Breast Neoplasms
Conditions
Keywords
Lapatinib, Letrozole, breast carcinoma, breast cancer, breast lump, HER2 positive metastatic breast cancer, breast cancer positive for human epidermal growth factor receptor 2, HER2, breast cancer progression, estrogen-receptor positive breast cancer, ER
Brief summary
This study evaluated and compared the efficacy and tolerability of lapatinib and letrozole, with letrozole and placebo in post-menopausal women with hormone receptor positive (ER positive and/or PgR positive) advanced or metastatic breast cancer, who had not received prior therapy for advanced or metastatic disease.
Detailed description
Subjects were randomly assigned to receive either lapatinib (1500 mg once daily orally) with letrozole (2.5 mg once daily orally), or letrozole (2.5 mg once daily orally) with placebo (which matched with lapatinib tablet). Randomization was stratified by site of disease (i.e., soft tissue/visceral disease versus bone only disease) and time since prior adjuvant endocrine therapy (\<6 months or ≥ 6 months from discontinuation of adjuvant anti-estrogen therapy (e.g. tamoxifen or raloxifene) or no prior adjuvant antiestrogen therapy). Study therapy was administered daily until disease progression (objective or symptomatic) or withdrawal from therapy (e.g., due to unacceptable toxicity, withdrawal of consent, or other reason). All subjects were to be followed for survival information until death. On 13 Apr 2015, after the introduction of the Long Term Follow UP (LTFU) phase (per protocol amendment 07), subjects receiving study treatment with lapatinib plus letrozole, or letrozole plus placebo had continued access to this study treatment until the occurrence of one of the following criteria: * Disease progression (as determined by the Investigator), * Intercurrent illness that prevented further administration of study treatment * Drug related AE which was considered by the investigator to warrant permanent discontinuation of study treatment * The subject decided to withdraw from the study. Investigators collected AEs and/or SAEs related to study participation, until 30 days following study treatment discontinuation. Subjects who were being followed-up for OS but were not taking study medication, were withdrawn from the study. The study was terminated on 22-Mar-2018 (last subject last visit).
Interventions
DRUGLapatinib
1500 mg orally once a day
DRUGLetrozole
2.5 mg orally once a day
DRUGPlacebo
Placebo (which matched with lapatinib tablet)
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key inclusion criteria 1. Signed informed consent; 2. Subjects with histologically confirmed invasive breast cancer with stage IV disease at primary diagnosis or at relapse after curative-intent surgery; * Subjects with either measurable or non-measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST). * If the disease was restricted to a solitary lesion, its neoplastic nature was confirmed by cytology or histology. 3. Tumors that were ER+ and/or PgR+; 4. Post-menopausal female subjects ≥ 18 years of age. 5. ECOG Performance Status of 0 or 1; 6. Subjects who had archived tumor tissue available to compare tumor response with intra-tumoral expression of ErbB1 and ErbB2. 7. Adjuvant therapy with an aromatase inhibitor and / or trastuzumab was allowed; however, treatment was to stop more than 1 year prior (\>12 months) to the first dose of randomized therapy. 8. Subjects must have ended hormonal replacement therapy (HRT) at least 1 month (30 days) prior to receiving the first dose of randomized therapy. Key
Exclusion criteria
1. Pre-menopausal, pregnant, or lactating; 2. Received prior chemotherapy, hormonal therapy, immunotherapy, biologic therapy, or anti-ErbB1/ErbB2 therapy for advanced or metastatic disease; 3. Bisphosphonate therapy for bone metastases was allowed; however, treatment was to be initiated prior to the first dose of randomized therapy. Prophylactic use of bisphosphonates in subjects without bone disease, except for the treatment of osteoporosis, was not permitted; 4. Used an investigational drug within 30 days or 5 half-lives, whichever is longer, preceding the first dose of randomized therapy (lapatinib or placebo); 5. Subjects with known history of/clinical evidence of CNS metastases or leptomeningeal carcinomatosis; and / or subjects on concurrent anti-cancer therapies other than letrozole; and / or who have not recovered from toxicities related to prior adjuvant therapy (surgery, radiotherapy, chemotherapy etc.) 6. Subjects with active or uncontrolled infection and/ or with history of uncontrolled or symptomatic angina, arrhythmias, or congestive heart failure.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 | 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 | 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. |
| Progression Free Survival (PFS) of Participants in the HER2-Positive Population as Assessed by the Investigator | 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 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival in the HER2-Positive Population | From date of randomization until date of death due to any cause, assessed up to 46 months | Overall survival was defined as the time from randomization until death due to any cause. |
| 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 | Up to 46 months | 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. |
| 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 | Up to 46 months | 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. |
| Clinical Benefit (CB) in the HER2-Positive Population as Assessed by the Investigator | Up to 46 months | 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. |
| Number of Participants With the Indicated Time to Response for CR or PR in the ITT Population as Assessed by the Investigator | Up to 46 months | 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. |
| 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. | Up to 46 months | 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. |
| 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. | Up to 46 months | 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. |
| Number of Participants With the Indicated Time to Response for CR or PR in the HER2-Positive Population as Assessed by the Investigator | Up to 46 months | 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. |
| Duration of Response for the Participants With CR or PR in the HER2-Positive Population as Assessed by the Investigator | Up to 46 months | 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. |
| Number of Participants With Evidence of Brain Metastases in the HER2-Positive Population | Up to 46 months | 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. |
| Time to Progression (TTP) for the HER2-Positive Population as Assessed by the Investigator | Up to 46 months | 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. |
| Overall Survival in the ITT Population | From date of randomization until date of death due to any cause, assessed up to 46 months | Overall survival was defined as the time from randomization until death due to any cause. |
