Study Comparing Lapatinib (GW572016) And Letrozole Versus Letrozole In Subjects With Advanced Or Metastatic Breast Cancer

Breast Neoplasms Clinical Trial

Official title:

A Randomized, Double-Blind, Placebo-Controlled, Multicenter Phase III Study Comparing GW572016 and Letrozole Versus Letrozole in Subjects With Estrogen/Progesterone Receptor- Positive Advanced or Metastatic Breast Cancer

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00073528
• Other study ID #: EGF30008
• Secondary ID: CLAP016A23082004
• Status: Completed
• Phase: Phase 3
• Start date: December 9, 2003
• Est. completion date: March 22, 2018

Study information

• Verified date: February 2021
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study evaluated and compared the efficacy and tolerability of lapatinib and letrozole, with letrozole and placebo in post-menopausal women with hormone receptor positive (ER positive and/or PgR positive) advanced or metastatic breast cancer, who had not received prior therapy for advanced or metastatic disease.

Description:

Subjects were randomly assigned to receive either lapatinib (1500 mg once daily orally) with letrozole (2.5 mg once daily orally), or letrozole (2.5 mg once daily orally) with placebo (which matched with lapatinib tablet). Randomization was stratified by site of disease (i.e., soft tissue/visceral disease versus bone only disease) and time since prior adjuvant endocrine therapy (<6 months or ≥ 6 months from discontinuation of adjuvant anti-estrogen therapy (e.g. tamoxifen or raloxifene) or no prior adjuvant antiestrogen therapy). Study therapy was administered daily until disease progression (objective or symptomatic) or withdrawal from therapy (e.g., due to unacceptable toxicity, withdrawal of consent, or other reason). All subjects were to be followed for survival information until death. On 13 Apr 2015, after the introduction of the Long Term Follow UP (LTFU) phase (per protocol amendment 07), subjects receiving study treatment with lapatinib plus letrozole, or letrozole plus placebo had continued access to this study treatment until the occurrence of one of the following criteria: - Disease progression (as determined by the Investigator), - Intercurrent illness that prevented further administration of study treatment - Drug related AE which was considered by the investigator to warrant permanent discontinuation of study treatment - The subject decided to withdraw from the study. Investigators collected AEs and/or SAEs related to study participation, until 30 days following study treatment discontinuation. Subjects who were being followed-up for OS but were not taking study medication, were withdrawn from the study. The study was terminated on 22-Mar-2018 (last subject last visit).

Other known NCT identifiers

• NCT00084968

Recruitment information / eligibility

• Status: Completed
• Enrollment: 1286
• Est. completion date: March 22, 2018
• Est. primary completion date: June 3, 2008
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

Key inclusion criteria

1. Signed informed consent;

2. Subjects with histologically confirmed invasive breast cancer with stage IV disease at primary diagnosis or at relapse after curative-intent surgery;

• Subjects with either measurable or non-measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST).
• If the disease was restricted to a solitary lesion, its neoplastic nature was confirmed by cytology or histology.

3. Tumors that were ER+ and/or PgR+;

4. Post-menopausal female subjects = 18 years of age.

5. ECOG Performance Status of 0 or 1;

6. Subjects who had archived tumor tissue available to compare tumor response with intra-tumoral expression of ErbB1 and ErbB2.

7. Adjuvant therapy with an aromatase inhibitor and / or trastuzumab was allowed; however, treatment was to stop more than 1 year prior (>12 months) to the first dose of randomized therapy.

8. Subjects must have ended hormonal replacement therapy (HRT) at least 1 month (30 days) prior to receiving the first dose of randomized therapy.

Key exclusion criteria:

1. Pre-menopausal, pregnant, or lactating;

2. Received prior chemotherapy, hormonal therapy, immunotherapy, biologic therapy, or anti-ErbB1/ErbB2 therapy for advanced or metastatic disease;

3. Bisphosphonate therapy for bone metastases was allowed; however, treatment was to be initiated prior to the first dose of randomized therapy. Prophylactic use of bisphosphonates in subjects without bone disease, except for the treatment of osteoporosis, was not permitted;

4. Used an investigational drug within 30 days or 5 half-lives, whichever is longer, preceding the first dose of randomized therapy (lapatinib or placebo);

5. Subjects with known history of/clinical evidence of CNS metastases or leptomeningeal carcinomatosis; and / or subjects on concurrent anti-cancer therapies other than letrozole; and / or who have not recovered from toxicities related to prior adjuvant therapy (surgery, radiotherapy, chemotherapy etc.)

6. Subjects with active or uncontrolled infection and/ or with history of uncontrolled or symptomatic angina, arrhythmias, or congestive heart failure.

