Trial Outcomes & Findings for Study Comparing Lapatinib (GW572016) And Letrozole Versus Letrozole In Subjects With Advanced Or Metastatic Breast Cancer (NCT NCT00073528)

Last Updated: 2021-02-24

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

1286 participants

Primary outcome timeframe

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

Results posted on

2021-02-24

Participant Flow

This study was conducted at 212 centers in 29 countries (Argentina, Australia, Brazil, Bulgaria, Canada, Chile, Colombia, Croatia, Czech Republic, Denmark, France, Germany, Hungary, Ireland, Italy, Republic of Korea, Mexico, Netherlands, New Zealand, Pakistan, Peru, Poland, Russian Federation, South-Africa, Spain, Tunisia, Turkey, UK, USA).

Participant milestones

Participant milestones
Measure	Placebo + Letrozole 2.5 mg Participants received 6 tablets of placebo, identical in appearance to lapatinib tablets, orally daily (approximately at the same time each day), either 1 hour (or more) before breakfast or 1 hour (or more) after breakfast. Participants also received 1 tablet of letrozole 2.5 milligrams (mg) orally daily, preferably with the daily dose of lapatinib.	Lapatinib 1500 mg + Letrozole 2.5 mg Participants received 6 tablets of Lapatinib orally daily (250 mg lapatinib/tablet for a total of 1500 mg of lapatinib/day; approximately at the same time each day), either 1 hour (or more) before breakfast or 1 hour (or more) after breakfast. Participants also received 1 tablet of letrozole 2.5 mg orally daily, preferably with the daily dose of lapatinib.
Overall Study STARTED	644	642
Overall Study COMPLETED	14	14
Overall Study NOT COMPLETED	630	628

Reasons for withdrawal

Reasons for withdrawal
Measure	Placebo + Letrozole 2.5 mg Participants received 6 tablets of placebo, identical in appearance to lapatinib tablets, orally daily (approximately at the same time each day), either 1 hour (or more) before breakfast or 1 hour (or more) after breakfast. Participants also received 1 tablet of letrozole 2.5 milligrams (mg) orally daily, preferably with the daily dose of lapatinib.	Lapatinib 1500 mg + Letrozole 2.5 mg Participants received 6 tablets of Lapatinib orally daily (250 mg lapatinib/tablet for a total of 1500 mg of lapatinib/day; approximately at the same time each day), either 1 hour (or more) before breakfast or 1 hour (or more) after breakfast. Participants also received 1 tablet of letrozole 2.5 mg orally daily, preferably with the daily dose of lapatinib.
Overall Study Death	488	473
Overall Study Lost to Follow-up	52	45
Overall Study Withdrawal by Subject	50	45
Overall Study Study terminated by Sponsor	10	29
Overall Study Other	9	12
Overall Study Protocol Violation	3	5

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo + Letrozole 2.5 mg n=644 Participants Participants received 6 tablets of placebo, identical in appearance to lapatinib tablets, orally daily (approximately at the same time each day), either 1 hour (or more) before breakfast or 1 hour (or more) after breakfast. Participants also received 1 tablet of letrozole 2.5 milligrams (mg) orally daily, preferably with the daily dose of lapatinib.	Lapatinib 1500 mg + Letrozole 2.5 mg n=642 Participants Participants received 6 tablets of Lapatinib orally daily (250 mg lapatinib/tablet for a total of 1500 mg of lapatinib/day; approximately at the same time each day), either 1 hour (or more) before breakfast or 1 hour (or more) after breakfast. Participants also received 1 tablet of letrozole 2.5 mg orally daily, preferably with the daily dose of lapatinib.	Total n=1286 Participants Total of all reporting groups
Age, Continuous	63.3 Years STANDARD_DEVIATION 9.95 • n=93 Participants	62.8 Years STANDARD_DEVIATION 9.70 • n=4 Participants	63.1 Years STANDARD_DEVIATION 9.83 • n=27 Participants
Sex: Female, Male Female	644 Participants n=93 Participants	642 Participants n=4 Participants	1286 Participants n=27 Participants
Sex: Female, Male Male	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants
Race/Ethnicity, Customized White	557 Participants n=93 Participants	529 Participants n=4 Participants	1086 Participants n=27 Participants
Race/Ethnicity, Customized Black	10 Participants n=93 Participants	17 Participants n=4 Participants	27 Participants n=27 Participants
Race/Ethnicity, Customized Asian	30 Participants n=93 Participants	30 Participants n=4 Participants	60 Participants n=27 Participants
Race/Ethnicity, Customized American Hispanic	44 Participants n=93 Participants	57 Participants n=4 Participants	101 Participants n=27 Participants
Race/Ethnicity, Customized Other	3 Participants n=93 Participants	9 Participants n=4 Participants	12 Participants n=27 Participants

PRIMARY outcome

Timeframe: 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

Population: HER2-Positive Population: all randomized participants who had documented amplification of baseline HER2 by fluorescence in situ hybridization (FISH) (=\>2.0) or 3+ immunohistochemistry (IHC) (or 2+ IHC and FISH +) in archived tumor tissue regardless of whether or not study treatment had been received.

Outcome measures

Outcome measures
Measure	Placebo + Letrozole 2.5 mg n=108 Participants Participants received 6 tablets of placebo, identical in appearance to lapatinib tablets, orally daily (approximately at the same time each day), either 1 hour (or more) before breakfast or 1 hour (or more) after breakfast. Participants also received 1 tablet of letrozole 2.5 milligrams (mg) orally daily, preferably with the daily dose of lapatinib.	Lapatinib 1500 mg + Letrozole 2.5 mg n=111 Participants Participants received 6 tablets of Lapatinib orally daily (250 mg lapatinib/tablet for a total of 1500 mg of lapatinib/day; approximately at the same time each day), either 1 hour (or more) before breakfast or 1 hour (or more) after breakfast. Participants also received 1 tablet of letrozole 2.5 mg orally daily, preferably with the daily dose of lapatinib.
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	89 Participants	88 Participants

PRIMARY outcome

Timeframe: 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

Population: HER2-Positive Population. Only those participants who experienced disease progression or died during their participation in the study were assessed.

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.

