4.0
(5.35)
|
-1.4
(NA)
|
| Change from BL at Cycle 117 |
-11.0
(NA)
|
|
| Change from BL at Cycle 120 |
-11.0
(NA)
|
Adverse Events
| Time Frame | From Baseline until end of post-treatment follow-up (up to 89 months) | |||
|---|---|---|---|---|
| Adverse Event Reporting Description | All adverse events that occurred during the study and until the post-treatment safety follow-up visit approximately 28 days after last study medication were to be recorded. Thereafter, only serious adverse events thought to be related to study drug were collected. | |||
| Arm/Group Title | Arm A: Pertuzumab + Trastuzumab + AI +/- Chemotherapy | Arm B: Trastuzumab + AI +/- Chemotherapy | ||
| Arm/Group Description | Participants received pertuzumab at a loading dose of 840 mg followed by 420 mg along with trastuzumab at a loading dose of 8 mg/kg of body weight followed by 6 mg/kg of body weight on Day 1 or Day 2 of each 3-weekly cycle until disease progression, unacceptable toxicity, withdrawal of consent, or death, or the predefined end of study whichever occurred first. Participants also received an aromatase inhibitor (AI), orally as per product labeling (anastrozole: 1 mg once daily or letrozole: 2.5 mg once daily). Participants receiving induction chemotherapy up to the first 18-24 weeks of the treatment period were to receive a taxane (docetaxel every 3 weeks or paclitaxel weekly), administered in line with the respective product labeling. | Participants received trastuzumab at a loading dose of 8 mg/kg of body weight followed by 6 mg/kg of body weight on Day 1 or Day 2 of each 3-weekly cycle until disease progression, unacceptable toxicity, withdrawal of consent, or death, or the predefined end of study whichever occurred first. Participants also received an aromatase inhibitor (AI), orally as per product labeling (anastrozole: 1 mg once daily or letrozole: 2.5 mg once daily). Participants receiving induction chemotherapy up to the first 18-24 weeks of the treatment period were to receive a taxane (docetaxel every 3 weeks or paclitaxel weekly), administered in line with the respective product labeling. | ||
All Cause Mortality |
||||
| Arm A: Pertuzumab + Trastuzumab + AI +/- Chemotherapy | Arm B: Trastuzumab + AI +/- Chemotherapy | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 63/129 (48.8%) | 57/129 (44.2%) | ||
Serious Adverse Events |
||||
| Arm A: Pertuzumab + Trastuzumab + AI +/- Chemotherapy | Arm B: Trastuzumab + AI +/- Chemotherapy | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 46/127 (36.2%) | 28/124 (22.6%) | ||
| Blood and lymphatic system disorders | ||||
| Febrile neutropenia | 4/127 (3.1%) | 4 | 2/124 (1.6%) | 2 |
| Neutropenia | 1/127 (0.8%) | 1 | 1/124 (0.8%) | 1 |
| Cardiac disorders | ||||
| Atrial fibrillation | 2/127 (1.6%) | 3 | 0/124 (0%) | 0 |
| Cardiac failure | 0/127 (0%) | 0 | 1/124 (0.8%) | 1 |
| Left ventricular dysfunction | 4/127 (3.1%) | 4 | 0/124 (0%) | 0 |
| Mitral valve disease | 1/127 (0.8%) | 1 | 0/124 (0%) | 0 |