Related Conditions & MeSH terms

• Breast Neoplasms

Intervention

Drug:
• Lapatinib
1500 mg orally once a day
• Letrozole
2.5 mg orally once a day
• Placebo
Placebo (which matched with lapatinib tablet)

Locations

Country	Name	City	State
Argentina	Novartis Investigative Site	Buenos Aires
Argentina	Novartis Investigative Site	Capital Federal	Buenos Aires
Argentina	Novartis Investigative Site	Ciudad Autonoma de Buenos Aires
Australia	Novartis Investigative Site	Adelaide	South Australia
Australia	Novartis Investigative Site	Douglas	Queensland
Australia	Novartis Investigative Site	Garran	Australian Capital Territory
Australia	Novartis Investigative Site	Herston	Queensland
Australia	Novartis Investigative Site	Redcliffe	Queensland
Brazil	Novartis Investigative Site	Rio de Janeiro
Brazil	Novartis Investigative Site	Salvador	Bahía
Bulgaria	Novartis Investigative Site	Plovdiv
Bulgaria	Novartis Investigative Site	Sofia
Bulgaria	Novartis Investigative Site	Sofia
Canada	Novartis Investigative Site	London	Ontario
Canada	Novartis Investigative Site	Mississauga	Ontario
Canada	Novartis Investigative Site	Montreal	Quebec
Canada	Novartis Investigative Site	Montreal	Quebec
Canada	Novartis Investigative Site	Montreal	Quebec
Canada	Novartis Investigative Site	Montreal	Quebec
Canada	Novartis Investigative Site	Oshawa	Ontario
Canada	Novartis Investigative Site	Quebec
Canada	Novartis Investigative Site	Sherbrooke	Quebec
Canada	Novartis Investigative Site	Sudbury	Ontario
Canada	Novartis Investigative Site	Toronto	Ontario
Canada	Novartis Investigative Site	Winnipeg	Manitoba
Chile	Novartis Investigative Site	Santiago	Región Metro De Santiago
Chile	Novartis Investigative Site	Santiago	Región Metro De Santiago
Colombia	Novartis Investigative Site	Bogota
Croatia	Novartis Investigative Site	Osijek
Croatia	Novartis Investigative Site	Pula
Croatia	Novartis Investigative Site	Split
Czechia	Novartis Investigative Site	Brno
Czechia	Novartis Investigative Site	Ceske Budejovice
Czechia	Novartis Investigative Site	Praha 8
Denmark	Novartis Investigative Site	Aalborg
Denmark	Novartis Investigative Site	Hillerod
Denmark	Novartis Investigative Site	Koebenhavn Oe
Denmark	Novartis Investigative Site	Naestved
Denmark	Novartis Investigative Site	Odense C
Denmark	Novartis Investigative Site	Roskilde
Denmark	Novartis Investigative Site	Vejle
France	Novartis Investigative Site	Angers Cedex 01
France	Novartis Investigative Site	Besancon
France	Novartis Investigative Site	Grenoble Cedex 9
France	Novartis Investigative Site	Lille Cedex
France	Novartis Investigative Site	Montpellier
France	Novartis Investigative Site	Paris Cedex 5
France	Novartis Investigative Site	Pierre Benite Cedex
France	Novartis Investigative Site	Toulouse Cedex9
France	Novartis Investigative Site	Villejuif Cedex
Germany	Novartis Investigative Site	Aalen	Baden-Wuerttemberg
Germany	Novartis Investigative Site	Altenkirchen	Rheinland-Pfalz
Germany	Novartis Investigative Site	Augsburg	Bayern
Germany	Novartis Investigative Site	Bayreuth	Bayern
Germany	Novartis Investigative Site	Berlin
Germany	Novartis Investigative Site	Berlin
Germany	Novartis Investigative Site	Berlin
Germany	Novartis Investigative Site	Berlin
Germany	Novartis Investigative Site	Bonn	Nordrhein-Westfalen
Germany	Novartis Investigative Site	Chemnitz	Sachsen
Germany	Novartis Investigative Site	Coesfeld	Nordrhein-Westfalen
Germany	Novartis Investigative Site	Dresden	Sachsen
Germany	Novartis Investigative Site	Duesseldorf	Nordrhein-Westfalen
Germany	Novartis Investigative Site	Erlangen	Bayern
Germany	Novartis Investigative Site	Frankfurt	Hessen
Germany	Novartis Investigative Site	Frankfurt am Main	Hessen
Germany	Novartis Investigative Site	Freiburg	Baden-Wuerttemberg
Germany	Novartis Investigative Site	Goslar	Niedersachsen
Germany	Novartis Investigative Site	Hamburg
Germany	Novartis Investigative Site	Hamburg
Germany	Novartis Investigative Site	Hamburg
Germany	Novartis Investigative Site	Hamburg
Germany	Novartis Investigative Site	Hamburg
Germany	Novartis Investigative Site	Heidelberg	Baden-Wuerttemberg
Germany	Novartis Investigative Site	Heidenheim	Baden-Wuerttemberg
Germany	Novartis Investigative Site	Ibbenbueren	Nordrhein-Westfalen
Germany	Novartis Investigative Site	Jena	Thueringen
Germany	Novartis Investigative Site	Kiel	Schleswig-Holstein
Germany	Novartis Investigative Site	Kiel	Schleswig-Holstein
Germany	Novartis Investigative Site	Leer	Niedersachsen
Germany	Novartis Investigative Site	Muenchen	Bayern
Germany	Novartis Investigative Site	Muenchen	Bayern
Germany	Novartis Investigative Site	Muenchen	Bayern
Germany	Novartis Investigative Site	Muenster	Nordrhein-Westfalen
Germany	Novartis Investigative Site	Pinneberg	Schleswig-Holstein
Germany	Novartis Investigative Site	Regensburg	Bayern
Germany	Novartis Investigative Site	Rehling	Bayern
Germany	Novartis Investigative Site	Rosenheim	Bayern
Germany	Novartis Investigative Site	Schwetzingen	Baden-Wuerttemberg
Germany	Novartis Investigative Site	Stuttgart	Baden-Wuerttemberg