| Overall Tumor Response (OR) for Participants With Measurable and Non-measurable Disease, Including Bone Scans, in the ITT Population as Assessed by the Investigator | Up to 46 months | 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. |
| 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 | Up to 46 months | Participants were stratified based on site of disease at screening (SDS) (soft tissue or visceral or bone-only disease) and prior adjuvant endocrine therapy (PAET) (discontinuation interval \[DI\] =\>6 months or DI \<6 months). OR is defined as the number of participants achieving either a confirmed CR or PR. Response was assessed via RECIST. CR: disappearance of all target lesions. PR: at least a 30% decrease in the sum of the LD of target lesions, taking as a reference the baseline sum LD. DI is defined as the time period from stopping the PEAT and the randomization date. |
| Number of Participants With PFS in the Intent-To-Treat (ITT) Population as Assessed by the Investigator | 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 | 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. |
| Duration of Response for the Participants With CR or PR in the ITT Population as Assessed by the Investigator | Up to 46 months | 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. |
| Number of Participants With Evidence of Brain Metastases From the ITT Population | Up to 46 months | 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. |
| TTP for Participants From the ITT Population as Assessed by the Investigator | Up to 46 months | 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. |
| Number of Participants Completing the Functional Assessment of Cancer Therapy-breast (FACT-B) Questionnaire at the Scheduled Visits | 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 | 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. |
| Adjusted Mean Change From Baseline for the FACT-B Total Score Using Observed Data | Week 12, 24, 36, and 48 visits; conclusion/withdrawal visit | 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. |
| Adjusted Mean Change From Baseline for the Functional Assessment of Cancer Therapy-General (FACT-G) Score Using Observed Data | Week 12, 24, 36, and 48 visits; conclusion/withdrawal visit | 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. |
| Adjusted Mean Change From Baseline for the Trial Outcome Index (TOI) Score Using Observed Data | Week 12, 24, 36, and 48 visits; conclusion/withdrawal visit | 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. |
| Number of Participants Classified as QOL Responders Based on the FACT-B, FACT-G, and TOI Total Scores | Up to 46 months | 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. |
| Number of Participants With Clinical Benefit Categorized by HER2 Fluorescence in Situ Hybridization (FISH) Status | Up to 46 months | 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. |
| Number of Participants With Clinical Benefit Categorized by HER2 ImmunoHistoChemistry (IHC) Intensity | Up to 46 months | 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. |
| 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 | Up to 46 months | 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. |
| Number of HER2-Negative Participants at Baseline With and Without Seroconversion to a Status of HER2 Positive | Up to 46 months | 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. |
| Time to Seroconversion for Participants Who Were HER2 Negative at Baseline But Became HER2 Positive | Up to 46 months | 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. |
| Number of Participants With the Indicated Expression of Tumor by Epidermal Growth Factor Receptor (ErbB1/HER1/EGFR) at Baseline | Baseline | EGFR is a cell surface receptor tyrosine kinase expressed in certain types of tumors. Depending upon the staining intensity, EGFR was graded as follows: 0=absence of membrane staining above background in all tumor cells; EGFR-positive=staining is defined as any IHC staining of tumor cell membranes above background level, whether it is complete or incomplete circumferential staining (1+, 2+, 3+). |
| Clinical Benefit (CB) in the ITT Population as Assessed by the Investigator | Up to 46 months | 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. |
| PFS in Participants in the ITT Population as Assessed by the Investigator | 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 | 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. |
Countries
Argentina, Australia, Brazil, Bulgaria, Canada, Chile, Colombia, Croatia, Czechia, Denmark, France, Germany, Hungary, Ireland, Italy, Mexico, Netherlands, New Zealand, Pakistan, Peru, Poland, Russia, South Africa, South Korea, Spain, Tunisia, Turkey (Türkiye), United Kingdom, United States
Participant flow
Recruitment details
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).
Participants by arm
| Arm | Count |
|---|---|
| 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. | 644 |
| 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. | 642 |
| Total | 1,286 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 488 | 473 |
| Overall Study | Lost to Follow-up | 52 | 45 |
| Overall Study | Other | 18 | 19 |
| Overall Study | Protocol Violation | 3 | 5 |
| Overall Study | Study terminated by Sponsor | 10 | 29 |
| Overall Study | Withdrawal by Subject | 50 | 45 |
Baseline characteristics
| Characteristic | Placebo + Letrozole 2.5 mg | Lapatinib 1500 mg + Letrozole 2.5 mg | Total |
|---|---|---|---|
| Age, Continuous | 63.3 Years STANDARD_DEVIATION 9.95 | 62.8 Years STANDARD_DEVIATION 9.7 | 63.1 Years STANDARD_DEVIATION 9.83 |
| Race/Ethnicity, Customized American Hispanic | 44 Participants | 57 Participants | 101 Participants |
| Race/Ethnicity, Customized Asian | 30 Participants | 30 Participants | 60 Participants |
| Race/Ethnicity, Customized Black | 10 Participants | 17 Participants | 27 Participants |
| Race/Ethnicity, Customized Other | 3 Participants | 9 Participants | 12 Participants |
| Race/Ethnicity, Customized White | 557 Participants | 529 Participants | 1086 Participants |
| Sex: Female, Male Female | 644 Participants | 642 Participants | 1286 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 23 / 624 | 18 / 654 |
| other Total, other adverse events | 481 / 624 | 589 / 654 |
| serious Total, serious adverse events | 103 / 624 | 150 / 654 |
Outcome results
Primary
Number of Participants With Progression Free Survival (PFS) in the Human Epidermal Growth Factor Receptor 2 (HER2)-Positive Advanced or Metastatic Breast Cancer as Assessed by the Investigator
PFS is defined as the time from randomization until the earliest date of disease progression (PD) or death due to any cause, if sooner. The date of documented PD is defined as the date of radiological PD as assessed by the investigator based on imaging data and also by the clinical assessment of symptomatic progression. Per Response Evaluation Criteria in Solid Tumors (RECIST 1.0), PD is defined as a 20% increase in the sum of the longest diameter (LD) of target lesions, taking as a reference the smallest sum LD recorded since the treatment started, or the appearance of 1 or more new lesions.
