A Study to Compare the Safety and Efficacy of an Aromatase Inhibitor in Combination With Lapatinib, Trastuzumab or Both for the Treatment of Hormone Receptor Positive, HER2+ Metastatic Breast Cancer

Neoplasms, Breast Clinical Trial

Official title:

A Phase III Trial to Compare the Safety and Efficacy of Lapatinib Plus Trastuzumab Plus an Aromatase Inhibitor (AI) vs. Trastuzumab Plus an AI vs. Lapatinib Plus an AI as 1st- or 2nd- Line Therapy in Postmenopausal Subjects With Hormone Receptor+, HER2-positive Metastatic Breast Cancer (MBC) Who Received Prior Trastuzumab and Endocrine Therapies

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01160211
• Other study ID #: 114299
• Secondary ID: 2010-019577-16CL
• Status: Completed
• Phase: Phase 3
• Start date: May 5, 2011
• Est. completion date: June 6, 2022

Study information

• Verified date: June 2022
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

A study to compare the safety and efficacy of an aromatase inhibitor in combination with lapatinib, trastuzumab or both for the treatment of hormone receptor positive, HER2+ metastatic breast cancer (MBC).

Description:

This was a Phase III, randomized, open-label, multi-center, three arm study of lapatinib plus trastuzumab plus an aromatase inhibitor (AI), trastuzumab plus an AI, or lapatinib plus an AI to evaluate the efficacy and safety of these regimens as first- or second-line therapy in postmenopausal subjects with hormone receptor positive (HR+), HER2-positive metastatic breast cancer (MBC) who have received prior trastuzumab and endocrine therapies. Eligible subjects was postmenopausal; had tumors that are ER and/or PgR positive and HER2-positive; had Stage IV metastatic breast cancer. The primary objective was to demonstrate superiority of lapatinib/trastuzumab/AI combination versus (vs.) trastuzumab/AI combination for progression free survival. The secondary objectives were to evaluate progression free survival in trastuzumab/AI vs. lapatinib/AI and trastuzumab/lapatinib/AI vs. lapatinib/AI, overall survival, overall response rate, clinical benefit rate, the safety and tolerability of all three treatment groups (lapatinib plus trastuzumab plus an AI, trastuzumab plus an AI, or lapatinib plus an AI), and quality of life status relative to baseline.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 369
• Est. completion date: June 6, 2022
• Est. primary completion date: March 11, 2016
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

Inclusion Criteria

Subjects eligible for enrollment in the study must meet all of the following criteria:

1. Signed written informed consent. In Korea and Japan, subjects between >=18 and <20 years of age must also have a legal representative sign the written informed consent.

2. Post-menopausal female subjects >=18 years of age. Post-menopausal as defined by any

of the following:

• Subjects at least 60 years of age.
• Subjects under 60 years of age and amenorrhic for at least 12 consecutive months AND follicle-stimulating hormone (FSH) and estradiol levels in postmenopausal range (utilizing ranges from the local laboratory facility).
• Prior bilateral oophorectomy.
• Prior radiation castration with amenorrhea for at least 6 months

3. Subjects must have a history of histologically confirmed breast cancer, with a clinically confirmed diagnosis of metastatic disease [confirmed by histology, cytology or other clinical means (e.g. CT, MRI)]. Subjects may have either measurable or non-measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST 1.1)

4. Tumors that are ER+ and/or PgR+ by local laboratory

5. Documentation of HER2 overexpression or gene amplification, in the invasive component

of either the primary tumor or metastatic disease site as defined as:

• 3+ by Immunohistochemistry (IHC) and/or
• HER2/neu gene amplification by fluorescence, chromogenic or silver in situ hybridization [FISH, CISH or SISH; >6 HER2/neu gene copies per nucleus or a FISH, CISH or SISH test ratio (HER2 gene copies to chromosome 17 signals) of =2.0]

6. Subject must have received at least one prior regimen containing trastuzumab in combination with chemotherapy for breast cancer:.

• Subject has ONLY received prior trastuzumab in combination with chemotherapy as neoadjuvant and/or adjuvant treatment. OR
• Subject has received ONE prior trastuzumab-containing regimen for metastatic disease (and has progressed), and may or may not have received prior trastuzumab in combination with chemotherapy as neoadjuvant and/or adjuvant treatment.