Outcome measures

Outcome measures
Measure	Placebo + Letrozole 2.5 mg n=89 Participants Participants received 6 tablets of placebo, identical in appearance to lapatinib tablets, orally daily (approximately at the same time each day), either 1 hour (or more) before breakfast or 1 hour (or more) after breakfast. Participants also received 1 tablet of letrozole 2.5 milligrams (mg) orally daily, preferably with the daily dose of lapatinib.	Lapatinib 1500 mg + Letrozole 2.5 mg n=88 Participants Participants received 6 tablets of Lapatinib orally daily (250 mg lapatinib/tablet for a total of 1500 mg of lapatinib/day; approximately at the same time each day), either 1 hour (or more) before breakfast or 1 hour (or more) after breakfast. Participants also received 1 tablet of letrozole 2.5 mg orally daily, preferably with the daily dose of lapatinib.
Progression Free Survival (PFS) of Participants in the HER2-Positive Population as Assessed by the Investigator	13.0 Weeks Interval 12.0 to 23.7	35.4 Weeks Interval 24.1 to 39.4

SECONDARY outcome

Timeframe: 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

Population: ITT Population: all randomized participants, regardless of whether or not study treatment had been received. The ITT Population included the HER2-Positive Population, the HER2-Negative Population, and the HER2-Missing Population.

Outcome measures

Outcome measures
Measure	Placebo + Letrozole 2.5 mg n=644 Participants Participants received 6 tablets of placebo, identical in appearance to lapatinib tablets, orally daily (approximately at the same time each day), either 1 hour (or more) before breakfast or 1 hour (or more) after breakfast. Participants also received 1 tablet of letrozole 2.5 milligrams (mg) orally daily, preferably with the daily dose of lapatinib.	Lapatinib 1500 mg + Letrozole 2.5 mg n=642 Participants Participants received 6 tablets of Lapatinib orally daily (250 mg lapatinib/tablet for a total of 1500 mg of lapatinib/day; approximately at the same time each day), either 1 hour (or more) before breakfast or 1 hour (or more) after breakfast. Participants also received 1 tablet of letrozole 2.5 mg orally daily, preferably with the daily dose of lapatinib.
Number of Participants With PFS in the Intent-To-Treat (ITT) Population as Assessed by the Investigator	476 Participants	413 Participants

SECONDARY outcome

Timeframe: 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

Population: ITT Population. Only those participants who experienced disease progression or died during their participation in the study were assessed.

Outcome measures

Outcome measures
Measure	Placebo + Letrozole 2.5 mg n=476 Participants Participants received 6 tablets of placebo, identical in appearance to lapatinib tablets, orally daily (approximately at the same time each day), either 1 hour (or more) before breakfast or 1 hour (or more) after breakfast. Participants also received 1 tablet of letrozole 2.5 milligrams (mg) orally daily, preferably with the daily dose of lapatinib.	Lapatinib 1500 mg + Letrozole 2.5 mg n=413 Participants Participants received 6 tablets of Lapatinib orally daily (250 mg lapatinib/tablet for a total of 1500 mg of lapatinib/day; approximately at the same time each day), either 1 hour (or more) before breakfast or 1 hour (or more) after breakfast. Participants also received 1 tablet of letrozole 2.5 mg orally daily, preferably with the daily dose of lapatinib.
PFS in Participants in the ITT Population as Assessed by the Investigator	47.0 Weeks Interval 36.9 to 50.9	51.7 Weeks Interval 47.6 to 59.6

SECONDARY outcome

Timeframe: From date of randomization until date of death due to any cause, assessed up to 46 months

Population: HER2-Positive Population. Only those participants who died during the study due to any cause were assessed.

Overall survival was defined as the time from randomization until death due to any cause.

Outcome measures

Outcome measures
Measure	Placebo + Letrozole 2.5 mg n=108 Participants Participants received 6 tablets of placebo, identical in appearance to lapatinib tablets, orally daily (approximately at the same time each day), either 1 hour (or more) before breakfast or 1 hour (or more) after breakfast. Participants also received 1 tablet of letrozole 2.5 milligrams (mg) orally daily, preferably with the daily dose of lapatinib.	Lapatinib 1500 mg + Letrozole 2.5 mg n=111 Participants Participants received 6 tablets of Lapatinib orally daily (250 mg lapatinib/tablet for a total of 1500 mg of lapatinib/day; approximately at the same time each day), either 1 hour (or more) before breakfast or 1 hour (or more) after breakfast. Participants also received 1 tablet of letrozole 2.5 mg orally daily, preferably with the daily dose of lapatinib.
Overall Survival in the HER2-Positive Population	140.3 Weeks Interval 92.1 to 159.4	144.7 Weeks Interval 95.6 to NA: Not estimable due to insufficient number of participants with events

SECONDARY outcome

Timeframe: Up to 46 months

Population: HER2-Positive Population

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.

Outcome measures

Outcome measures
Measure	Placebo + Letrozole 2.5 mg n=108 Participants Participants received 6 tablets of placebo, identical in appearance to lapatinib tablets, orally daily (approximately at the same time each day), either 1 hour (or more) before breakfast or 1 hour (or more) after breakfast. Participants also received 1 tablet of letrozole 2.5 milligrams (mg) orally daily, preferably with the daily dose of lapatinib.	Lapatinib 1500 mg + Letrozole 2.5 mg n=111 Participants Participants received 6 tablets of Lapatinib orally daily (250 mg lapatinib/tablet for a total of 1500 mg of lapatinib/day; approximately at the same time each day), either 1 hour (or more) before breakfast or 1 hour (or more) after breakfast. Participants also received 1 tablet of letrozole 2.5 mg orally daily, preferably with the daily dose of lapatinib.
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	14.8 Percent response rate Interval 8.7 to 22.9	27.9 Percent response rate Interval 19.8 to 37.2

SECONDARY outcome

Timeframe: Up to 46 months

Population: HER2-Positive Population. Only those participants with measurable disease, including bone scans, were assessed.

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.

Outcome measures

Outcome measures
Measure	Placebo + Letrozole 2.5 mg n=75 Participants Participants received 6 tablets of placebo, identical in appearance to lapatinib tablets, orally daily (approximately at the same time each day), either 1 hour (or more) before breakfast or 1 hour (or more) after breakfast. Participants also received 1 tablet of letrozole 2.5 milligrams (mg) orally daily, preferably with the daily dose of lapatinib.	Lapatinib 1500 mg + Letrozole 2.5 mg n=93 Participants Participants received 6 tablets of Lapatinib orally daily (250 mg lapatinib/tablet for a total of 1500 mg of lapatinib/day; approximately at the same time each day), either 1 hour (or more) before breakfast or 1 hour (or more) after breakfast. Participants also received 1 tablet of letrozole 2.5 mg orally daily, preferably with the daily dose of lapatinib.
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 SDS, Soft tissue or visceral	14 Participants	31 Participants
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 SDS, Bone-only disease	0 Participants	0 Participants
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 PAET, DI =>6 months	12 Participants	24 Participants
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 PAET, DI <6 months	2 Participants	7 Participants

SECONDARY outcome

Timeframe: Up to 46 months

Population: HER2-Positive Population

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.