Time frame: 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.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo + Letrozole 2.5 mg | 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 |
| Lapatinib 1500 mg + Letrozole 2.5 mg | 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 | 88 Participants |
p-value: 0.01995% CI: [0.53, 0.96]Log Rank
Primary
Progression Free Survival (PFS) of Participants in the HER2-Positive Population as Assessed by the Investigator
PFS is defined as the time from randomization until the earliest date of disease progression or death due to any cause, if sooner. The date of documented disease progression is defined as the date of radiological disease progression as assessed by the investigator based on imaging data and also by the clinical assessment of symptomatic progression. Per RECIST 1.0, disease progression is defined as a 20% increase in the sum of the LD of target lesions, taking as a reference the smallest sum LD recorded since the treatment started, or the appearance of 1 or more new lesions.
Time frame: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo + Letrozole 2.5 mg | Progression Free Survival (PFS) of Participants in the HER2-Positive Population as Assessed by the Investigator | 13.0 Weeks |
| Lapatinib 1500 mg + Letrozole 2.5 mg | Progression Free Survival (PFS) of Participants in the HER2-Positive Population as Assessed by the Investigator | 35.4 Weeks |
p-value: 0.01995% CI: [0.53, 0.96]Log Rank
Secondary
Adjusted Mean Change From Baseline for the FACT-B Total Score Using Observed Data
Quality of Life (QOL) was assessed using the FACT-B questionnaire, which is a 37-item (27 general and 10 breast cancer-specific questions) self-reporting instrument consisting of 5 dimensions: physical-, social/family-, emotional-, functional-well being, and a breast cancer subscale. Higher scores on the FACT-B scales indicate a higher QOL; each ranging from 0 (not at all) to 4 (very much). The score is transformed for FACT-B and results in a total score ranging from 0 to 144. The FACT-B is designed to measure multidimensional QOL in participants with breast cancer.
Time frame: 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.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo + Letrozole 2.5 mg | Adjusted Mean Change From Baseline for the FACT-B Total Score Using Observed Data | Week 24 | 3.8 Adjusted mean change |
| Placebo + Letrozole 2.5 mg | Adjusted Mean Change From Baseline for the FACT-B Total Score Using Observed Data | Week 48 | 2.9 Adjusted mean change |
| Placebo + Letrozole 2.5 mg | Adjusted Mean Change From Baseline for the FACT-B Total Score Using Observed Data | Week 36 | 3.3 Adjusted mean change |
| Placebo + Letrozole 2.5 mg | Adjusted Mean Change From Baseline for the FACT-B Total Score Using Observed Data | Conclusion/WD | -9.4 Adjusted mean change |
| Placebo + Letrozole 2.5 mg | Adjusted Mean Change From Baseline for the FACT-B Total Score Using Observed Data | Week 12 | 1.5 Adjusted mean change |
| Lapatinib 1500 mg + Letrozole 2.5 mg | Adjusted Mean Change From Baseline for the FACT-B Total Score Using Observed Data | Conclusion/WD | -9.0 Adjusted mean change |
| Lapatinib 1500 mg + Letrozole 2.5 mg | Adjusted Mean Change From Baseline for the FACT-B Total Score Using Observed Data | Week 12 | 3.3 Adjusted mean change |
| Lapatinib 1500 mg + Letrozole 2.5 mg | Adjusted Mean Change From Baseline for the FACT-B Total Score Using Observed Data | Week 24 | 1.9 Adjusted mean change |
| Lapatinib 1500 mg + Letrozole 2.5 mg | Adjusted Mean Change From Baseline for the FACT-B Total Score Using Observed Data | Week 36 | 1.4 Adjusted mean change |
| Lapatinib 1500 mg + Letrozole 2.5 mg | Adjusted Mean Change From Baseline for the FACT-B Total Score Using Observed Data | Week 48 | 0.3 Adjusted mean change |
Secondary
Adjusted Mean Change From Baseline for the Functional Assessment of Cancer Therapy-General (FACT-G) Score Using Observed Data
FACT-G is a subscale of the FACT-B QOL questionnaire and consists of 27 questions grouped into 4 domains that measure a participant's physical, functional, social and family, and emotional well-being. FACT-G is assessed on a five-point Likert-type scale, with scores ranging from 0 to 4 (0=not at all, 1=a little bit, 2=somewhat, 3=quite a bit, 4=very much). The total score is calculated as the sum of the item scores on the subscale; the total ranges from 0 to 108, with higher score indicating a better quality of life.