7. Subject must have received prior endocrine therapy (such as aromatase inhibitors or selective estrogen receptor modulators). 8. Subjects who have a life expectancy of > 6 months as assessed by the treating investigator

9. Subjects must have baseline Left Ventricular Ejection Fraction (LVEF) =50% measured by echocardiography (ECHO) or multi-gated acquisition scan (MUGA) 10. Subject must have an ECOG performance status of 0-1 11. All prior treatment related toxicities must be CTCAE (Version 4.0) = Grade 1 at the time of randomization 12. Completion of screening assessments 13. Adequate baseline organ function. 14. Subjects must meet all of the

following criteria:

• QTc <450msec or
• QTc <480msec for subjects with bundle branch block The QTc is the QT interval corrected for heart rate according to either Bazett's formula (QTcB) or to Fridericia's formula (QTcF), machine or manual over read, for males and females. The specific formula that will be used in a protocol should be determined prior to initiation of the study, and the formula used to determine inclusion and discontinuation should be the same throughout the study. The QTc should be based on single or averaged QTc values of triplicate electrocardiograms (ECGs) obtained over a brief recording period

Exclusion criteria:

1. History of another malignancy. Exception: Subjects who have been disease-free for 5 years, or subjects with a history of completely resected non-melanoma skin cancer or successfully treated in situ carcinoma are eligible.

2. Subjects with extensive symptomatic visceral disease including hepatic involvement and pulmonary lymphangitic spread of tumor, or the disease is considered by the investigator to be rapidly progressing or life threatening (subjects who are intended for chemotherapy)

3. Serious cardiac illness or medical condition including but not confined to:

• Uncontrolled arrhythmias
• Uncontrolled or symptomatic angina
• History of congestive heart failure (CHF)
• Documented myocardial infarction <6 months from study entry

4. Known history of, or clinical evidence of, central nervous system (CNS) metastases or leptomeningeal carcinomatosis

5. Have acute or currently active/requiring anti-viral therapy hepatic or biliary disease (with the exception of subjects with Gilbert's syndrome, asymptomatic gallstones, liver metastases or stable chronic liver disease per investigator assessment)

6. Have a concurrent disease or condition that may interfere with study participation, or any serious medical disorder that would interfere with the subject's safety (for example, active or uncontrolled infection or any psychiatric condition prohibiting understanding or rendering of informed consent)

7. Have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels

8. Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to any of the study agents or their excipients that, in the opinion of the Investigator or GSK medical monitor, contraindicates their participation

9. Any prohibited medication.

10. Administration of an investigational drug within 30 days or 5 half-lives, whichever is longer, preceding the first dose of study treatment.

Related Conditions & MeSH terms

• Breast Neoplasms
• Neoplasms, Breast

Intervention

Drug:
• lapatinib
1000 mg by mouth once a day
• trastuzumab
Loading dose of 8 mg/kg IV followed by the maintenance dose of 6 mg/kg IV every 3 weeks
• Aromatase inhibitor
Aromatase inhibitor (either letrozole, anastrozole, or exemestane) of investigator's choice given by mouth once daily
• lapatinib
1500 mg by mouth once daily