Outcome measures

Outcome measures
Measure	Placebo + Letrozole 2.5 mg n=108 Participants Participants received 6 tablets of placebo, identical in appearance to lapatinib tablets, orally daily (approximately at the same time each day), either 1 hour (or more) before breakfast or 1 hour (or more) after breakfast. Participants also received 1 tablet of letrozole 2.5 milligrams (mg) orally daily, preferably with the daily dose of lapatinib.	Lapatinib 1500 mg + Letrozole 2.5 mg n=111 Participants Participants received 6 tablets of Lapatinib orally daily (250 mg lapatinib/tablet for a total of 1500 mg of lapatinib/day; approximately at the same time each day), either 1 hour (or more) before breakfast or 1 hour (or more) after breakfast. Participants also received 1 tablet of letrozole 2.5 mg orally daily, preferably with the daily dose of lapatinib.
Clinical Benefit (CB) in the HER2-Positive Population as Assessed by the Investigator	28.7 Months Interval 20.4 to 38.2	47.7 Months Interval 38.2 to 57.4

SECONDARY outcome

Timeframe: Up to 46 months

Population: HER2-Positive Population

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.

Outcome measures

Outcome measures
Measure	Placebo + Letrozole 2.5 mg n=108 Participants Participants received 6 tablets of placebo, identical in appearance to lapatinib tablets, orally daily (approximately at the same time each day), either 1 hour (or more) before breakfast or 1 hour (or more) after breakfast. Participants also received 1 tablet of letrozole 2.5 milligrams (mg) orally daily, preferably with the daily dose of lapatinib.	Lapatinib 1500 mg + Letrozole 2.5 mg n=111 Participants Participants received 6 tablets of Lapatinib orally daily (250 mg lapatinib/tablet for a total of 1500 mg of lapatinib/day; approximately at the same time each day), either 1 hour (or more) before breakfast or 1 hour (or more) after breakfast. Participants also received 1 tablet of letrozole 2.5 mg orally daily, preferably with the daily dose of lapatinib.
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	4 Participants	5 Participants
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. PR	12 Participants	26 Participants
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. SD	35 Participants	44 Participants
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. PD	49 Participants	30 Participants
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. Unknown	8 Participants	6 Participants

SECONDARY outcome

Timeframe: Up to 46 months

Population: ITT Population

Outcome measures

Outcome measures
Measure	Placebo + Letrozole 2.5 mg n=644 Participants Participants received 6 tablets of placebo, identical in appearance to lapatinib tablets, orally daily (approximately at the same time each day), either 1 hour (or more) before breakfast or 1 hour (or more) after breakfast. Participants also received 1 tablet of letrozole 2.5 milligrams (mg) orally daily, preferably with the daily dose of lapatinib.	Lapatinib 1500 mg + Letrozole 2.5 mg n=642 Participants Participants received 6 tablets of Lapatinib orally daily (250 mg lapatinib/tablet for a total of 1500 mg of lapatinib/day; approximately at the same time each day), either 1 hour (or more) before breakfast or 1 hour (or more) after breakfast. Participants also received 1 tablet of letrozole 2.5 mg orally daily, preferably with the daily dose of lapatinib.
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	26 Participants	28 Participants
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. PR	153 Participants	168 Participants
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. SD	243 Participants	280 Participants
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. PD	174 Participants	113 Participants
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. Unknown	48 Participants	53 Participants

SECONDARY outcome

Timeframe: Up to 46 months

Population: HER2-Positive Population. Only those participants with CR or PR were assessed.

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.

Outcome measures

Outcome measures
Measure	Placebo + Letrozole 2.5 mg n=16 Participants Participants received 6 tablets of placebo, identical in appearance to lapatinib tablets, orally daily (approximately at the same time each day), either 1 hour (or more) before breakfast or 1 hour (or more) after breakfast. Participants also received 1 tablet of letrozole 2.5 milligrams (mg) orally daily, preferably with the daily dose of lapatinib.	Lapatinib 1500 mg + Letrozole 2.5 mg n=31 Participants Participants received 6 tablets of Lapatinib orally daily (250 mg lapatinib/tablet for a total of 1500 mg of lapatinib/day; approximately at the same time each day), either 1 hour (or more) before breakfast or 1 hour (or more) after breakfast. Participants also received 1 tablet of letrozole 2.5 mg orally daily, preferably with the daily dose of lapatinib.
Number of Participants With the Indicated Time to Response for CR or PR in the HER2-Positive Population as Assessed by the Investigator Week 12	11 Participants	23 Participants
Number of Participants With the Indicated Time to Response for CR or PR in the HER2-Positive Population as Assessed by the Investigator Week 16	1 Participants	3 Participants
Number of Participants With the Indicated Time to Response for CR or PR in the HER2-Positive Population as Assessed by the Investigator Week 24 or longer	4 Participants	5 Participants

SECONDARY outcome

Timeframe: Up to 46 months

Population: HER2-Positive Population. Only those participants with CR or PR were assessed.

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.

Outcome measures

Outcome measures
Measure	Placebo + Letrozole 2.5 mg n=16 Participants Participants received 6 tablets of placebo, identical in appearance to lapatinib tablets, orally daily (approximately at the same time each day), either 1 hour (or more) before breakfast or 1 hour (or more) after breakfast. Participants also received 1 tablet of letrozole 2.5 milligrams (mg) orally daily, preferably with the daily dose of lapatinib.	Lapatinib 1500 mg + Letrozole 2.5 mg n=31 Participants Participants received 6 tablets of Lapatinib orally daily (250 mg lapatinib/tablet for a total of 1500 mg of lapatinib/day; approximately at the same time each day), either 1 hour (or more) before breakfast or 1 hour (or more) after breakfast. Participants also received 1 tablet of letrozole 2.5 mg orally daily, preferably with the daily dose of lapatinib.
Duration of Response for the Participants With CR or PR in the HER2-Positive Population as Assessed by the Investigator	84.4 weeks Interval 29.1 to NA: Not estimable due to insufficient number of participants with events	47.4 weeks Interval 25.1 to 108.0

SECONDARY outcome

Timeframe: Up to 46 months

Population: 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.

Outcome measures

Outcome measures
Measure	Placebo + Letrozole 2.5 mg n=108 Participants Participants received 6 tablets of placebo, identical in appearance to lapatinib tablets, orally daily (approximately at the same time each day), either 1 hour (or more) before breakfast or 1 hour (or more) after breakfast. Participants also received 1 tablet of letrozole 2.5 milligrams (mg) orally daily, preferably with the daily dose of lapatinib.	Lapatinib 1500 mg + Letrozole 2.5 mg n=111 Participants Participants received 6 tablets of Lapatinib orally daily (250 mg lapatinib/tablet for a total of 1500 mg of lapatinib/day; approximately at the same time each day), either 1 hour (or more) before breakfast or 1 hour (or more) after breakfast. Participants also received 1 tablet of letrozole 2.5 mg orally daily, preferably with the daily dose of lapatinib.
Number of Participants With Evidence of Brain Metastases in the HER2-Positive Population	2 participants	1 participants

SECONDARY outcome

Timeframe: Up to 46 months

Population: HER2-Positive Population. Only those participants who experienced disease progression or died due to breast cancer were assessed.