Germany	Novartis Investigative Site	Troisdorf	Nordrhein-Westfalen
Germany	Novartis Investigative Site	Ulm	Baden-Wuerttemberg
Germany	Novartis Investigative Site	Velbert	Nordrhein-Westfalen
Germany	Novartis Investigative Site	Wiesbaden	Hessen
Germany	Novartis Investigative Site	Wiesbaden	Hessen
Hungary	Novartis Investigative Site	Budapest
Hungary	Novartis Investigative Site	Budapest
Hungary	Novartis Investigative Site	Budapest
Hungary	Novartis Investigative Site	Kecskemet
Hungary	Novartis Investigative Site	Kistarcsa
Hungary	Novartis Investigative Site	Szeged
Hungary	Novartis Investigative Site	Tatabanya
Ireland	Novartis Investigative Site	Cork
Ireland	Novartis Investigative Site	Dooradoyle
Ireland	Novartis Investigative Site	Dublin
Ireland	Novartis Investigative Site	Dublin
Ireland	Novartis Investigative Site	Dublin
Ireland	Novartis Investigative Site	Galway
Ireland	Novartis Investigative Site	Tallaght, Dublin
Ireland	Novartis Investigative Site	Wilton, Cork
Italy	Novartis Investigative Site	Bologna	Emilia-Romagna
Italy	Novartis Investigative Site	Crema	Lombardia
Italy	Novartis Investigative Site	Genova	Liguria
Italy	Novartis Investigative Site	Genova	Liguria
Italy	Novartis Investigative Site	Milano	Lombardia
Italy	Novartis Investigative Site	Parma	Emilia-Romagna
Italy	Novartis Investigative Site	Roma	Lazio
Italy	Novartis Investigative Site	Roma	Lazio
Korea, Republic of	Novartis Investigative Site	Gyeonggi-do
Korea, Republic of	Novartis Investigative Site	Seodaemun-gu, Seoul
Korea, Republic of	Novartis Investigative Site	Seoul
Mexico	Novartis Investigative Site	Acapulco	Guerrero
Mexico	Novartis Investigative Site	Colima
Mexico	Novartis Investigative Site	Durango
Mexico	Novartis Investigative Site	Durango
Mexico	Novartis Investigative Site	Mexico, D.F.
Netherlands	Novartis Investigative Site	Amersfoort
Netherlands	Novartis Investigative Site	Delft
Netherlands	Novartis Investigative Site	Den Haag
Netherlands	Novartis Investigative Site	Den Haag
Netherlands	Novartis Investigative Site	Doetinchem
Netherlands	Novartis Investigative Site	Eindhoven
Netherlands	Novartis Investigative Site	Heerlen
Netherlands	Novartis Investigative Site	Leidschendam
Netherlands	Novartis Investigative Site	Maastricht
Netherlands	Novartis Investigative Site	Nieuwegein
Netherlands	Novartis Investigative Site	Sittard-geleen
Netherlands	Novartis Investigative Site	Utrecht
Netherlands	Novartis Investigative Site	Utrecht
New Zealand	Novartis Investigative Site	Christchurch
Pakistan	Novartis Investigative Site	Lahore
Pakistan	Novartis Investigative Site	Lahore
Pakistan	Novartis Investigative Site	Rawalpindi
Peru	Novartis Investigative Site	Callao
Peru	Novartis Investigative Site	Lima
Poland	Novartis Investigative Site	Bydogoszcz
Poland	Novartis Investigative Site	Krakow
Poland	Novartis Investigative Site	Poznan
Poland	Novartis Investigative Site	Warszawa
Poland	Novartis Investigative Site	Wroclaw
Russian Federation	Novartis Investigative Site	Moscow
Russian Federation	Novartis Investigative Site	Moscow
Russian Federation	Novartis Investigative Site	St. Petersburg
Russian Federation	Novartis Investigative Site	St. Petersburg
South Africa	Novartis Investigative Site	Capital Park
South Africa	Novartis Investigative Site	Panorama
South Africa	Novartis Investigative Site	Parktown
South Africa	Novartis Investigative Site	Port Elizabeth
Spain	Novartis Investigative Site	Alcala De Henares (Madrid)
Spain	Novartis Investigative Site	Badalona
Spain	Novartis Investigative Site	Barcelona
Spain	Novartis Investigative Site	Elche
Spain	Novartis Investigative Site	Girona
Spain	Novartis Investigative Site	Leganes, Madrid
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Malaga
Spain	Novartis Investigative Site	Mostoles
Spain	Novartis Investigative Site	Oviedo
Spain	Novartis Investigative Site	Palma de Mallorca
Spain	Novartis Investigative Site	San Sebastian
Spain	Novartis Investigative Site	Valencia
Spain	Novartis Investigative Site	Vigo ( Pontevedra)
Spain	Novartis Investigative Site	Zaragoza
Tunisia	Novartis Investigative Site	Sfax
Tunisia	Novartis Investigative Site	Sousse
Tunisia	Novartis Investigative Site	Tunis
Tunisia	Novartis Investigative Site	Tunis
Turkey	Novartis Investigative Site	Ankara
Turkey	Novartis Investigative Site	Istanbul
Turkey	Novartis Investigative Site	Istanbul
United Kingdom	Novartis Investigative Site	Birmingham	West Midlands
United Kingdom	Novartis Investigative Site	Chelmsford	Essex
United Kingdom	Novartis Investigative Site	Huddersfield
United Kingdom	Novartis Investigative Site	London
United Kingdom	Novartis Investigative Site	London
United Kingdom	Novartis Investigative Site	London
United Kingdom	Novartis Investigative Site	Manchester	Lancashire
United Kingdom	Novartis Investigative Site	Northwood	Middlesex
United Kingdom	Novartis Investigative Site	Sheffield
United Kingdom	Novartis Investigative Site	Sutton	Surrey
United States	Novartis Investigative Site	Alhambra	California
United States	Novartis Investigative Site	Amarillo	Texas
United States	Novartis Investigative Site	Atlanta	Georgia