Time frame: 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.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo + Letrozole 2.5 mg | 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 |
| Placebo + Letrozole 2.5 mg | 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 |
| Placebo + Letrozole 2.5 mg | 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 |
| Placebo + Letrozole 2.5 mg | 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 |
| Placebo + Letrozole 2.5 mg | 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 |
| Lapatinib 1500 mg + Letrozole 2.5 mg | Adjusted Mean Change From Baseline for the Functional Assessment of Cancer Therapy-General (FACT-G) Score Using Observed Data | Conclusion/WD | -8.5 Adjusted mean change |
| Lapatinib 1500 mg + Letrozole 2.5 mg | Adjusted Mean Change From Baseline for the Functional Assessment of Cancer Therapy-General (FACT-G) Score Using Observed Data | Week 12 | 1.5 Adjusted mean change |
| Lapatinib 1500 mg + Letrozole 2.5 mg | Adjusted Mean Change From Baseline for the Functional Assessment of Cancer Therapy-General (FACT-G) Score Using Observed Data | Week 24 | 0.6 Adjusted mean change |
| Lapatinib 1500 mg + Letrozole 2.5 mg | Adjusted Mean Change From Baseline for the Functional Assessment of Cancer Therapy-General (FACT-G) Score Using Observed Data | Week 36 | 0.9 Adjusted mean change |
| Lapatinib 1500 mg + Letrozole 2.5 mg | Adjusted Mean Change From Baseline for the Functional Assessment of Cancer Therapy-General (FACT-G) Score Using Observed Data | Week 48 | -0.9 Adjusted mean change |
Secondary
Adjusted Mean Change From Baseline for the Trial Outcome Index (TOI) Score Using Observed Data
The TOI score is the sum of the physical well-being, functional well-being, and breast cancer unweighted subscale scores. The total TOI score ranges from 0 to 92, with higher scores representing a better quality of life.
Time frame: 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.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo + Letrozole 2.5 mg | Adjusted Mean Change From Baseline for the Trial Outcome Index (TOI) Score Using Observed Data | Week 24 | 3.9 Adjusted mean change |
| Placebo + Letrozole 2.5 mg | Adjusted Mean Change From Baseline for the Trial Outcome Index (TOI) Score Using Observed Data | Week 48 | 2.2 Adjusted mean change |
| Placebo + Letrozole 2.5 mg | Adjusted Mean Change From Baseline for the Trial Outcome Index (TOI) Score Using Observed Data | Week 36 | 3.3 Adjusted mean change |
| Placebo + Letrozole 2.5 mg | Adjusted Mean Change From Baseline for the Trial Outcome Index (TOI) Score Using Observed Data | Conclusion/WD | -6.2 Adjusted mean change |
| Placebo + Letrozole 2.5 mg | Adjusted Mean Change From Baseline for the Trial Outcome Index (TOI) Score Using Observed Data | Week 12 | -0.3 Adjusted mean change |
| Lapatinib 1500 mg + Letrozole 2.5 mg | Adjusted Mean Change From Baseline for the Trial Outcome Index (TOI) Score Using Observed Data | Conclusion/WD | -6.4 Adjusted mean change |
| Lapatinib 1500 mg + Letrozole 2.5 mg | Adjusted Mean Change From Baseline for the Trial Outcome Index (TOI) Score Using Observed Data | Week 12 | 2.7 Adjusted mean change |
| Lapatinib 1500 mg + Letrozole 2.5 mg | Adjusted Mean Change From Baseline for the Trial Outcome Index (TOI) Score Using Observed Data | Week 24 | 2.0 Adjusted mean change |
| Lapatinib 1500 mg + Letrozole 2.5 mg | Adjusted Mean Change From Baseline for the Trial Outcome Index (TOI) Score Using Observed Data | Week 36 | 0.8 Adjusted mean change |
| Lapatinib 1500 mg + Letrozole 2.5 mg | Adjusted Mean Change From Baseline for the Trial Outcome Index (TOI) Score Using Observed Data | Week 48 | -0.7 Adjusted mean change |
Secondary
Clinical Benefit (CB) in the HER2-Positive Population as Assessed by the Investigator
CB is defined as the percentage of participants with evidence of confirmed CR, PR, or stable disease (SD) for at least 6 months. CR: disappearance of all target lesions. PR: at least a 30% decrease in the sum of the LD of target lesions, taking as a reference the baseline sum LD. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the baseline measurement.
Time frame: Up to 46 months
Population: HER2-Positive Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo + Letrozole 2.5 mg | Clinical Benefit (CB) in the HER2-Positive Population as Assessed by the Investigator | 28.7 Months |
| Lapatinib 1500 mg + Letrozole 2.5 mg | Clinical Benefit (CB) in the HER2-Positive Population as Assessed by the Investigator | 47.7 Months |
Secondary
Clinical Benefit (CB) in the ITT Population as Assessed by the Investigator
CB is defined as the percentage of participants with evidence of confirmed CR, PR, or stable disease (SD) for at least 6 months. CR: disappearance of all target lesions. PR: at least a 30% decrease in the sum of the LD of target lesions, taking as a reference the baseline sum LD. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the baseline measurement.
Time frame: Up to 46 months
Population: ITT Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo + Letrozole 2.5 mg | Clinical Benefit (CB) in the ITT Population as Assessed by the Investigator | 50.6 percentage of participants |
| Lapatinib 1500 mg + Letrozole 2.5 mg | Clinical Benefit (CB) in the ITT Population as Assessed by the Investigator | 55.8 percentage of participants |
Secondary
Duration of Response for the Participants With CR or PR in the HER2-Positive Population as Assessed by the Investigator
Duration of response is defined as the time from the first documented evidence of CR (disappearance of all target lesions) or PR (at least a 30% decrease in the sum of the LD of target lesions, taking as a reference the baseline sum LD) until the first documented sign of disease progression or death due to any cause. The assessments of CR or PR required confirmation using bone scans.
Time frame: Up to 46 months
Population: HER2-Positive Population. Only those participants with CR or PR were assessed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo + Letrozole 2.5 mg | Duration of Response for the Participants With CR or PR in the HER2-Positive Population as Assessed by the Investigator | 84.4 weeks |
| Lapatinib 1500 mg + Letrozole 2.5 mg | Duration of Response for the Participants With CR or PR in the HER2-Positive Population as Assessed by the Investigator | 47.4 weeks |
Secondary
Duration of Response for the Participants With CR or PR in the ITT Population as Assessed by the Investigator
Duration of response is defined as the time from the first documented evidence of CR (disappearance of all target lesions) or PR (at least a 30% decrease in the sum of the LD of target lesions, taking as a reference the baseline sum LD) until the first documented sign of disease progression or death due to any cause. The assessments of CR or PR required confirmation using bone scans.