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.

Outcome measures

Outcome measures
Measure	Placebo + Letrozole 2.5 mg n=89 Participants Participants received 6 tablets of placebo, identical in appearance to lapatinib tablets, orally daily (approximately at the same time each day), either 1 hour (or more) before breakfast or 1 hour (or more) after breakfast. Participants also received 1 tablet of letrozole 2.5 milligrams (mg) orally daily, preferably with the daily dose of lapatinib.	Lapatinib 1500 mg + Letrozole 2.5 mg n=87 Participants Participants received 6 tablets of Lapatinib orally daily (250 mg lapatinib/tablet for a total of 1500 mg of lapatinib/day; approximately at the same time each day), either 1 hour (or more) before breakfast or 1 hour (or more) after breakfast. Participants also received 1 tablet of letrozole 2.5 mg orally daily, preferably with the daily dose of lapatinib.
Time to Progression (TTP) for the HER2-Positive Population as Assessed by the Investigator	13.0 weeks Interval 12.0 to 23.7	35.4 weeks Interval 24.1 to 39.4

SECONDARY outcome

Timeframe: From date of randomization until date of death due to any cause, assessed up to 46 months

Population: ITT Population. Only those participants who died during the study due to any cause were assessed.

Overall survival was defined as the time from randomization until death due to any cause.

Outcome measures

Outcome measures
Measure	Placebo + Letrozole 2.5 mg n=234 Participants Participants received 6 tablets of placebo, identical in appearance to lapatinib tablets, orally daily (approximately at the same time each day), either 1 hour (or more) before breakfast or 1 hour (or more) after breakfast. Participants also received 1 tablet of letrozole 2.5 milligrams (mg) orally daily, preferably with the daily dose of lapatinib.	Lapatinib 1500 mg + Letrozole 2.5 mg n=240 Participants Participants received 6 tablets of Lapatinib orally daily (250 mg lapatinib/tablet for a total of 1500 mg of lapatinib/day; approximately at the same time each day), either 1 hour (or more) before breakfast or 1 hour (or more) after breakfast. Participants also received 1 tablet of letrozole 2.5 mg orally daily, preferably with the daily dose of lapatinib.
Overall Survival in the ITT Population	176.3 weeks Interval 156.1 to 189.7	170.9 weeks Interval 157.7 to 196.3

SECONDARY outcome

Timeframe: Up to 46 months

Population: ITT Population. Only those participants who achieved either a confirmed CR or PR were assessed.

Outcome measures

Outcome measures
Measure	Placebo + Letrozole 2.5 mg n=644 Participants Participants received 6 tablets of placebo, identical in appearance to lapatinib tablets, orally daily (approximately at the same time each day), either 1 hour (or more) before breakfast or 1 hour (or more) after breakfast. Participants also received 1 tablet of letrozole 2.5 milligrams (mg) orally daily, preferably with the daily dose of lapatinib.	Lapatinib 1500 mg + Letrozole 2.5 mg n=642 Participants Participants received 6 tablets of Lapatinib orally daily (250 mg lapatinib/tablet for a total of 1500 mg of lapatinib/day; approximately at the same time each day), either 1 hour (or more) before breakfast or 1 hour (or more) after breakfast. Participants also received 1 tablet of letrozole 2.5 mg orally daily, preferably with the daily dose of lapatinib.
Overall Tumor Response (OR) for Participants With Measurable and Non-measurable Disease, Including Bone Scans, in the ITT Population as Assessed by the Investigator	27.8 percentage of participants	30.5 percentage of participants

SECONDARY outcome

Timeframe: Up to 46 months

Population: ITT Population. Only those participants with some measurable disease were assessed. Response with bone scan confirmation was required. Participants with bone-only disease were excluded from the analysis because bone-only disease is non-measurable only per RECIST 1.0.

Outcome measures

Outcome measures
Measure	Placebo + Letrozole 2.5 mg n=486 Participants Participants received 6 tablets of placebo, identical in appearance to lapatinib tablets, orally daily (approximately at the same time each day), either 1 hour (or more) before breakfast or 1 hour (or more) after breakfast. Participants also received 1 tablet of letrozole 2.5 milligrams (mg) orally daily, preferably with the daily dose of lapatinib.	Lapatinib 1500 mg + Letrozole 2.5 mg n=480 Participants Participants received 6 tablets of Lapatinib orally daily (250 mg lapatinib/tablet for a total of 1500 mg of lapatinib/day; approximately at the same time each day), either 1 hour (or more) before breakfast or 1 hour (or more) after breakfast. Participants also received 1 tablet of letrozole 2.5 mg orally daily, preferably with the daily dose of lapatinib.
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 SDS, Soft tissue or visceral	170 participants	190 participants
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 PAET, DI =>6 months	151 participants	168 participants
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 PAET, DI <6 months	19 participants	22 participants

SECONDARY outcome

Timeframe: Up to 46 months

Population: ITT Population

Outcome measures

Outcome measures
Measure	Placebo + Letrozole 2.5 mg n=644 Participants Participants received 6 tablets of placebo, identical in appearance to lapatinib tablets, orally daily (approximately at the same time each day), either 1 hour (or more) before breakfast or 1 hour (or more) after breakfast. Participants also received 1 tablet of letrozole 2.5 milligrams (mg) orally daily, preferably with the daily dose of lapatinib.	Lapatinib 1500 mg + Letrozole 2.5 mg n=642 Participants Participants received 6 tablets of Lapatinib orally daily (250 mg lapatinib/tablet for a total of 1500 mg of lapatinib/day; approximately at the same time each day), either 1 hour (or more) before breakfast or 1 hour (or more) after breakfast. Participants also received 1 tablet of letrozole 2.5 mg orally daily, preferably with the daily dose of lapatinib.
Clinical Benefit (CB) in the ITT Population as Assessed by the Investigator	50.6 percentage of participants	55.8 percentage of participants

SECONDARY outcome

Timeframe: Up to 46 months

Population: ITT Population. Only those participants with CR or PR were assessed.