United States	Novartis Investigative Site	Aurora	Colorado
United States	Novartis Investigative Site	Bakersfield	California
United States	Novartis Investigative Site	Bettendorf	Iowa
United States	Novartis Investigative Site	Boca Raton	Florida
United States	Novartis Investigative Site	Boca Raton	Florida
United States	Novartis Investigative Site	Burlington	Vermont
United States	Novartis Investigative Site	Canton	Ohio
United States	Novartis Investigative Site	Chapel Hill	North Carolina
United States	Novartis Investigative Site	Charleston	West Virginia
United States	Novartis Investigative Site	Dallas	Texas
United States	Novartis Investigative Site	Dallas	Texas
United States	Novartis Investigative Site	Danville	Virginia
United States	Novartis Investigative Site	Denver	Colorado
United States	Novartis Investigative Site	Duarte	California
United States	Novartis Investigative Site	Duluth	Minnesota
United States	Novartis Investigative Site	Fargo	North Dakota
United States	Novartis Investigative Site	Fountain Valley	California
United States	Novartis Investigative Site	Fresno	California
United States	Novartis Investigative Site	Fullerton	California
United States	Novartis Investigative Site	Gainesville	Florida
United States	Novartis Investigative Site	Gainesville	Florida
United States	Novartis Investigative Site	Germantown	Tennessee
United States	Novartis Investigative Site	Greenville	North Carolina
United States	Novartis Investigative Site	Hershey	Pennsylvania
United States	Novartis Investigative Site	Hollywood	Florida
United States	Novartis Investigative Site	Hot Springs	Arkansas
United States	Novartis Investigative Site	Houston	Texas
United States	Novartis Investigative Site	Indianapolis	Indiana
United States	Novartis Investigative Site	Irving	Texas
United States	Novartis Investigative Site	Jonesboro	Arkansas
United States	Novartis Investigative Site	Knoxville	Tennessee
United States	Novartis Investigative Site	La Jolla	California
United States	Novartis Investigative Site	Lakeland	Florida
United States	Novartis Investigative Site	Las Vegas	Nevada
United States	Novartis Investigative Site	Long Beach	California
United States	Novartis Investigative Site	Longmont	Colorado
United States	Novartis Investigative Site	Los Angeles	California
United States	Novartis Investigative Site	Louisville	Kentucky
United States	Novartis Investigative Site	Manhasset	New York
United States	Novartis Investigative Site	Marietta	Georgia
United States	Novartis Investigative Site	Metairie	Louisiana
United States	Novartis Investigative Site	Miami	Florida
United States	Novartis Investigative Site	Minneapolis	Minnesota
United States	Novartis Investigative Site	Montebello	California
United States	Novartis Investigative Site	New Haven	Connecticut
United States	Novartis Investigative Site	New Orleans	Louisiana
United States	Novartis Investigative Site	Northridge	California
United States	Novartis Investigative Site	Ogden	Utah
United States	Novartis Investigative Site	Omaha	Nebraska
United States	Novartis Investigative Site	Orlando	Florida
United States	Novartis Investigative Site	Oxnard	California
United States	Novartis Investigative Site	Peoria	Illinois
United States	Novartis Investigative Site	Philadelphia	Pennsylvania
United States	Novartis Investigative Site	Pittsburgh	Pennsylvania
United States	Novartis Investigative Site	Pleasant Hill	California
United States	Novartis Investigative Site	Port Saint Lucie	Florida
United States	Novartis Investigative Site	Porterville	California
United States	Novartis Investigative Site	Redondo Beach	California
United States	Novartis Investigative Site	Richmond	Virginia
United States	Novartis Investigative Site	Robbinsdale	Minnesota
United States	Novartis Investigative Site	Rochester	New York
United States	Novartis Investigative Site	Saint Charles	Missouri
United States	Novartis Investigative Site	Saint Louis	Missouri
United States	Novartis Investigative Site	Saint Louis Park	Minnesota
United States	Novartis Investigative Site	Salt Lake City	Utah
United States	Novartis Investigative Site	San Diego	California
United States	Novartis Investigative Site	Santa Barbara	California
United States	Novartis Investigative Site	Santa Fe	New Mexico
United States	Novartis Investigative Site	Santa Maria	California
United States	Novartis Investigative Site	Savannah	Georgia
United States	Novartis Investigative Site	Seattle	Washington
United States	Novartis Investigative Site	Skokie	Illinois
United States	Novartis Investigative Site	Tacoma	Washington
United States	Novartis Investigative Site	Tucson	Arizona
United States	Novartis Investigative Site	Vallejo	California
United States	Novartis Investigative Site	Vista	California
United States	Novartis Investigative Site	Voorhees	New Jersey
United States	Novartis Investigative Site	West Columbia	South Carolina
United States	Novartis Investigative Site	West Palm Beach	Florida
United States	Novartis Investigative Site	Wheat Ridge	Colorado
United States	Novartis Investigative Site	Worcester	Massachusetts