Locations

Country	Name	City	State
Argentina	Novartis Investigative Site	Berazategui	Buenos Aires
Argentina	Novartis Investigative Site	Capital Federal	Buenos Aires
Argentina	Novartis Investigative Site	Ciudad Aut6noma de Buenos Aires	Buenos Aires
Argentina	Novartis Investigative Site	Ciudad Autonoma de Buenos Aires	Buenos Aires
Argentina	Novartis Investigative Site	Ciudad Autonoma de Buenos Aires	Buenos Aires
Argentina	Novartis Investigative Site	Ciudad Autonoma de Buenos Aires
Argentina	Novartis Investigative Site	Cordoba
Argentina	Novartis Investigative Site	La Plata	Buenos Aires
Argentina	Novartis Investigative Site	La Rioja
Argentina	Novartis Investigative Site	Quilmes
Argentina	Novartis Investigative Site	Rosario	Santa Fe
Argentina	Novartis Investigative Site	San Miguel de Tucuman
Argentina	Novartis Investigative Site	Viedma	Río Negro
Australia	Novartis Investigative Site	Adelaide
Australia	Novartis Investigative Site	Box Hill	Victoria
Australia	Novartis Investigative Site	Douglas
Australia	Novartis Investigative Site	Ringwood East
Australia	Novartis Investigative Site	Tweed Heads
Australia	Novartis Investigative Site	Wodonga	Victoria
Belgium	Novartis Investigative Site	Leuven
Belgium	Novartis Investigative Site	Liege
Belgium	Novartis Investigative Site	Namur
Brazil	Novartis Investigative Site	Barretos	São Paulo
Brazil	Novartis Investigative Site	Fortaleza	Ceará
Brazil	Novartis Investigative Site	Goiania	Goiás
Brazil	Novartis Investigative Site	Porto Alegre	Rio Grande Do Sul
Brazil	Novartis Investigative Site	Porto Alegre	Rio Grande Do Sul
Brazil	Novartis Investigative Site	Rio de Janeiro
Brazil	Novartis Investigative Site	Sao Paulo	São Paulo
Brazil	Novartis Investigative Site	Sao Paulo	São Paulo
Brazil	Novartis Investigative Site	Sao Paulo	São Paulo
Brazil	Novartis Investigative Site	Sao Paulo	São Paulo
Bulgaria	Novartis Investigative Site	Plovdiv
Bulgaria	Novartis Investigative Site	Sofia
Bulgaria	Novartis Investigative Site	Sofia
Bulgaria	Novartis Investigative Site	Sofia
Bulgaria	Novartis Investigative Site	Varna
Canada	Novartis Investigative Site	Calgary	Alberta
China	Novartis Investigative Site	Changchun	Jilin
China	Novartis Investigative Site	Fuzhou	Fujian
China	Novartis Investigative Site	Guangzhou	Guangdong
China	Novartis Investigative Site	Harbin
China	Novartis Investigative Site	Shanghai
Colombia	Novartis Investigative Site	Monteria
Croatia	Novartis Investigative Site	Osijek
Croatia	Novartis Investigative Site	Pula
Croatia	Novartis Investigative Site	Zagreb
France	Novartis Investigative Site	Besancon
France	Novartis Investigative Site	Le Mans
France	Novartis Investigative Site	Lille
France	Novartis Investigative Site	Montpellier Cedex 5
France	Novartis Investigative Site	Nancy
France	Novartis Investigative Site	Paris Cedex 20
Germany	Novartis Investigative Site	Aachen	Nordrhein-Westfalen
Germany	Novartis Investigative Site	Berlin
Germany	Novartis Investigative Site	Berlin
Germany	Novartis Investigative Site	Bottrop	Nordrhein-Westfalen
Germany	Novartis Investigative Site	Fuerstenwalde	Brandenburg
Germany	Novartis Investigative Site	Goslar	Niedersachsen
Germany	Novartis Investigative Site	Halle	Sachsen-Anhalt
Germany	Novartis Investigative Site	Hamburg
Germany	Novartis Investigative Site	Hamburg
Germany	Novartis Investigative Site	Hamburg
Germany	Novartis Investigative Site	Hannover	Niedersachsen
Germany	Novartis Investigative Site	Heidelberg	Baden-Wuerttemberg
Germany	Novartis Investigative Site	Kiel	Schleswig-Holstein
Germany	Novartis Investigative Site	Muenchen	Bayern
Germany	Novartis Investigative Site	Muenchen	Bayern
Germany	Novartis Investigative Site	Regensburg	Bayern
Germany	Novartis Investigative Site	Rosenheim	Bayern
Germany	Novartis Investigative Site	Rostock	Mecklenburg-Vorpommern