Outcome measures

Outcome measures
Measure	Placebo + Letrozole 2.5 mg n=179 Participants Participants received 6 tablets of placebo, identical in appearance to lapatinib tablets, orally daily (approximately at the same time each day), either 1 hour (or more) before breakfast or 1 hour (or more) after breakfast. Participants also received 1 tablet of letrozole 2.5 milligrams (mg) orally daily, preferably with the daily dose of lapatinib.	Lapatinib 1500 mg + Letrozole 2.5 mg n=196 Participants Participants received 6 tablets of Lapatinib orally daily (250 mg lapatinib/tablet for a total of 1500 mg of lapatinib/day; approximately at the same time each day), either 1 hour (or more) before breakfast or 1 hour (or more) after breakfast. Participants also received 1 tablet of letrozole 2.5 mg orally daily, preferably with the daily dose of lapatinib.
Number of Participants With the Indicated Time to Response for CR or PR in the ITT Population as Assessed by the Investigator Week 12	76 participants	94 participants
Number of Participants With the Indicated Time to Response for CR or PR in the ITT Population as Assessed by the Investigator Week 16	21 participants	18 participants
Number of Participants With the Indicated Time to Response for CR or PR in the ITT Population as Assessed by the Investigator Week 24	28 participants	28 participants
Number of Participants With the Indicated Time to Response for CR or PR in the ITT Population as Assessed by the Investigator Week 28	17 participants	14 participants
Number of Participants With the Indicated Time to Response for CR or PR in the ITT Population as Assessed by the Investigator Week 36 or longer	37 participants	42 participants

SECONDARY outcome

Timeframe: Up to 46 months

Population: ITT Population. Only those participants with CR or PR response were assessed.

Outcome measures

Outcome measures
Measure	Placebo + Letrozole 2.5 mg n=179 Participants Participants received 6 tablets of placebo, identical in appearance to lapatinib tablets, orally daily (approximately at the same time each day), either 1 hour (or more) before breakfast or 1 hour (or more) after breakfast. Participants also received 1 tablet of letrozole 2.5 milligrams (mg) orally daily, preferably with the daily dose of lapatinib.	Lapatinib 1500 mg + Letrozole 2.5 mg n=196 Participants Participants received 6 tablets of Lapatinib orally daily (250 mg lapatinib/tablet for a total of 1500 mg of lapatinib/day; approximately at the same time each day), either 1 hour (or more) before breakfast or 1 hour (or more) after breakfast. Participants also received 1 tablet of letrozole 2.5 mg orally daily, preferably with the daily dose of lapatinib.
Duration of Response for the Participants With CR or PR in the ITT Population as Assessed by the Investigator	72.6 weeks Interval 39.1 to 145.7	60.1 weeks Interval 36.0 to 138.9

SECONDARY outcome

Timeframe: Up to 46 months

Population: ITT Population

Outcome measures

Outcome measures
Measure	Placebo + Letrozole 2.5 mg n=644 Participants Participants received 6 tablets of placebo, identical in appearance to lapatinib tablets, orally daily (approximately at the same time each day), either 1 hour (or more) before breakfast or 1 hour (or more) after breakfast. Participants also received 1 tablet of letrozole 2.5 milligrams (mg) orally daily, preferably with the daily dose of lapatinib.	Lapatinib 1500 mg + Letrozole 2.5 mg n=642 Participants Participants received 6 tablets of Lapatinib orally daily (250 mg lapatinib/tablet for a total of 1500 mg of lapatinib/day; approximately at the same time each day), either 1 hour (or more) before breakfast or 1 hour (or more) after breakfast. Participants also received 1 tablet of letrozole 2.5 mg orally daily, preferably with the daily dose of lapatinib.
Number of Participants With Evidence of Brain Metastases From the ITT Population	4 participants	6 participants

SECONDARY outcome

Timeframe: Up to 46 months

Population: ITT Population. Only those participants who experienced disease progression or died due to breast cancer were assessed.

Outcome measures

Outcome measures
Measure	Placebo + Letrozole 2.5 mg n=469 Participants Participants received 6 tablets of placebo, identical in appearance to lapatinib tablets, orally daily (approximately at the same time each day), either 1 hour (or more) before breakfast or 1 hour (or more) after breakfast. Participants also received 1 tablet of letrozole 2.5 milligrams (mg) orally daily, preferably with the daily dose of lapatinib.	Lapatinib 1500 mg + Letrozole 2.5 mg n=409 Participants Participants received 6 tablets of Lapatinib orally daily (250 mg lapatinib/tablet for a total of 1500 mg of lapatinib/day; approximately at the same time each day), either 1 hour (or more) before breakfast or 1 hour (or more) after breakfast. Participants also received 1 tablet of letrozole 2.5 mg orally daily, preferably with the daily dose of lapatinib.
TTP for Participants From the ITT Population as Assessed by the Investigator	47.0 weeks Interval 36.9 to 50.9	51.7 weeks Interval 47.6 to 59.6

SECONDARY outcome

Timeframe: 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

Population: ITT Population

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.

Outcome measures

Outcome measures
Measure	Placebo + Letrozole 2.5 mg n=644 Participants Participants received 6 tablets of placebo, identical in appearance to lapatinib tablets, orally daily (approximately at the same time each day), either 1 hour (or more) before breakfast or 1 hour (or more) after breakfast. Participants also received 1 tablet of letrozole 2.5 milligrams (mg) orally daily, preferably with the daily dose of lapatinib.	Lapatinib 1500 mg + Letrozole 2.5 mg n=642 Participants Participants received 6 tablets of Lapatinib orally daily (250 mg lapatinib/tablet for a total of 1500 mg of lapatinib/day; approximately at the same time each day), either 1 hour (or more) before breakfast or 1 hour (or more) after breakfast. Participants also received 1 tablet of letrozole 2.5 mg orally daily, preferably with the daily dose of lapatinib.
Number of Participants Completing the Functional Assessment of Cancer Therapy-breast (FACT-B) Questionnaire at the Scheduled Visits Day 1, baseline	605 Participants	605 Participants
Number of Participants Completing the Functional Assessment of Cancer Therapy-breast (FACT-B) Questionnaire at the Scheduled Visits Week 12	460 Participants	476 Participants
Number of Participants Completing the Functional Assessment of Cancer Therapy-breast (FACT-B) Questionnaire at the Scheduled Visits Week 24	350 Participants	382 Participants
Number of Participants Completing the Functional Assessment of Cancer Therapy-breast (FACT-B) Questionnaire at the Scheduled Visits Week 36	291 Participants	294 Participants
Number of Participants Completing the Functional Assessment of Cancer Therapy-breast (FACT-B) Questionnaire at the Scheduled Visits Week 48	254 Participants	243 Participants
Number of Participants Completing the Functional Assessment of Cancer Therapy-breast (FACT-B) Questionnaire at the Scheduled Visits Week 60	199 Participants	183 Participants
Number of Participants Completing the Functional Assessment of Cancer Therapy-breast (FACT-B) Questionnaire at the Scheduled Visits Week 72	181 Participants	153 Participants
Number of Participants Completing the Functional Assessment of Cancer Therapy-breast (FACT-B) Questionnaire at the Scheduled Visits Week 84	144 Participants	119 Participants
Number of Participants Completing the Functional Assessment of Cancer Therapy-breast (FACT-B) Questionnaire at the Scheduled Visits Week 96	117 Participants	98 Participants
Number of Participants Completing the Functional Assessment of Cancer Therapy-breast (FACT-B) Questionnaire at the Scheduled Visits Week 108	80 Participants	62 Participants
Number of Participants Completing the Functional Assessment of Cancer Therapy-breast (FACT-B) Questionnaire at the Scheduled Visits Week 120	59 Participants	56 Participants
Number of Participants Completing the Functional Assessment of Cancer Therapy-breast (FACT-B) Questionnaire at the Scheduled Visits Week 132	43 Participants	43 Participants
Number of Participants Completing the Functional Assessment of Cancer Therapy-breast (FACT-B) Questionnaire at the Scheduled Visits Week 144	33 Participants	33 Participants
Number of Participants Completing the Functional Assessment of Cancer Therapy-breast (FACT-B) Questionnaire at the Scheduled Visits Week 156	22 Participants	21 Participants
Number of Participants Completing the Functional Assessment of Cancer Therapy-breast (FACT-B) Questionnaire at the Scheduled Visits Week 168	15 Participants	11 Participants
Number of Participants Completing the Functional Assessment of Cancer Therapy-breast (FACT-B) Questionnaire at the Scheduled Visits Week 180	11 Participants	5 Participants
Number of Participants Completing the Functional Assessment of Cancer Therapy-breast (FACT-B) Questionnaire at the Scheduled Visits Week 192	6 Participants	1 Participants
Number of Participants Completing the Functional Assessment of Cancer Therapy-breast (FACT-B) Questionnaire at the Scheduled Visits Conclusion/withdrawal	327 Participants	359 Participants