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Brazil,  Bulgaria,  Canada,  Chile,  Colombia,  Croatia,  Czechia,  Denmark,  France,  Germany,  Hungary,  Ireland,  Italy,  Korea, Republic of,  Mexico,  Netherlands,  New Zealand,  Pakistan,  Peru,  Poland,  Russian Federation,  South Africa,  Spain,  Tunisia,  Turkey,  United Kingdom, 

References & Publications (5)

Finn RS, Press MF, Dering J, O'Rourke L, Florance A, Ellis C, Martin AM, Johnston S. Quantitative ER and PgR assessment as predictors of benefit from lapatinib in postmenopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer. Clin Cancer Res. 2014 Feb 1;20(3):736-43. doi: 10.1158/1078-0432.CCR-13-1260. Epub 2013 Nov 6. — View Citation

Johnston S, Pippen J Jr, Pivot X, Lichinitser M, Sadeghi S, Dieras V, Gomez HL, Romieu G, Manikhas A, Kennedy MJ, Press MF, Maltzman J, Florance A, O'Rourke L, Oliva C, Stein S, Pegram M. Lapatinib combined with letrozole versus letrozole and placebo as first-line therapy for postmenopausal hormone receptor-positive metastatic breast cancer. J Clin Oncol. 2009 Nov 20;27(33):5538-46. doi: 10.1200/JCO.2009.23.3734. Epub 2009 Sep 28. — View Citation

Prat A, Cheang MCU, Galván P, et al (2016). Prognostic and predictive abilities of intrinsic subtype in hormone receptor-positive metastatic breast cancer from the EGF30008 phase III clinical trial. JAMA Oncol. 2(10):1287-94.

Schwartzberg LS, Franco SX, Florance A, O'Rourke L, Maltzman J, Johnston S. Lapatinib plus letrozole as first-line therapy for HER-2+ hormone receptor-positive metastatic breast cancer. Oncologist. 2010;15(2):122-9. doi: 10.1634/theoncologist.2009-0240. Epub 2010 Feb 15. Erratum in: Oncologist. 2010;15(3):327. Schwarzberg, Lee S [corrected to Schwartzberg, Lee S]. — View Citation