Germany	Novartis Investigative Site	Troisdorf	Nordrhein-Westfalen
Germany	Novartis Investigative Site	Tuebingen	Baden-Wuerttemberg
Germany	Novartis Investigative Site	Velbert	Nordrhein-Westfalen
Greece	Novartis Investigative Site	Athens
Greece	Novartis Investigative Site	Chania
Greece	Novartis Investigative Site	Heraklion
Greece	Novartis Investigative Site	Perioxi Dragana, Alexandroupolis
Hong Kong	Novartis Investigative Site	Hong Kong
Hong Kong	Novartis Investigative Site	Kowloon
Hong Kong	Novartis Investigative Site	Pokfulam
Hong Kong	Novartis Investigative Site	Tuen Mun
Hungary	Novartis Investigative Site	Budapest
Hungary	Novartis Investigative Site	Budapest
Hungary	Novartis Investigative Site	Debrecen
Hungary	Novartis Investigative Site	Gyor
Hungary	Novartis Investigative Site	Gyula
Hungary	Novartis Investigative Site	Kaposvar
Hungary	Novartis Investigative Site	Miskolc
Hungary	Novartis Investigative Site	Nyiregyhaza
Hungary	Novartis Investigative Site	Pecs
Hungary	Novartis Investigative Site	Szeged
Hungary	Novartis Investigative Site	Szolnok
Hungary	Novartis Investigative Site	Veszprem
Hungary	Novartis Investigative Site	Zalaegerszeg
India	Novartis Investigative Site	Bangalore
India	Novartis Investigative Site	Chennai
India	Novartis Investigative Site	Delhi
India	Novartis Investigative Site	Nagpur
India	Novartis Investigative Site	New Delhi
India	Novartis Investigative Site	Pune
India	Novartis Investigative Site	Surat
Ireland	Novartis Investigative Site	Dublin
Ireland	Novartis Investigative Site	Dublin
Ireland	Novartis Investigative Site	Dublin
Ireland	Novartis Investigative Site	Dublin 7
Ireland	Novartis Investigative Site	Galway
Israel	Novartis Investigative Site	Haifa
Israel	Novartis Investigative Site	Jerusalem
Israel	Novartis Investigative Site	Petah-Tikva
Israel	Novartis Investigative Site	Ramat Gan
Israel	Novartis Investigative Site	Rehovot
Israel	Novartis Investigative Site	Tel Aviv
Italy	Novartis Investigative Site	Monza	Lombardia
Italy	Novartis Investigative Site	Parma	Emilia-Romagna
Italy	Novartis Investigative Site	Pavia	Lombardia
Italy	Novartis Investigative Site	Piacenza	Emilia-Romagna
Italy	Novartis Investigative Site	Rozzano (MI)	Lombardia
Italy	Novartis Investigative Site	San Giovanni Rotondo
Japan	Novartis Investigative Site	Aichi
Japan	Novartis Investigative Site	Chiba
Japan	Novartis Investigative Site	Ehime
Japan	Novartis Investigative Site	Kagoshima
Japan	Novartis Investigative Site	Osaka
Japan	Novartis Investigative Site	Osaka
Japan	Novartis Investigative Site	Saitama
Japan	Novartis Investigative Site	Saitama
Japan	Novartis Investigative Site	Shizuoka
Japan	Novartis Investigative Site	Tokyo
Japan	Novartis Investigative Site	Tokyo
Japan	Novartis Investigative Site	Tokyo
Korea, Republic of	Novartis Investigative Site	Gyeonggi-do
Korea, Republic of	Novartis Investigative Site	Seoul
Korea, Republic of	Novartis Investigative Site	Seoul
Korea, Republic of	Novartis Investigative Site	Seoul
Lithuania	Novartis Investigative Site	Vilnius
Norway	Novartis Investigative Site	Lorenskog
Peru	Novartis Investigative Site	Arequipa
Peru	Novartis Investigative Site	Lima
Peru	Novartis Investigative Site	Miraflores	Lima
Peru	Novartis Investigative Site	San Borja	Lima
Peru	Novartis Investigative Site	San Isidro	Lima
Peru	Novartis Investigative Site	Trujillo
Philippines	Novartis Investigative Site	Makati City
Philippines	Novartis Investigative Site	Quezon City
Poland	Novartis Investigative Site	Konin
Poland	Novartis Investigative Site	Lubin
Poland	Novartis Investigative Site	Otwock
Poland	Novartis Investigative Site	Warszawa
Poland	Novartis Investigative Site	Warszawa
Poland	Novartis Investigative Site	Wieliszew
Poland	Novartis Investigative Site	Wroclaw
Portugal	Novartis Investigative Site	Coimbra