SECONDARY outcome

Timeframe: Week 12, 24, 36, and 48 visits; conclusion/withdrawal visit

Population: HER2-Positive Population. Only those participants whose item response rate was greater than 80% were assessed.

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.

Outcome measures

Outcome measures
Measure	Placebo + Letrozole 2.5 mg n=61 Participants Participants received 6 tablets of placebo, identical in appearance to lapatinib tablets, orally daily (approximately at the same time each day), either 1 hour (or more) before breakfast or 1 hour (or more) after breakfast. Participants also received 1 tablet of letrozole 2.5 milligrams (mg) orally daily, preferably with the daily dose of lapatinib.	Lapatinib 1500 mg + Letrozole 2.5 mg n=78 Participants Participants received 6 tablets of Lapatinib orally daily (250 mg lapatinib/tablet for a total of 1500 mg of lapatinib/day; approximately at the same time each day), either 1 hour (or more) before breakfast or 1 hour (or more) after breakfast. Participants also received 1 tablet of letrozole 2.5 mg orally daily, preferably with the daily dose of lapatinib.
Adjusted Mean Change From Baseline for the FACT-B Total Score Using Observed Data Week 12	1.5 Adjusted mean change	3.3 Adjusted mean change
Adjusted Mean Change From Baseline for the FACT-B Total Score Using Observed Data Week 24	3.8 Adjusted mean change	1.9 Adjusted mean change
Adjusted Mean Change From Baseline for the FACT-B Total Score Using Observed Data Week 36	3.3 Adjusted mean change	1.4 Adjusted mean change
Adjusted Mean Change From Baseline for the FACT-B Total Score Using Observed Data Week 48	2.9 Adjusted mean change	0.3 Adjusted mean change
Adjusted Mean Change From Baseline for the FACT-B Total Score Using Observed Data Conclusion/WD	-9.4 Adjusted mean change	-9.0 Adjusted mean change

SECONDARY outcome

Timeframe: Week 12, 24, 36, and 48 visits; conclusion/withdrawal visit

Population: HER2-Positive Population. Only those participants whose item response rate was greater than 80% were assessed.

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.

Outcome measures

Outcome measures
Measure	Placebo + Letrozole 2.5 mg n=63 Participants Participants received 6 tablets of placebo, identical in appearance to lapatinib tablets, orally daily (approximately at the same time each day), either 1 hour (or more) before breakfast or 1 hour (or more) after breakfast. Participants also received 1 tablet of letrozole 2.5 milligrams (mg) orally daily, preferably with the daily dose of lapatinib.	Lapatinib 1500 mg + Letrozole 2.5 mg n=79 Participants Participants received 6 tablets of Lapatinib orally daily (250 mg lapatinib/tablet for a total of 1500 mg of lapatinib/day; approximately at the same time each day), either 1 hour (or more) before breakfast or 1 hour (or more) after breakfast. Participants also received 1 tablet of letrozole 2.5 mg orally daily, preferably with the daily dose of lapatinib.
Adjusted Mean Change From Baseline for the Functional Assessment of Cancer Therapy-General (FACT-G) Score Using Observed Data Week 12	1.6 Adjusted mean change	1.5 Adjusted mean change
Adjusted Mean Change From Baseline for the Functional Assessment of Cancer Therapy-General (FACT-G) Score Using Observed Data Week 24	2.2 Adjusted mean change	0.6 Adjusted mean change
Adjusted Mean Change From Baseline for the Functional Assessment of Cancer Therapy-General (FACT-G) Score Using Observed Data Week 36	2.6 Adjusted mean change	0.9 Adjusted mean change
Adjusted Mean Change From Baseline for the Functional Assessment of Cancer Therapy-General (FACT-G) Score Using Observed Data Week 48	2.0 Adjusted mean change	-0.9 Adjusted mean change
Adjusted Mean Change From Baseline for the Functional Assessment of Cancer Therapy-General (FACT-G) Score Using Observed Data Conclusion/WD	-7.8 Adjusted mean change	-8.5 Adjusted mean change

SECONDARY outcome

Timeframe: Week 12, 24, 36, and 48 visits; conclusion/withdrawal visit

Population: HER2-Positive Population. Only those participants whose item response rate was greater than 80% were assessed.

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.

Outcome measures

Outcome measures
Measure	Placebo + Letrozole 2.5 mg n=62 Participants Participants received 6 tablets of placebo, identical in appearance to lapatinib tablets, orally daily (approximately at the same time each day), either 1 hour (or more) before breakfast or 1 hour (or more) after breakfast. Participants also received 1 tablet of letrozole 2.5 milligrams (mg) orally daily, preferably with the daily dose of lapatinib.	Lapatinib 1500 mg + Letrozole 2.5 mg n=77 Participants Participants received 6 tablets of Lapatinib orally daily (250 mg lapatinib/tablet for a total of 1500 mg of lapatinib/day; approximately at the same time each day), either 1 hour (or more) before breakfast or 1 hour (or more) after breakfast. Participants also received 1 tablet of letrozole 2.5 mg orally daily, preferably with the daily dose of lapatinib.
Adjusted Mean Change From Baseline for the Trial Outcome Index (TOI) Score Using Observed Data Week 12	-0.3 Adjusted mean change	2.7 Adjusted mean change
Adjusted Mean Change From Baseline for the Trial Outcome Index (TOI) Score Using Observed Data Week 24	3.9 Adjusted mean change	2.0 Adjusted mean change
Adjusted Mean Change From Baseline for the Trial Outcome Index (TOI) Score Using Observed Data Week 36	3.3 Adjusted mean change	0.8 Adjusted mean change
Adjusted Mean Change From Baseline for the Trial Outcome Index (TOI) Score Using Observed Data Week 48	2.2 Adjusted mean change	-0.7 Adjusted mean change
Adjusted Mean Change From Baseline for the Trial Outcome Index (TOI) Score Using Observed Data Conclusion/WD	-6.2 Adjusted mean change	-6.4 Adjusted mean change

SECONDARY outcome

Timeframe: Up to 46 months

Population: HER2-Positive Population. Only those participants with a baseline score and at least one post-baseline score were assessed.