Time frame: Up to 46 months
Population: ITT Population. Only those participants with CR or PR response were assessed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo + Letrozole 2.5 mg | Duration of Response for the Participants With CR or PR in the ITT Population as Assessed by the Investigator | 72.6 weeks |
| Lapatinib 1500 mg + Letrozole 2.5 mg | Duration of Response for the Participants With CR or PR in the ITT Population as Assessed by the Investigator | 60.1 weeks |
Secondary
Number of HER2-Negative Participants at Baseline With and Without Seroconversion to a Status of HER2 Positive
Participants who had a HER2-negative tumor status based on baseline tissue with baseline serum HER2 ECD values =\<15 ng/mL but later had at least two consecutive serum HER2 ECD values \>15 ng/mL experienced seroconversion.
Time frame: 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.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo + Letrozole 2.5 mg | Number of HER2-Negative Participants at Baseline With and Without Seroconversion to a Status of HER2 Positive | Seroconversion, No | 323 Participants |
| Placebo + Letrozole 2.5 mg | Number of HER2-Negative Participants at Baseline With and Without Seroconversion to a Status of HER2 Positive | Seroconversion, Yes | 52 Participants |
| Placebo + Letrozole 2.5 mg | Number of HER2-Negative Participants at Baseline With and Without Seroconversion to a Status of HER2 Positive | Missing | 99 Participants |
| Lapatinib 1500 mg + Letrozole 2.5 mg | Number of HER2-Negative Participants at Baseline With and Without Seroconversion to a Status of HER2 Positive | Seroconversion, No | 140 Participants |
| Lapatinib 1500 mg + Letrozole 2.5 mg | Number of HER2-Negative Participants at Baseline With and Without Seroconversion to a Status of HER2 Positive | Seroconversion, Yes | 219 Participants |
| Lapatinib 1500 mg + Letrozole 2.5 mg | Number of HER2-Negative Participants at Baseline With and Without Seroconversion to a Status of HER2 Positive | Missing | 119 Participants |
Secondary
Number of Participants Classified as QOL Responders Based on the FACT-B, FACT-G, and TOI Total Scores
A minimally important difference (MID) is the smallest difference in a score for a measure of QOL that corresponds to a difference in function or clinical course. Responders are defined as participants with an MID =\> 8 for the FACT-B score, and an MID =\>6 for the FACT-G and TOI scores.
Time frame: Up to 46 months
Population: HER2-Positive Population. Only those participants with a baseline score and at least one post-baseline score were assessed.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo + Letrozole 2.5 mg | 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 |
| Placebo + Letrozole 2.5 mg | 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 |
| Placebo + Letrozole 2.5 mg | 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 |
| Lapatinib 1500 mg + Letrozole 2.5 mg | 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) | 33 Participants |
| Lapatinib 1500 mg + Letrozole 2.5 mg | Number of Participants Classified as QOL Responders Based on the FACT-B, FACT-G, and TOI Total Scores | FACT-G, =>6 (MID upper bound) | 38 Participants |
| Lapatinib 1500 mg + Letrozole 2.5 mg | Number of Participants Classified as QOL Responders Based on the FACT-B, FACT-G, and TOI Total Scores | TOI, =>6 (MID upper bound) | 33 Participants |
Secondary
Number of Participants Completing the Functional Assessment of Cancer Therapy-breast (FACT-B) Questionnaire at the Scheduled Visits
Quality of Life (QOL) was assessed using the FACT-B questionnaire, which was a 37-item (27 general and 10 breast cancer-specific questions) self-reporting instrument consisting of 5 dimensions: physical-, social/family-, emotional-, functional-well being, and a breast cancer subscale. Higher scores on the FACT-B scales (each ranging from 0 \[not at all\] to 4 \[very much\]) indicate a higher QOL. The score is transformed for FACT-B and results in a total score ranging from 0 to 144. Complete: completing at least 1 question from FACT-B.