Portugal	Novartis Investigative Site	Evora
Portugal	Novartis Investigative Site	Lisboa
Portugal	Novartis Investigative Site	Lisbon
Portugal	Novartis Investigative Site	Porto
Puerto Rico	Novartis Investigative Site	San Juan
Puerto Rico	Novartis Investigative Site	San Juan
Romania	Novartis Investigative Site	Bucharest
Romania	Novartis Investigative Site	Bucuresti
Romania	Novartis Investigative Site	Timisoara
Russian Federation	Novartis Investigative Site	Arkhangelsk
Russian Federation	Novartis Investigative Site	Kazan
Russian Federation	Novartis Investigative Site	Moscow
Russian Federation	Novartis Investigative Site	Moscow
Russian Federation	Novartis Investigative Site	Ryazan
Russian Federation	Novartis Investigative Site	St. Petersburg
Russian Federation	Novartis Investigative Site	St. Petersburg
Russian Federation	Novartis Investigative Site	Tver
Serbia	Novartis Investigative Site	Belgrade
Serbia	Novartis Investigative Site	Kragujevac
Serbia	Novartis Investigative Site	Sremska Kamenica
Singapore	Novartis Investigative Site	Singapore
South Africa	Novartis Investigative Site	Cape Town
South Africa	Novartis Investigative Site	Durban
South Africa	Novartis Investigative Site	Port Elizabeth
South Africa	Novartis Investigative Site	Pretoria
South Africa	Novartis Investigative Site	Saxonwold, Johannesburg
Spain	Novartis Investigative Site	Barcelona
Spain	Novartis Investigative Site	Barcelona
Spain	Novartis Investigative Site	Castellon
Spain	Novartis Investigative Site	Cordoba
Spain	Novartis Investigative Site	La Coruna
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Santa Cruz de Tenerife
Taiwan	Novartis Investigative Site	Changhua
Taiwan	Novartis Investigative Site	Kaohsiung Hsien
Taiwan	Novartis Investigative Site	Taipei City
Turkey	Novartis Investigative Site	Ankara
Turkey	Novartis Investigative Site	Izmir
Ukraine	Novartis Investigative Site	Chernivtsi
Ukraine	Novartis Investigative Site	Dnipropetrovsk
Ukraine	Novartis Investigative Site	Kharkiv
Ukraine	Novartis Investigative Site	Khmelnytskyi
Ukraine	Novartis Investigative Site	Lyutizh
Ukraine	Novartis Investigative Site	Sumy
Ukraine	Novartis Investigative Site	Uzhgorod
Ukraine	Novartis Investigative Site	Vinnitsia
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	Maidstone
United Kingdom	Novartis Investigative Site	Manchester
United Kingdom	Novartis Investigative Site	Nottingham
United Kingdom	Novartis Investigative Site	Peterborough
United Kingdom	Novartis Investigative Site	Sutton
United States	Novartis Investigative Site	Albuquerque	New Mexico
United States	Novartis Investigative Site	Albuquerque	New Mexico
United States	Novartis Investigative Site	Augusta	Georgia
United States	Novartis Investigative Site	Billings	Montana
United States	Novartis Investigative Site	Cary	North Carolina
United States	Novartis Investigative Site	Chicago	Illinois
United States	Novartis Investigative Site	Dayton	Ohio
United States	Novartis Investigative Site	Germantown	Tennessee
United States	Novartis Investigative Site	Goshen	Indiana
United States	Novartis Investigative Site	Grand Rapids	Michigan
United States	Novartis Investigative Site	Hollywood	Florida
United States	Novartis Investigative Site	Houston	Texas
United States	Novartis Investigative Site	La Jolla	California
United States	Novartis Investigative Site	Lawrenceville	Georgia
United States	Novartis Investigative Site	Miami	Florida
United States	Novartis Investigative Site	Milwaukee	Wisconsin
United States	Novartis Investigative Site	Minneapolis	Minnesota
United States	Novartis Investigative Site	Omaha	Nebraska
United States	Novartis Investigative Site	Pleasant Hill	California
United States	Novartis Investigative Site	Tacoma	Washington
United States	Novartis Investigative Site	Waterloo	Iowa