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.

Outcome measures

Outcome measures
Measure	Placebo + Letrozole 2.5 mg n=87 Participants Participants received 6 tablets of placebo, identical in appearance to lapatinib tablets, orally daily (approximately at the same time each day), either 1 hour (or more) before breakfast or 1 hour (or more) after breakfast. Participants also received 1 tablet of letrozole 2.5 milligrams (mg) orally daily, preferably with the daily dose of lapatinib.	Lapatinib 1500 mg + Letrozole 2.5 mg n=99 Participants Participants received 6 tablets of Lapatinib orally daily (250 mg lapatinib/tablet for a total of 1500 mg of lapatinib/day; approximately at the same time each day), either 1 hour (or more) before breakfast or 1 hour (or more) after breakfast. Participants also received 1 tablet of letrozole 2.5 mg orally daily, preferably with the daily dose of lapatinib.
Number of Participants Classified as QOL Responders Based on the FACT-B, FACT-G, and TOI Total Scores FACT-B total, =>8 (MID upper bound)	29 Participants	33 Participants
Number of Participants Classified as QOL Responders Based on the FACT-B, FACT-G, and TOI Total Scores FACT-G, =>6 (MID upper bound)	29 Participants	38 Participants
Number of Participants Classified as QOL Responders Based on the FACT-B, FACT-G, and TOI Total Scores TOI, =>6 (MID upper bound)	29 Participants	33 Participants

SECONDARY outcome

Timeframe: Up to 46 months

Population: ITT Population

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.

Outcome measures

Outcome measures
Measure	Placebo + Letrozole 2.5 mg n=644 Participants Participants received 6 tablets of placebo, identical in appearance to lapatinib tablets, orally daily (approximately at the same time each day), either 1 hour (or more) before breakfast or 1 hour (or more) after breakfast. Participants also received 1 tablet of letrozole 2.5 milligrams (mg) orally daily, preferably with the daily dose of lapatinib.	Lapatinib 1500 mg + Letrozole 2.5 mg n=642 Participants Participants received 6 tablets of Lapatinib orally daily (250 mg lapatinib/tablet for a total of 1500 mg of lapatinib/day; approximately at the same time each day), either 1 hour (or more) before breakfast or 1 hour (or more) after breakfast. Participants also received 1 tablet of letrozole 2.5 mg orally daily, preferably with the daily dose of lapatinib.
Number of Participants With Clinical Benefit Categorized by HER2 Fluorescence in Situ Hybridization (FISH) Status FISH status, Positive	28 Participants	49 Participants
Number of Participants With Clinical Benefit Categorized by HER2 Fluorescence in Situ Hybridization (FISH) Status FISH status, Negative	237 Participants	245 Participants
Number of Participants With Clinical Benefit Categorized by HER2 Fluorescence in Situ Hybridization (FISH) Status FISH status, missing	61 Participants	64 Participants

SECONDARY outcome

Timeframe: Up to 46 months

Population: ITT Population

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.

Outcome measures

Outcome measures
Measure	Placebo + Letrozole 2.5 mg n=644 Participants Participants received 6 tablets of placebo, identical in appearance to lapatinib tablets, orally daily (approximately at the same time each day), either 1 hour (or more) before breakfast or 1 hour (or more) after breakfast. Participants also received 1 tablet of letrozole 2.5 milligrams (mg) orally daily, preferably with the daily dose of lapatinib.	Lapatinib 1500 mg + Letrozole 2.5 mg n=642 Participants Participants received 6 tablets of Lapatinib orally daily (250 mg lapatinib/tablet for a total of 1500 mg of lapatinib/day; approximately at the same time each day), either 1 hour (or more) before breakfast or 1 hour (or more) after breakfast. Participants also received 1 tablet of letrozole 2.5 mg orally daily, preferably with the daily dose of lapatinib.
Number of Participants With Clinical Benefit Categorized by HER2 ImmunoHistoChemistry (IHC) Intensity IHC Intensity 2	94 Participants	85 Participants
Number of Participants With Clinical Benefit Categorized by HER2 ImmunoHistoChemistry (IHC) Intensity IHC Intensity 0	74 Participants	106 Participants
Number of Participants With Clinical Benefit Categorized by HER2 ImmunoHistoChemistry (IHC) Intensity IHC Intensity 1	108 Participants	106 Participants
Number of Participants With Clinical Benefit Categorized by HER2 ImmunoHistoChemistry (IHC) Intensity IHC Intensity 3	16 Participants	26 Participants
Number of Participants With Clinical Benefit Categorized by HER2 ImmunoHistoChemistry (IHC) Intensity IHC Intensity Missing	34 Participants	35 Participants

SECONDARY outcome

Timeframe: Up to 46 months

Population: HER2-Positive Population

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.

Outcome measures

Outcome measures
Measure	Placebo + Letrozole 2.5 mg n=108 Participants Participants received 6 tablets of placebo, identical in appearance to lapatinib tablets, orally daily (approximately at the same time each day), either 1 hour (or more) before breakfast or 1 hour (or more) after breakfast. Participants also received 1 tablet of letrozole 2.5 milligrams (mg) orally daily, preferably with the daily dose of lapatinib.	Lapatinib 1500 mg + Letrozole 2.5 mg n=111 Participants Participants received 6 tablets of Lapatinib orally daily (250 mg lapatinib/tablet for a total of 1500 mg of lapatinib/day; approximately at the same time each day), either 1 hour (or more) before breakfast or 1 hour (or more) after breakfast. Participants also received 1 tablet of letrozole 2.5 mg orally daily, preferably with the daily dose of lapatinib.
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 >15 ng/mL, CR/PR	3 Participants	9 Participants
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 >15 ng/mL, SD	11 Participants	13 Participants
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 >15 ng/mL, PD/NE	39 Participants	12 Participants
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 =<15 ng/mL, CR/PR	12 Participants	17 Participants
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 =<15 ng/mL, SD	23 Participants	30 Participants
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 =<15 ng/mL, PD/NE	16 Participants	23 Participants

SECONDARY outcome

Timeframe: Up to 46 months

Population: HER2-Negative Population: all randomized participants regardless of whether or not study treatment had been received and who at baseline were evaluated by the central laboratory to have retrospectively documented non-amplification or missing amplification of HER2 by FISH (\<2.0) and documented IHC scores of 0, 1+, 2+, or missing in tumor tissue.