Time frame: 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
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo + Letrozole 2.5 mg | Number of Participants Completing the Functional Assessment of Cancer Therapy-breast (FACT-B) Questionnaire at the Scheduled Visits | Day 1, baseline | 605 Participants |
| Placebo + Letrozole 2.5 mg | Number of Participants Completing the Functional Assessment of Cancer Therapy-breast (FACT-B) Questionnaire at the Scheduled Visits | Week 12 | 460 Participants |
| Placebo + Letrozole 2.5 mg | Number of Participants Completing the Functional Assessment of Cancer Therapy-breast (FACT-B) Questionnaire at the Scheduled Visits | Week 24 | 350 Participants |
| Placebo + Letrozole 2.5 mg | Number of Participants Completing the Functional Assessment of Cancer Therapy-breast (FACT-B) Questionnaire at the Scheduled Visits | Week 36 | 291 Participants |
| Placebo + Letrozole 2.5 mg | Number of Participants Completing the Functional Assessment of Cancer Therapy-breast (FACT-B) Questionnaire at the Scheduled Visits | Week 48 | 254 Participants |
| Placebo + Letrozole 2.5 mg | Number of Participants Completing the Functional Assessment of Cancer Therapy-breast (FACT-B) Questionnaire at the Scheduled Visits | Week 60 | 199 Participants |
| Placebo + Letrozole 2.5 mg | Number of Participants Completing the Functional Assessment of Cancer Therapy-breast (FACT-B) Questionnaire at the Scheduled Visits | Week 72 | 181 Participants |
| Placebo + Letrozole 2.5 mg | Number of Participants Completing the Functional Assessment of Cancer Therapy-breast (FACT-B) Questionnaire at the Scheduled Visits | Week 84 | 144 Participants |
| Placebo + Letrozole 2.5 mg | Number of Participants Completing the Functional Assessment of Cancer Therapy-breast (FACT-B) Questionnaire at the Scheduled Visits | Week 96 | 117 Participants |
| Placebo + Letrozole 2.5 mg | Number of Participants Completing the Functional Assessment of Cancer Therapy-breast (FACT-B) Questionnaire at the Scheduled Visits | Week 108 | 80 Participants |
| Placebo + Letrozole 2.5 mg | Number of Participants Completing the Functional Assessment of Cancer Therapy-breast (FACT-B) Questionnaire at the Scheduled Visits | Week 120 | 59 Participants |
| Placebo + Letrozole 2.5 mg | Number of Participants Completing the Functional Assessment of Cancer Therapy-breast (FACT-B) Questionnaire at the Scheduled Visits | Week 132 | 43 Participants |
| Placebo + Letrozole 2.5 mg | Number of Participants Completing the Functional Assessment of Cancer Therapy-breast (FACT-B) Questionnaire at the Scheduled Visits | Week 144 | 33 Participants |
| Placebo + Letrozole 2.5 mg | Number of Participants Completing the Functional Assessment of Cancer Therapy-breast (FACT-B) Questionnaire at the Scheduled Visits | Week 156 | 22 Participants |
| Placebo + Letrozole 2.5 mg | Number of Participants Completing the Functional Assessment of Cancer Therapy-breast (FACT-B) Questionnaire at the Scheduled Visits | Week 168 | 15 Participants |
| Placebo + Letrozole 2.5 mg | Number of Participants Completing the Functional Assessment of Cancer Therapy-breast (FACT-B) Questionnaire at the Scheduled Visits | Week 180 | 11 Participants |
| Placebo + Letrozole 2.5 mg | Number of Participants Completing the Functional Assessment of Cancer Therapy-breast (FACT-B) Questionnaire at the Scheduled Visits | Week 192 | 6 Participants |
| Placebo + Letrozole 2.5 mg | Number of Participants Completing the Functional Assessment of Cancer Therapy-breast (FACT-B) Questionnaire at the Scheduled Visits | Conclusion/withdrawal | 327 Participants |
| Lapatinib 1500 mg + Letrozole 2.5 mg | Number of Participants Completing the Functional Assessment of Cancer Therapy-breast (FACT-B) Questionnaire at the Scheduled Visits | Week 156 | 21 Participants |
| Lapatinib 1500 mg + Letrozole 2.5 mg | Number of Participants Completing the Functional Assessment of Cancer Therapy-breast (FACT-B) Questionnaire at the Scheduled Visits | Day 1, baseline | 605 Participants |
| Lapatinib 1500 mg + Letrozole 2.5 mg | Number of Participants Completing the Functional Assessment of Cancer Therapy-breast (FACT-B) Questionnaire at the Scheduled Visits | Week 108 | 62 Participants |
| Lapatinib 1500 mg + Letrozole 2.5 mg | Number of Participants Completing the Functional Assessment of Cancer Therapy-breast (FACT-B) Questionnaire at the Scheduled Visits | Week 12 | 476 Participants |
| Lapatinib 1500 mg + Letrozole 2.5 mg | Number of Participants Completing the Functional Assessment of Cancer Therapy-breast (FACT-B) Questionnaire at the Scheduled Visits | Conclusion/withdrawal | 359 Participants |
| Lapatinib 1500 mg + Letrozole 2.5 mg | Number of Participants Completing the Functional Assessment of Cancer Therapy-breast (FACT-B) Questionnaire at the Scheduled Visits | Week 24 | 382 Participants |
| Lapatinib 1500 mg + Letrozole 2.5 mg | Number of Participants Completing the Functional Assessment of Cancer Therapy-breast (FACT-B) Questionnaire at the Scheduled Visits | Week 120 | 56 Participants |
| Lapatinib 1500 mg + Letrozole 2.5 mg | Number of Participants Completing the Functional Assessment of Cancer Therapy-breast (FACT-B) Questionnaire at the Scheduled Visits | Week 36 | 294 Participants |
| Lapatinib 1500 mg + Letrozole 2.5 mg | Number of Participants Completing the Functional Assessment of Cancer Therapy-breast (FACT-B) Questionnaire at the Scheduled Visits | Week 168 | 11 Participants |
| Lapatinib 1500 mg + Letrozole 2.5 mg | Number of Participants Completing the Functional Assessment of Cancer Therapy-breast (FACT-B) Questionnaire at the Scheduled Visits | Week 48 | 243 Participants |
| Lapatinib 1500 mg + Letrozole 2.5 mg | Number of Participants Completing the Functional Assessment of Cancer Therapy-breast (FACT-B) Questionnaire at the Scheduled Visits | Week 132 | 43 Participants |
| Lapatinib 1500 mg + Letrozole 2.5 mg | Number of Participants Completing the Functional Assessment of Cancer Therapy-breast (FACT-B) Questionnaire at the Scheduled Visits | Week 60 | 183 Participants |
| Lapatinib 1500 mg + Letrozole 2.5 mg | Number of Participants Completing the Functional Assessment of Cancer Therapy-breast (FACT-B) Questionnaire at the Scheduled Visits | Week 192 | 1 Participants |
| Lapatinib 1500 mg + Letrozole 2.5 mg | Number of Participants Completing the Functional Assessment of Cancer Therapy-breast (FACT-B) Questionnaire at the Scheduled Visits | Week 72 | 153 Participants |
| Lapatinib 1500 mg + Letrozole 2.5 mg | Number of Participants Completing the Functional Assessment of Cancer Therapy-breast (FACT-B) Questionnaire at the Scheduled Visits | Week 144 | 33 Participants |
| Lapatinib 1500 mg + Letrozole 2.5 mg | Number of Participants Completing the Functional Assessment of Cancer Therapy-breast (FACT-B) Questionnaire at the Scheduled Visits | Week 84 | 119 Participants |
| Lapatinib 1500 mg + Letrozole 2.5 mg | Number of Participants Completing the Functional Assessment of Cancer Therapy-breast (FACT-B) Questionnaire at the Scheduled Visits | Week 180 | 5 Participants |
| Lapatinib 1500 mg + Letrozole 2.5 mg | Number of Participants Completing the Functional Assessment of Cancer Therapy-breast (FACT-B) Questionnaire at the Scheduled Visits | Week 96 | 98 Participants |
Secondary
Number of Participants With Clinical Benefit Categorized by HER2 Fluorescence in Situ Hybridization (FISH) Status
Clinical benefit: participants with CR, PR, or SD for =\>6-month period. FISH testing measures the amount of the HER2 gene in each cell. This gene is responsible for the overproduction of the HER2 protein. FISH-positive: excessive amounts of the gene are present; FISH-negative: normal levels of the gene are present.