Sherrill B, Amonkar MM, Sherif B, Maltzman J, O'Rourke L, Johnston S. Quality of life in hormone receptor-positive HER-2+ metastatic breast cancer patients during treatment with letrozole alone or in combination with lapatinib. Oncologist. 2010;15(9):944-53. doi: 10.1634/theoncologist.2010-0012. Epub 2010 Aug 26. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants With Progression Free Survival (PFS) in the Human Epidermal Growth Factor Receptor 2 (HER2)-Positive Advanced or Metastatic Breast Cancer as Assessed by the Investigator	PFS is defined as the time from randomization until the earliest date of disease progression (PD) or death due to any cause, if sooner. The date of documented PD is defined as the date of radiological PD as assessed by the investigator based on imaging data and also by the clinical assessment of symptomatic progression. Per Response Evaluation Criteria in Solid Tumors (RECIST 1.0), PD is defined as a 20% increase in the sum of the longest diameter (LD) of target lesions, taking as a reference the smallest sum LD recorded since the treatment started, or the appearance of 1 or more new lesions.	From the date of randomization until the date of the first documented progression or date of death from any cause, whichever came first, assessed for up to 46 months
Primary	Progression Free Survival (PFS) of Participants in the HER2-Positive Population as Assessed by the Investigator	PFS is defined as the time from randomization until the earliest date of disease progression or death due to any cause, if sooner. The date of documented disease progression is defined as the date of radiological disease progression as assessed by the investigator based on imaging data and also by the clinical assessment of symptomatic progression. Per RECIST 1.0, disease progression is defined as a 20% increase in the sum of the LD of target lesions, taking as a reference the smallest sum LD recorded since the treatment started, or the appearance of 1 or more new lesions.	From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 46 months
Secondary	Number of Participants With PFS in the Intent-To-Treat (ITT) Population as Assessed by the Investigator	PFS is defined as the time from randomization until the earliest date of disease progression or death due to any cause, if sooner. The date of documented disease progression is defined as the date of radiological disease progression as assessed by the investigator based on imaging data and also by the clinical assessment of symptomatic progression. Per RECIST 1.0, disease progression is defined as a 20% increase in the sum of the LD of target lesions, taking as a reference the smallest sum LD recorded since the treatment started, or the appearance of 1 or more new lesions.	From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 46 months
Secondary	PFS in Participants in the ITT Population as Assessed by the Investigator	PFS is defined as the time from randomization until the earliest date of disease progression or death due to any cause, if sooner. The date of documented disease progression is defined as the date of radiological disease progression as assessed by the investigator based on imaging data and also by the clinical assessment of symptomatic progression. Per RECIST 1.0, disease progression is defined as a 20% increase in the sum of the LD of target lesions, taking as a reference the smallest sum LD recorded since the treatment started, or the appearance of 1 or more new lesions.	From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 46 months
Secondary	Overall Survival in the HER2-Positive Population	Overall survival was defined as the time from randomization until death due to any cause.	From date of randomization until date of death due to any cause, assessed up to 46 months
Secondary	Overall Tumor Response (OR) for Participants With Measurable and Non-measurable Disease, Including Bone Scans, in the HER2-Positive Population as Assessed by the Investigator	OR is defined as the percentage of participants achieving either a confirmed complete response (CR) or partial response (PR). Response was assessed via Response Evaluation criteria in Solid Tumors (RECIST). The percentage of participants with response was calculated by using the formula: 100 * (number of participants with CR + number of participants with PR)/total number of participants. CR: disappearance of all target lesions. PR: at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as a reference the baseline sum LD.	Up to 46 months
Secondary	Number of Participants With Overall Tumor Response (OR) by Stratification Factors With Measurable Disease, Including Bone Scans, in the HER2-Positive Population as Assessed by the Investigator	Participants were stratified based on site of disease at screening (SDS) (soft tissue or visceral or bone-only disease) and prior adjuvant endocrine therapy (PAET) (discontinuation interval [DI] =>6 months or DI <6 months). OR is defined as the number of participants achieving either a confirmed CR or PR. Response was assessed via RECIST. CR: disappearance of all target lesions. PR: at least a 30% decrease in the sum of the LD of target lesions, taking as a reference the baseline sum LD. DI is defined as the time period from stopping the PEAT to the randomization date.	Up to 46 months
Secondary	Clinical Benefit (CB) in the HER2-Positive Population as Assessed by the Investigator	CB is defined as the percentage of participants with evidence of confirmed CR, PR, or stable disease (SD) for at least 6 months. CR: disappearance of all target lesions. PR: at least a 30% decrease in the sum of the LD of target lesions, taking as a reference the baseline sum LD. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the baseline measurement.	Up to 46 months
Secondary	Number of Participants With the Indicated Best Response From the Participants With Measurable and Non-measurable Disease, Including Bone Scans, in the HER2-Positive Population as Assessed by the Investigator.	CR: disappearance of all target lesions. PR: at least a 30% decrease in the sum of the LD of target lesions, taking as reference the baseline sum LD. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as a reference the smallest sum LD since the baseline measurement. The best overall response is defined as the best response recorded from the start of treatment until disease progression/recurrence. PD: presence of target lesions, non-target lesions, and/or new lesions.	Up to 46 months