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.

Outcome measures

Outcome measures
Measure	Placebo + Letrozole 2.5 mg n=474 Participants Participants received 6 tablets of placebo, identical in appearance to lapatinib tablets, orally daily (approximately at the same time each day), either 1 hour (or more) before breakfast or 1 hour (or more) after breakfast. Participants also received 1 tablet of letrozole 2.5 milligrams (mg) orally daily, preferably with the daily dose of lapatinib.	Lapatinib 1500 mg + Letrozole 2.5 mg n=478 Participants Participants received 6 tablets of Lapatinib orally daily (250 mg lapatinib/tablet for a total of 1500 mg of lapatinib/day; approximately at the same time each day), either 1 hour (or more) before breakfast or 1 hour (or more) after breakfast. Participants also received 1 tablet of letrozole 2.5 mg orally daily, preferably with the daily dose of lapatinib.
Number of HER2-Negative Participants at Baseline With and Without Seroconversion to a Status of HER2 Positive Seroconversion, No	323 Participants	140 Participants
Number of HER2-Negative Participants at Baseline With and Without Seroconversion to a Status of HER2 Positive Seroconversion, Yes	52 Participants	219 Participants
Number of HER2-Negative Participants at Baseline With and Without Seroconversion to a Status of HER2 Positive Missing	99 Participants	119 Participants

SECONDARY outcome

Timeframe: Up to 46 months

Population: HER2-Negative Population. Only those 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 were assessed.

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.

Outcome measures

Outcome measures
Measure	Placebo + Letrozole 2.5 mg n=52 Participants Participants received 6 tablets of placebo, identical in appearance to lapatinib tablets, orally daily (approximately at the same time each day), either 1 hour (or more) before breakfast or 1 hour (or more) after breakfast. Participants also received 1 tablet of letrozole 2.5 milligrams (mg) orally daily, preferably with the daily dose of lapatinib.	Lapatinib 1500 mg + Letrozole 2.5 mg n=219 Participants Participants received 6 tablets of Lapatinib orally daily (250 mg lapatinib/tablet for a total of 1500 mg of lapatinib/day; approximately at the same time each day), either 1 hour (or more) before breakfast or 1 hour (or more) after breakfast. Participants also received 1 tablet of letrozole 2.5 mg orally daily, preferably with the daily dose of lapatinib.
Time to Seroconversion for Participants Who Were HER2 Negative at Baseline But Became HER2 Positive	NA Weeks As \>80% of the participants were censored, no median or confidence intervals could be established.	36.1 Weeks Interval 24.0 to 48.9

SECONDARY outcome

Timeframe: Baseline

Population: ITT Population

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+).

Outcome measures

Outcome measures
Measure	Placebo + Letrozole 2.5 mg n=644 Participants Participants received 6 tablets of placebo, identical in appearance to lapatinib tablets, orally daily (approximately at the same time each day), either 1 hour (or more) before breakfast or 1 hour (or more) after breakfast. Participants also received 1 tablet of letrozole 2.5 milligrams (mg) orally daily, preferably with the daily dose of lapatinib.	Lapatinib 1500 mg + Letrozole 2.5 mg n=642 Participants Participants received 6 tablets of Lapatinib orally daily (250 mg lapatinib/tablet for a total of 1500 mg of lapatinib/day; approximately at the same time each day), either 1 hour (or more) before breakfast or 1 hour (or more) after breakfast. Participants also received 1 tablet of letrozole 2.5 mg orally daily, preferably with the daily dose of lapatinib.
Number of Participants With the Indicated Expression of Tumor by Epidermal Growth Factor Receptor (ErbB1/HER1/EGFR) at Baseline EGFR, 0	513 Participants	522 Participants
Number of Participants With the Indicated Expression of Tumor by Epidermal Growth Factor Receptor (ErbB1/HER1/EGFR) at Baseline EGFR, 1+	43 Participants	45 Participants
Number of Participants With the Indicated Expression of Tumor by Epidermal Growth Factor Receptor (ErbB1/HER1/EGFR) at Baseline EGFR, 2+	17 Participants	12 Participants
Number of Participants With the Indicated Expression of Tumor by Epidermal Growth Factor Receptor (ErbB1/HER1/EGFR) at Baseline EGFR, 3+	3 Participants	1 Participants

POST_HOC outcome

Timeframe: up to 663 weeks (on-treatment), up to approximately 14 years (study duration)

Population: Clinical database population; all treated patients.

On treatment deaths were collected from FPFT up to 30 days after study drug discontinuation, for a maximum duration of 663.9 weeks (treatment duration ranged from 0.1 to 659.9 weeks). Deaths post treatment survival follow up were collected after the on- treatment period, up to approximately 14 years. Patients who didn't die during the on-treatment period and had not stopped study participation at the time of data cut-off (end of study) were censored.

Outcome measures

Outcome measures
Measure	Placebo + Letrozole 2.5 mg n=624 Participants Participants received 6 tablets of placebo, identical in appearance to lapatinib tablets, orally daily (approximately at the same time each day), either 1 hour (or more) before breakfast or 1 hour (or more) after breakfast. Participants also received 1 tablet of letrozole 2.5 milligrams (mg) orally daily, preferably with the daily dose of lapatinib.	Lapatinib 1500 mg + Letrozole 2.5 mg n=654 Participants Participants received 6 tablets of Lapatinib orally daily (250 mg lapatinib/tablet for a total of 1500 mg of lapatinib/day; approximately at the same time each day), either 1 hour (or more) before breakfast or 1 hour (or more) after breakfast. Participants also received 1 tablet of letrozole 2.5 mg orally daily, preferably with the daily dose of lapatinib.
All Collected Deaths All deaths	484 Participants	488 Participants
All Collected Deaths On-treatment deaths	23 Participants	18 Participants

Adverse Events

Placebo + Letrozole 2.5 mg

Serious events: 103 serious events

Other events: 481 other events

Deaths: 23 deaths

Lapatinib 1500 mg + Letrozole 2.5 mg

Serious events: 150 serious events

Other events: 589 other events

Deaths: 18 deaths

Serious adverse events

Other adverse events

Additional Information

Study Director

Novartis Pharmaceuticals

Phone: 862-778-8300

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (ie, data from all sites) in the clinical trial.
Publication restrictions are in place

Restriction type: OTHER