Time frame: Up to 46 months
Population: ITT Population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo + Letrozole 2.5 mg | Number of Participants With Clinical Benefit Categorized by HER2 Fluorescence in Situ Hybridization (FISH) Status | FISH status, Positive | 28 Participants |
| Placebo + Letrozole 2.5 mg | Number of Participants With Clinical Benefit Categorized by HER2 Fluorescence in Situ Hybridization (FISH) Status | FISH status, Negative | 237 Participants |
| Placebo + Letrozole 2.5 mg | Number of Participants With Clinical Benefit Categorized by HER2 Fluorescence in Situ Hybridization (FISH) Status | FISH status, missing | 61 Participants |
| Lapatinib 1500 mg + Letrozole 2.5 mg | Number of Participants With Clinical Benefit Categorized by HER2 Fluorescence in Situ Hybridization (FISH) Status | FISH status, Positive | 49 Participants |
| Lapatinib 1500 mg + Letrozole 2.5 mg | Number of Participants With Clinical Benefit Categorized by HER2 Fluorescence in Situ Hybridization (FISH) Status | FISH status, Negative | 245 Participants |
| Lapatinib 1500 mg + Letrozole 2.5 mg | Number of Participants With Clinical Benefit Categorized by HER2 Fluorescence in Situ Hybridization (FISH) Status | FISH status, missing | 64 Participants |
Secondary
Number of Participants With Clinical Benefit Categorized by HER2 ImmunoHistoChemistry (IHC) Intensity
IHC is a commonly used test to assess the amount of the HER2 receptor protein on the surface of the cancer cells. The IHC test results in a score of 0 to 3+, which indicates the amount of HER2 receptor protein on the cells in a sample of breast cancer tissue. Tissue scores of 0 to 1+ indicate HER2 negativity; scores of 2+ and 3+ indicate HER2 positivity. Clinical benefit is defined as participants with CR, PR, or SD for =\>6-month period.
Time frame: Up to 46 months
Population: ITT Population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo + Letrozole 2.5 mg | Number of Participants With Clinical Benefit Categorized by HER2 ImmunoHistoChemistry (IHC) Intensity | IHC Intensity 1 | 108 Participants |
| Placebo + Letrozole 2.5 mg | Number of Participants With Clinical Benefit Categorized by HER2 ImmunoHistoChemistry (IHC) Intensity | IHC Intensity 3 | 16 Participants |
| Placebo + Letrozole 2.5 mg | Number of Participants With Clinical Benefit Categorized by HER2 ImmunoHistoChemistry (IHC) Intensity | IHC Intensity 2 | 94 Participants |
| Placebo + Letrozole 2.5 mg | Number of Participants With Clinical Benefit Categorized by HER2 ImmunoHistoChemistry (IHC) Intensity | IHC Intensity Missing | 34 Participants |
| Placebo + Letrozole 2.5 mg | Number of Participants With Clinical Benefit Categorized by HER2 ImmunoHistoChemistry (IHC) Intensity | IHC Intensity 0 | 74 Participants |
| Lapatinib 1500 mg + Letrozole 2.5 mg | Number of Participants With Clinical Benefit Categorized by HER2 ImmunoHistoChemistry (IHC) Intensity | IHC Intensity Missing | 35 Participants |
| Lapatinib 1500 mg + Letrozole 2.5 mg | Number of Participants With Clinical Benefit Categorized by HER2 ImmunoHistoChemistry (IHC) Intensity | IHC Intensity 0 | 106 Participants |
| Lapatinib 1500 mg + Letrozole 2.5 mg | Number of Participants With Clinical Benefit Categorized by HER2 ImmunoHistoChemistry (IHC) Intensity | IHC Intensity 1 | 106 Participants |
| Lapatinib 1500 mg + Letrozole 2.5 mg | Number of Participants With Clinical Benefit Categorized by HER2 ImmunoHistoChemistry (IHC) Intensity | IHC Intensity 2 | 85 Participants |
| Lapatinib 1500 mg + Letrozole 2.5 mg | Number of Participants With Clinical Benefit Categorized by HER2 ImmunoHistoChemistry (IHC) Intensity | IHC Intensity 3 | 26 Participants |
Secondary
Number of Participants With Evidence of Brain Metastases From the ITT Population
The confirmation criteria for the evidence of brain metastases was the incidence of lesions occurring within any part of the central nervous system (CNS) as evidenced by radiological scans. Metastases are defined as the spread of cancer from one part of the body to another.