Secondary	Number of Participants With the Indicated Best Response From the Participants With Measurable and Non-measurable Disease, Including Bone Scans, in the ITT Population as Assessed by the Investigator.	CR: disappearance of all target lesions. PR: at least a 30% decrease in the sum of the LD of target lesions, taking as reference the baseline sum LD. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as a reference the smallest sum LD since the baseline measurement. The best overall response is defined as the best response recorded from the start of treatment until disease progression/recurrence. PD: presence of target lesions, non-target lesions, and/or new lesions.	Up to 46 months
Secondary	Number of Participants With the Indicated Time to Response for CR or PR in the HER2-Positive Population as Assessed by the Investigator	Time to response is defined as the time from randomization until the first documented evidence of CR (disappearance of all target lesions) or PR (at least a 30% decrease in the sume of the LD of target lesions, taking as reference the baseline sum LD) (whichever status was recorded first). The assessments of CR or PR required confirmation using bone scans.	Up to 46 months
Secondary	Duration of Response for the Participants With CR or PR in the HER2-Positive Population as Assessed by the Investigator	Duration of response is defined as the time from the first documented evidence of CR (disappearance of all target lesions) or PR (at least a 30% decrease in the sum of the LD of target lesions, taking as a reference the baseline sum LD) until the first documented sign of disease progression or death due to any cause. The assessments of CR or PR required confirmation using bone scans.	Up to 46 months
Secondary	Number of Participants With Evidence of Brain Metastases in the HER2-Positive Population	The confirmation criteria for the evidence of brain metastases was the incidence of lesions occurring within any part of the central nervous system (CNS) as evidenced by radiological scans. Metastases are defined as the spread of cancer from one part of the body to another.	Up to 46 months
Secondary	Time to Progression (TTP) for the HER2-Positive Population as Assessed by the Investigator	TTP is defined as the interval between the date of randomization and the earliest date of disease progression or death due to breast cancer. Disease progression was based on the assessments by the Investigator.	Up to 46 months
Secondary	Overall Survival in the ITT Population	Overall survival was defined as the time from randomization until death due to any cause.	From date of randomization until date of death due to any cause, assessed up to 46 months
Secondary	Overall Tumor Response (OR) for Participants With Measurable and Non-measurable Disease, Including Bone Scans, in the ITT Population as Assessed by the Investigator	OR is defined as the percentage of participants achieving either a confirmed complete response (CR) or partial response (PR). Response was assessed via Response Evaluation criteria in Solid Tumors (RECIST). The percentage of participants with response was calculated by using the formula: 100 * (number of participants with CR + number of participants with PR)/total number of participants. CR: disappearance of all target lesions. PR: at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as a reference the baseline sum LD.	Up to 46 months
Secondary	Number of Participants With Overall Tumor Response (OR) by Stratification Factors With Measurable Disease, Including Bone Scans, in the ITT Population as Assessed by the Investigator	Participants were stratified based on site of disease at screening (SDS) (soft tissue or visceral or bone-only disease) and prior adjuvant endocrine therapy (PAET) (discontinuation interval [DI] =>6 months or DI <6 months). OR is defined as the number of participants achieving either a confirmed CR or PR. Response was assessed via RECIST. CR: disappearance of all target lesions. PR: at least a 30% decrease in the sum of the LD of target lesions, taking as a reference the baseline sum LD. DI is defined as the time period from stopping the PEAT and the randomization date.	Up to 46 months
Secondary	Clinical Benefit (CB) in the ITT Population as Assessed by the Investigator	CB is defined as the percentage of participants with evidence of confirmed CR, PR, or stable disease (SD) for at least 6 months. CR: disappearance of all target lesions. PR: at least a 30% decrease in the sum of the LD of target lesions, taking as a reference the baseline sum LD. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the baseline measurement.	Up to 46 months
Secondary	Number of Participants With the Indicated Time to Response for CR or PR in the ITT Population as Assessed by the Investigator	Time to response is defined as the time from randomization until the first documented evidence of CR (disappearance of all target lesions) or PR (at least a 30% decrease in the sume of the LD of target lesions, taking as reference the baseline sum LD) (whichever status was recorded first). The assessments of CR or PR required confirmation using bone scans.	Up to 46 months
Secondary	Duration of Response for the Participants With CR or PR in the ITT Population as Assessed by the Investigator	Duration of response is defined as the time from the first documented evidence of CR (disappearance of all target lesions) or PR (at least a 30% decrease in the sum of the LD of target lesions, taking as a reference the baseline sum LD) until the first documented sign of disease progression or death due to any cause. The assessments of CR or PR required confirmation using bone scans.	Up to 46 months
Secondary	Number of Participants With Evidence of Brain Metastases From the ITT Population	The confirmation criteria for the evidence of brain metastases was the incidence of lesions occurring within any part of the central nervous system (CNS) as evidenced by radiological scans. Metastases are defined as the spread of cancer from one part of the body to another.	Up to 46 months