| Myocardial ischaemia | 1/127 (0.8%) | 1 | 0/124 (0%) | 0 |
| Sinus tachycardia | 1/127 (0.8%) | 1 | 0/124 (0%) | 0 |
| Myocardial infarction | 1/127 (0.8%) | 1 | 0/124 (0%) | 0 |
| Endocrine disorders | ||||
| Adrenal haemorrhage | 1/127 (0.8%) | 1 | 0/124 (0%) | 0 |
| Gastrointestinal disorders | ||||
| Abdominal distension | 1/127 (0.8%) | 1 | 0/124 (0%) | 0 |
| Abdominal pain | 1/127 (0.8%) | 1 | 1/124 (0.8%) | 1 |
| Constipation | 1/127 (0.8%) | 1 | 0/124 (0%) | 0 |
| Diarrhoea | 2/127 (1.6%) | 2 | 1/124 (0.8%) | 1 |
| Vomiting | 2/127 (1.6%) | 3 | 1/124 (0.8%) | 1 |
| Large intestinal obstruction | 1/127 (0.8%) | 1 | 0/124 (0%) | 0 |
| General disorders | ||||
| Chest pain | 0/127 (0%) | 0 | 1/124 (0.8%) | 1 |
| Pyrexia | 0/127 (0%) | 0 | 1/124 (0.8%) | 1 |
| Sudden death | 0/127 (0%) | 0 | 1/124 (0.8%) | 1 |
| Hepatobiliary disorders | ||||
| Cholecystitis | 1/127 (0.8%) | 1 | 0/124 (0%) | 0 |
| Immune system disorders | ||||
| Anaphylactic shock | 1/127 (0.8%) | 1 | 0/124 (0%) | 0 |
| Contrast media allergy | 1/127 (0.8%) | 1 | 0/124 (0%) | 0 |
| Hypersensitivity | 3/127 (2.4%) | 3 | 0/124 (0%) | 0 |
| Infections and infestations | ||||
| Abscess | 1/127 (0.8%) | 1 | 0/124 (0%) | 0 |
| Colonic abscess | 0/127 (0%) | 0 | 1/124 (0.8%) | 1 |
| Device related infection | 0/127 (0%) | 0 | 2/124 (1.6%) | 2 |
| Erysipelas | 0/127 (0%) | 0 | 1/124 (0.8%) | 1 |
| Escherichia urinary tract infection | 0/127 (0%) | 0 | 1/124 (0.8%) | 2 |
| Gastroenteritis | 3/127 (2.4%) | 3 | 0/124 (0%) | 0 |
| Gastroenteritis viral | 1/127 (0.8%) | 1 | 1/124 (0.8%) | 1 |
| Infection | 1/127 (0.8%) | 1 | 0/124 (0%) | 0 |
| Mastitis | 0/127 (0%) | 0 | 1/124 (0.8%) | 1 |
| Neutropenic sepsis | 1/127 (0.8%) | 1 | 1/124 (0.8%) | 1 |
| Pneumonia | 6/127 (4.7%) | 7 | 1/124 (0.8%) | 1 |
| Respiratory tract infection | 1/127 (0.8%) | 1 | 0/124 (0%) | 0 |
| Sepsis | 0/127 (0%) | 0 | 1/124 (0.8%) | 1 |
| Tooth infection | 0/127 (0%) | 0 | 1/124 (0.8%) | 1 |
| Vascular device infection | 1/127 (0.8%) | 1 | 0/124 (0%) | 0 |
| Injury, poisoning and procedural complications | ||||
| Femoral neck fracture | 0/127 (0%) | 0 | 1/124 (0.8%) | 1 |
| Fracture | 1/127 (0.8%) | 1 | 1/124 (0.8%) | 1 |
| Humerus fracture | 1/127 (0.8%) | 1 | 0/124 (0%) | 0 |
| Post procedural haematoma | 0/127 (0%) | 0 | 1/124 (0.8%) | 1 |
| Spinal fracture | 1/127 (0.8%) | 1 | 0/124 (0%) | 0 |
| Fall | 1/127 (0.8%) | 1 | 0/124 (0%) | 0 |
| Metabolism and nutrition disorders | ||||
| Hyperglycaemia | 1/127 (0.8%) | 1 | 0/124 (0%) | 0 |
| Hyperuricaemia | 0/127 (0%) | 0 | 1/124 (0.8%) | 1 |
| Hyponatraemia | 0/127 (0%) | 0 | 1/124 (0.8%) | 1 |
| Dehydration | 0/127 (0%) | 0 | 1/124 (0.8%) | 1 |
| Musculoskeletal and connective tissue disorders | ||||
| Back pain | 1/127 (0.8%) | 1 | 0/124 (0%) | 0 |
| Pain in extremity | 0/127 (0%) | 0 | 1/124 (0.8%) | 1 |
| Pathological fracture | 1/127 (0.8%) | 1 | 1/124 (0.8%) | 1 |
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||||
| Adenocarcinoma of colon | 1/127 (0.8%) | 1 | 0/124 (0%) | 0 |