Sponsors (2)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals	GlaxoSmithKline

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Belgium,  Brazil,  Bulgaria,  Canada,  China,  Colombia,  Croatia,  France,  Germany,  Greece,  Hong Kong,  Hungary,  India,  Ireland,  Israel,  Italy,  Japan,  Korea, Republic of,  Lithuania,  Norway,  Peru,  Philippines,  Poland,  Portugal,  Puerto Rico,  Romania,  Russian Federation,  Serbia,  Singapore,  South Africa,  Spain,  Taiwan,  Turkey,  Ukraine,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	PFS of Lapatinib+Trastuzumab+AI Combination vs. Trastuzumab+AI Combination	Progression free survival (PFS) of lapatinib/trastuzumab/aromatase inhibitor (AI) combination vs. trastuzumab/AI combination. PFS is defined as the time from randomization to the earliest date of disease progression (with radiological evidence) or death from any cause, or to the date of censor.	approximately 5 years
Primary	Median Kaplan Meier Estimates for PFS of Lapatinib+Trastuzumab+AI Combination vs. Trastuzumab+AI Combination	Progression free survival (PFS) of lapatinib/trastuzumab/aromatase inhibitor (AI) combination vs. trastuzumab/AI combination. PFS is defined as the time from randomization to the earliest date of disease progression (with radiological evidence) or death from any cause, or to the date of censor.	approximately 5 years
Secondary	PFS of Trastuzumab/AI vs. Lapatinib/AI and Trastuzumab/Lapatinib/AI vs. Lapatinib/AI	PFS in the lapatinib arm vs. the trastuzumab arm and in the lapatinib+trastuzumab arm vs. the lapatinib arm.	approximately 5 years
Secondary	Overall Survival (OS) Events of Lapatinib+Trastuzumab+AI vs. Trastuzumab+AI and Lapatinib+AI vs. Trastuzumab+AI	OS was defined as the interval of time (in weeks) between the date of randomization and the date of death due to any cause. For subjects who did not die during the study, death was censored at the date of last contact.	approximately 5 years
Secondary	Overall Response Rate (ORR; Complete or Partial Response) in Lapatinib+Trastuzumab+AI vs. Trastuzumab+AI and Lapatinib+AI vs. Trastuzumab+AI	The best overall response was the best response recorded from the start of the treatment until disease progression/recurrence & was determined programmatically using investigators assessment of responses of target lesion, non-target lesion and new lesions based on RECIST v1.1. CR=disappearance of all target lesion & non-target lesions, if applicable, and no new lesion; PR = =30% decrease in the sum of the longest diameter of target lesions & non-target lesion was neither non-CR nor progressive disease (Non-PD) or not evaluable (NE); stable disease (SD) = Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD (SD should maintain for at least 56 days); PD = =20% increase from nadir (smallest sum diameters recorded since treatment start) of the target lesions and/or any status for non-target lesions or appearance of new lesion; NE = cannot be classified by the above definitions. Overall Response (OR) = CR + PR.	approximately 5 years
Secondary	Clinical Benefit Rate (CBR; Complete Response, Partial Response, or Stable Disease for at Least 6 Months) in Lapatinib+Trastuzumab+AI vs. Trastuzumab+AI and Lapatinib+AI vs. Trastuzumab+AI	Clinical Benefit Rate (CBR) was defined as the percentage of patients with evidence of complete response (CR) or partial response (PR) at any time or maintaining SD for at least 24 weeks while on study, according to the investigator assessment of response per RECIST 1.1 criteria.	approximately 5 years
Secondary	Duration of Response in Lapatinib+Trastuzumab+AI vs. Trastuzumab+AI and Lapatinib+AI vs. Trastuzumab+AI	Kaplan-Meier estimates for duration of response in lapatinib+trastuzumab+AI vs. trastuzumab+AI and lapatinib+AI vs. trastuzumab+AI. Duration of response is defined as the time from first documented Complete Response or Partial Response until the first documented sign of Progressive Disease or Death, or to the date of censor.	approximately 5 years
Secondary	Changes in the Quality of Life (QoL) Status Relative to Baseline FACT-B Overall and Subscale Scores at Last On-treatment Assessment	Quality of life was assessed using the Functional Assessment of Cancer Therapy-Breast (FACT-B) questionnaire. It is a 37-item (27 general questions and 10 breast cancer specific questions) self-reporting instrument consisting of 5 dimensions: physical well-being (PWB), social well-being (SWB), emotional well-being (EWB), functional well-being (FWB), and a breast cancer subscale (BCS). The followings are the score ranges for each self-reporting subscale: • PWB : 0-28 • SWB : 0-28 • EWB : 0-24 • FWB : 0-28 • BCS : 0-40 FACT-B Total Outcome Index (TOI) = PWB + FWB + BCS (range:0 - 96) FACT-B Total Score = PWB + SWB + EWB + FWB + BCS (range:0-148) FACT-G Total Score = PWB + SWB + EWB + FWB (range:0-108) In the scoring system, negative stated items are reversed by subtracting the response from "4" and after reversing proper items, all subscale items are summed to a total, which is the subscale score. For all the FACIT scales and symptom indices, the higher the score the better cut off	approximately 5 years
Secondary	Time to Response in Lapatinib+Trastuzumab+AI vs. Trastuzumab+AI and Lapatinib+AI vs. Trastuzumab+AI	Time to response in lapatinib+trastuzumab+AI vs. trastuzumab+AI and lapatinib+AI vs. trastuzumab+AI. Time to response is defined as time from randomization to first documented Complete Response or Partial Response.	approximately 5 years