Secondary	TTP for Participants From the ITT Population as Assessed by the Investigator	TTP is defined as the interval between the date of randomization and the earliest date of disease progression or death due to breast cancer. Disease progression was based on the assessments by the Investigator.	Up to 46 months
Secondary	Number of Participants Completing the Functional Assessment of Cancer Therapy-breast (FACT-B) Questionnaire at the Scheduled Visits	Quality of Life (QOL) was assessed using the FACT-B questionnaire, which was a 37-item (27 general and 10 breast cancer-specific questions) self-reporting instrument consisting of 5 dimensions: physical-, social/family-, emotional-, functional-well being, and a breast cancer subscale. Higher scores on the FACT-B scales (each ranging from 0 [not at all] to 4 [very much]) indicate a higher QOL. The score is transformed for FACT-B and results in a total score ranging from 0 to 144. Complete: completing at least 1 question from FACT-B.	Day 1 (baseline) visit; Week 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168, 180, and 192 visits; conclusion/withdrawal visit
Secondary	Adjusted Mean Change From Baseline for the FACT-B Total Score Using Observed Data	Quality of Life (QOL) was assessed using the FACT-B questionnaire, which is a 37-item (27 general and 10 breast cancer-specific questions) self-reporting instrument consisting of 5 dimensions: physical-, social/family-, emotional-, functional-well being, and a breast cancer subscale. Higher scores on the FACT-B scales indicate a higher QOL; each ranging from 0 (not at all) to 4 (very much). The score is transformed for FACT-B and results in a total score ranging from 0 to 144. The FACT-B is designed to measure multidimensional QOL in participants with breast cancer.	Week 12, 24, 36, and 48 visits; conclusion/withdrawal visit
Secondary	Adjusted Mean Change From Baseline for the Functional Assessment of Cancer Therapy-General (FACT-G) Score Using Observed Data	FACT-G is a subscale of the FACT-B QOL questionnaire and consists of 27 questions grouped into 4 domains that measure a participant's physical, functional, social and family, and emotional well-being. FACT-G is assessed on a five-point Likert-type scale, with scores ranging from 0 to 4 (0=not at all, 1=a little bit, 2=somewhat, 3=quite a bit, 4=very much). The total score is calculated as the sum of the item scores on the subscale; the total ranges from 0 to 108, with higher score indicating a better quality of life.	Week 12, 24, 36, and 48 visits; conclusion/withdrawal visit
Secondary	Adjusted Mean Change From Baseline for the Trial Outcome Index (TOI) Score Using Observed Data	The TOI score is the sum of the physical well-being, functional well-being, and breast cancer unweighted subscale scores. The total TOI score ranges from 0 to 92, with higher scores representing a better quality of life.	Week 12, 24, 36, and 48 visits; conclusion/withdrawal visit
Secondary	Number of Participants Classified as QOL Responders Based on the FACT-B, FACT-G, and TOI Total Scores	A minimally important difference (MID) is the smallest difference in a score for a measure of QOL that corresponds to a difference in function or clinical course. Responders are defined as participants with an MID => 8 for the FACT-B score, and an MID =>6 for the FACT-G and TOI scores.	Up to 46 months
Secondary	Number of Participants With Clinical Benefit Categorized by HER2 Fluorescence in Situ Hybridization (FISH) Status	Clinical benefit: participants with CR, PR, or SD for =>6-month period. FISH testing measures the amount of the HER2 gene in each cell. This gene is responsible for the overproduction of the HER2 protein. FISH-positive: excessive amounts of the gene are present; FISH-negative: normal levels of the gene are present.	Up to 46 months
Secondary	Number of Participants With Clinical Benefit Categorized by HER2 ImmunoHistoChemistry (IHC) Intensity	IHC is a commonly used test to assess the amount of the HER2 receptor protein on the surface of the cancer cells. The IHC test results in a score of 0 to 3+, which indicates the amount of HER2 receptor protein on the cells in a sample of breast cancer tissue. Tissue scores of 0 to 1+ indicate HER2 negativity; scores of 2+ and 3+ indicate HER2 positivity. Clinical benefit is defined as participants with CR, PR, or SD for =>6-month period.	Up to 46 months
Secondary	Number of Participants With Response in Participants With Baseline Serum HER2 Extracellular Domain (ECD) Baseline Values Greater Than 15 Nanograms Per Milliliter (ng/mL) and 15 ng/mL or Lower	The HER2 ECD is a glycoprotein that can be shed from the cell surface into the blood of normal individuals and can be elevated in different pathologic conditions. The serum HER2 ECD level generally reflects the tissue HER2 status. The HER2 ECD is quantified in serum with an enzyme-linked immunosorbent assay (ELISA). Non-Evaluable (NE): any participant who could not be classified as CR, PR, SD, or PD.	Up to 46 months
Secondary	Number of HER2-Negative Participants at Baseline With and Without Seroconversion to a Status of HER2 Positive	Participants who had a HER2-negative tumor status based on baseline tissue with baseline serum HER2 ECD values =<15 ng/mL but later had at least two consecutive serum HER2 ECD values >15 ng/mL experienced seroconversion.	Up to 46 months
Secondary	Time to Seroconversion for Participants Who Were HER2 Negative at Baseline But Became HER2 Positive	Time to seroconversion was defined as the time from the date of randomization until the first instance of serum HER2 (>15 ng/mL) on two consecutive occasions.	Up to 46 months
Secondary	Number of Participants With the Indicated Expression of Tumor by Epidermal Growth Factor Receptor (ErbB1/HER1/EGFR) at Baseline	EGFR is a cell surface receptor tyrosine kinase expressed in certain types of tumors. Depending upon the staining intensity, EGFR was graded as follows: 0=absence of membrane staining above background in all tumor cells; EGFR-positive=staining is defined as any IHC staining of tumor cell membranes above background level, whether it is complete or incomplete circumferential staining (1+, 2+, 3+).	Baseline