| Adenoid cystic carcinoma of salivary gland | 0/127 (0%) | 0 | 1/124 (0.8%) | 1 |
| High-grade B-cell lymphoma | 1/127 (0.8%) | 1 | 0/124 (0%) | 0 |
| Cancer pain | 0/127 (0%) | 0 | 1/124 (0.8%) | 1 |
| Lung neoplasm | 1/127 (0.8%) | 1 | 0/124 (0%) | 0 |
| Transitional cell carcinoma | 0/127 (0%) | 0 | 1/124 (0.8%) | 1 |
| Tumour exudation | 1/127 (0.8%) | 1 | 0/124 (0%) | 0 |
| Nervous system disorders | ||||
| Hypoglycaemic coma | 1/127 (0.8%) | 1 | 0/124 (0%) | 0 |
| Spinal cord compression | 1/127 (0.8%) | 1 | 0/124 (0%) | 0 |
| Psychiatric disorders | ||||
| Depression | 1/127 (0.8%) | 1 | 0/124 (0%) | 0 |
| Confusional state | 0/127 (0%) | 0 | 1/124 (0.8%) | 1 |
| Respiratory, thoracic and mediastinal disorders | ||||
| Asthma | 0/127 (0%) | 0 | 1/124 (0.8%) | 1 |
| Chronic obstructive pulmonary disease | 2/127 (1.6%) | 2 | 0/124 (0%) | 0 |
| Dyspnoea | 1/127 (0.8%) | 1 | 0/124 (0%) | 0 |
| Pleural effusion | 1/127 (0.8%) | 1 | 0/124 (0%) | 0 |
| Pneumonitis | 1/127 (0.8%) | 1 | 0/124 (0%) | 0 |
| Pulmonary embolism | 1/127 (0.8%) | 1 | 1/124 (0.8%) | 1 |
| Pulmonary oedema | 1/127 (0.8%) | 1 | 0/124 (0%) | 0 |
| Painful respiration | 1/127 (0.8%) | 1 | 0/124 (0%) | 0 |
| Surgical and medical procedures | ||||
| Colostomy closure | 0/127 (0%) | 0 | 1/124 (0.8%) | 1 |
| Vascular disorders | ||||
| Haematoma | 1/127 (0.8%) | 1 | 0/124 (0%) | 0 |
Other (Not Including Serious) Adverse Events |
||||
| Arm A: Pertuzumab + Trastuzumab + AI +/- Chemotherapy | Arm B: Trastuzumab + AI +/- Chemotherapy | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 120/127 (94.5%) | 116/124 (93.5%) | ||
| Blood and lymphatic system disorders | ||||
| Anaemia | 28/127 (22%) | 53 | 18/124 (14.5%) | 30 |
| Neutropenia | 11/127 (8.7%) | 14 | 13/124 (10.5%) | 23 |
| Eye disorders | ||||
| Lacrimation increased | 9/127 (7.1%) | 9 | 7/124 (5.6%) | 8 |
| Gastrointestinal disorders | ||||
| Abdominal pain | 10/127 (7.9%) | 11 | 16/124 (12.9%) | 18 |
| Abdominal pain upper | 12/127 (9.4%) | 17 | 6/124 (4.8%) | 6 |
| Constipation | 18/127 (14.2%) | 27 | 19/124 (15.3%) | 25 |
| Diarrhoea | 70/127 (55.1%) | 213 | 45/124 (36.3%) | 88 |
| Dyspepsia | 8/127 (6.3%) | 9 | 9/124 (7.3%) | 11 |
| Nausea | 47/127 (37%) | 68 | 34/124 (27.4%) | 56 |
| Stomatitis | 17/127 (13.4%) | 24 | 11/124 (8.9%) | 22 |
| Vomiting | 31/127 (24.4%) | 42 | 21/124 (16.9%) | 33 |
| Haemorrhoids | 7/127 (5.5%) | 7 | 2/124 (1.6%) | 2 |
| General disorders | ||||
| Asthenia | 39/127 (30.7%) | 76 | 32/124 (25.8%) | 77 |
| Chest Pain | 9/127 (7.1%) | 11 | 9/124 (7.3%) | 11 |
| Chills | 8/127 (6.3%) | 8 | 7/124 (5.6%) | 8 |
| Fatigue | 21/127 (16.5%) | 33 | 25/124 (20.2%) | 43 |
| Influenza like illness | 10/127 (7.9%) | 17 | 7/124 (5.6%) | 10 |
| Mucosal inflammation | 14/127 (11%) | 20 | 13/124 (10.5%) | 15 |
| Oedema peripheral | 34/127 (26.8%) | 53 | 23/124 (18.5%) | 34 |
| Pyrexia | 17/127 (13.4%) | 22 | 13/124 (10.5%) | 14 |
| Infections and infestations | ||||
| Influenza | 6/127 (4.7%) | 10 | 7/124 (5.6%) | 12 |
| Nasopharyngitis | 13/127 (10.2%) | 21 | 7/124 (5.6%) | 8 |
| Upper respiratory tract infection | 13/127 (10.2%) | 36 | 15/124 (12.1%) | 23 |
| Urinary tract infection | 17/127 (13.4%) | 25 | 16/124 (12.9%) | 20 |
| Paronychia | 7/127 (5.5%) | 12 | 3/124 (2.4%) | 6 |
| Investigations | ||||
| Ejection fraction decreased | 13/127 (10.2%) | 19 | 8/124 (6.5%) | 9 |
| Weight decreased | 14/127 (11%) | 16 | 11/124 (8.9%) | 12 |
| Weight increased | 11/127 (8.7%) | 13 | 5/124 (4%) | 10 |
| Metabolism and nutrition disorders | ||||
| Decreased appetite | 23/127 (18.1%) | 27 | 10/124 (8.1%) | 14 |
| Hyperglycaemia | 8/127 (6.3%) | 17 | 5/124 (4%) | 9 |
| Musculoskeletal and connective tissue disorders | ||||
| Arthralgia | 38/127 (29.9%) | 60 | 31/124 (25%) | 49 |
| Back pain | 23/127 (18.1%) | 29 | 21/124 (16.9%) | 27 |
| Bone pain | 16/127 (12.6%) | 25 | 10/124 (8.1%) | 12 |
| Muscle spasms | 14/127 (11%) | 17 | 5/124 (4%) | 6 |
| Musculoskeletal chest pain | 11/127 (8.7%) | 13 | 4/124 (3.2%) | 6 |
| Musculoskeletal pain | 11/127 (8.7%) | 11 | 6/124 (4.8%) | 8 |
| Myalgia | 12/127 (9.4%) | 16 | 9/124 (7.3%) | 9 |
| Pain in extremity | 22/127 (17.3%) | 44 | 16/124 (12.9%) | 23 |
| Nervous system disorders | ||||
| Dizziness | 21/127 (16.5%) | 32 | 12/124 (9.7%) | 12 |
| Headache | 22/127 (17.3%) | 33 | 14/124 (11.3%) | 24 |
| Neuropathy peripheral | 18/127 (14.2%) | 26 | 17/124 (13.7%) | 19 |
| Paraesthesia | 13/127 (10.2%) | 19 | 11/124 (8.9%) | 13 |
| Peripheral sensory neuropathy | 10/127 (7.9%) | 12 | 9/124 (7.3%) | 9 |
| Psychiatric disorders | ||||
| Anxiety | 14/127 (11%) | 15 | 5/124 (4%) | 6 |
| Depression | 13/127 (10.2%) | 14 | 5/124 (4%) | 6 |
| Insomnia | 15/127 (11.8%) | 18 | 18/124 (14.5%) | 23 |
| Renal and urinary disorders | ||||
| Dysuria | 9/127 (7.1%) | 14 | 2/124 (1.6%) | 4 |
| Respiratory, thoracic and mediastinal disorders | ||||
| Cough | 25/127 (19.7%) | 36 | 18/124 (14.5%) | 27 |
| Dyspnoea | 20/127 (15.7%) | 22 | 13/124 (10.5%) | 17 |
| Epistaxis | 14/127 (11%) | 18 | 13/124 (10.5%) | 20 |
| Skin and subcutaneous tissue disorders | ||||
| Alopecia | 38/127 (29.9%) | 40 | 40/124 (32.3%) | 50 |
| Dry skin | 8/127 (6.3%) | 10 | 6/124 (4.8%) | 7 |
| Nail disorder | 9/127 (7.1%) | 13 | 5/124 (4%) | 7 |
| Pruritus | 20/127 (15.7%) | 42 | 14/124 (11.3%) | 19 |
| Rash | 23/127 (18.1%) | 35 | 12/124 (9.7%) | 17 |
| Vascular disorders | ||||
| Hot flush | 9/127 (7.1%) | 14 | 9/124 (7.3%) | 17 |
| Hypertension | 22/127 (17.3%) | 54 | 24/124 (19.4%) | 65 |
| Lymphoedema | 7/127 (5.5%) | 10 | 5/124 (4%) | 5 |
Limitations/Caveats
[Not Specified]
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.
Results Point of Contact
| Name/Title | Medical Communications |
|---|---|
| Organization | Hoffmann-La Roche |
| Phone | 800 821-8590 |
| genentech@druginfo.com |
Responsible Party:
Hoffmann-La Roche
ClinicalTrials.gov Identifier:
NCT01491737
Other Study ID Numbers:
- MO27775
- 2011-002132-10
First Posted:
Dec 14, 2011
Last Update Posted:
Oct 28, 2020
Last Verified:
Oct 1, 2020