Time frame: Up to 46 months
Population: ITT Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo + Letrozole 2.5 mg | Number of Participants With Evidence of Brain Metastases From the ITT Population | 4 participants |
| Lapatinib 1500 mg + Letrozole 2.5 mg | Number of Participants With Evidence of Brain Metastases From the ITT Population | 6 participants |
Secondary
Number of Participants With Evidence of Brain Metastases in the HER2-Positive Population
The confirmation criteria for the evidence of brain metastases was the incidence of lesions occurring within any part of the central nervous system (CNS) as evidenced by radiological scans. Metastases are defined as the spread of cancer from one part of the body to another.
Time frame: Up to 46 months
Population: HER2-Positive Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo + Letrozole 2.5 mg | Number of Participants With Evidence of Brain Metastases in the HER2-Positive Population | 2 participants |
| Lapatinib 1500 mg + Letrozole 2.5 mg | Number of Participants With Evidence of Brain Metastases in the HER2-Positive Population | 1 participants |
Secondary
Number of Participants With Overall Tumor Response (OR) by Stratification Factors With Measurable Disease, Including Bone Scans, in the HER2-Positive Population as Assessed by the Investigator
Participants were stratified based on site of disease at screening (SDS) (soft tissue or visceral or bone-only disease) and prior adjuvant endocrine therapy (PAET) (discontinuation interval \[DI\] =\>6 months or DI \<6 months). OR is defined as the number of participants achieving either a confirmed CR or PR. Response was assessed via RECIST. CR: disappearance of all target lesions. PR: at least a 30% decrease in the sum of the LD of target lesions, taking as a reference the baseline sum LD. DI is defined as the time period from stopping the PEAT to the randomization date.
Time frame: Up to 46 months
Population: HER2-Positive Population. Only those participants with measurable disease, including bone scans, were assessed.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo + Letrozole 2.5 mg | 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 |
| Placebo + Letrozole 2.5 mg | 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 |
| Placebo + Letrozole 2.5 mg | 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 |
| Placebo + Letrozole 2.5 mg | 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 |
| Lapatinib 1500 mg + Letrozole 2.5 mg | 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 | 7 Participants |
| Lapatinib 1500 mg + Letrozole 2.5 mg | 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 |
| Lapatinib 1500 mg + Letrozole 2.5 mg | 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 | 24 Participants |
| Lapatinib 1500 mg + Letrozole 2.5 mg | 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 | 31 Participants |
Secondary
Number of Participants With Overall Tumor Response (OR) by Stratification Factors With Measurable Disease, Including Bone Scans, in the ITT Population as Assessed by the Investigator
Participants were stratified based on site of disease at screening (SDS) (soft tissue or visceral or bone-only disease) and prior adjuvant endocrine therapy (PAET) (discontinuation interval \[DI\] =\>6 months or DI \<6 months). OR is defined as the number of participants achieving either a confirmed CR or PR. Response was assessed via RECIST. CR: disappearance of all target lesions. PR: at least a 30% decrease in the sum of the LD of target lesions, taking as a reference the baseline sum LD. DI is defined as the time period from stopping the PEAT and the randomization date.
Time frame: 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.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo + Letrozole 2.5 mg | 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 |
| Placebo + Letrozole 2.5 mg | 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 |
| Placebo + Letrozole 2.5 mg | 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 |
| Lapatinib 1500 mg + Letrozole 2.5 mg | 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 | 190 participants |
| Lapatinib 1500 mg + Letrozole 2.5 mg | 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 | 168 participants |
| Lapatinib 1500 mg + Letrozole 2.5 mg | 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 | 22 participants |
Secondary
Number of Participants With PFS in the Intent-To-Treat (ITT) Population as Assessed by the Investigator
PFS is defined as the time from randomization until the earliest date of disease progression or death due to any cause, if sooner. The date of documented disease progression is defined as the date of radiological disease progression as assessed by the investigator based on imaging data and also by the clinical assessment of symptomatic progression. Per RECIST 1.0, disease progression is defined as a 20% increase in the sum of the LD of target lesions, taking as a reference the smallest sum LD recorded since the treatment started, or the appearance of 1 or more new lesions.
Time frame: 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.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo + Letrozole 2.5 mg | Number of Participants With PFS in the Intent-To-Treat (ITT) Population as Assessed by the Investigator | 476 Participants |
| Lapatinib 1500 mg + Letrozole 2.5 mg | Number of Participants With PFS in the Intent-To-Treat (ITT) Population as Assessed by the Investigator | 413 Participants |
Secondary
Number of Participants With Response in Participants With Baseline Serum HER2 Extracellular Domain (ECD) Baseline Values Greater Than 15 Nanograms Per Milliliter (ng/mL) and 15 ng/mL or Lower
The HER2 ECD is a glycoprotein that can be shed from the cell surface into the blood of normal individuals and can be elevated in different pathologic conditions. The serum HER2 ECD level generally reflects the tissue HER2 status. The HER2 ECD is quantified in serum with an enzyme-linked immunosorbent assay (ELISA). Non-Evaluable (NE): any participant who could not be classified as CR, PR, SD, or PD.
Time frame: Up to 46 months
Population: HER2-Positive Population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo + Letrozole 2.5 mg | 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 |
| Placebo + Letrozole 2.5 mg | 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 |
| Placebo + Letrozole 2.5 mg | 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 |
| Placebo + Letrozole 2.5 mg | 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 |
| Placebo + Letrozole 2.5 mg | 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 |
| Placebo + Letrozole 2.5 mg | 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 |
| Lapatinib 1500 mg + Letrozole 2.5 mg | 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 | 30 Participants |
| Lapatinib 1500 mg + Letrozole 2.5 mg | 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 | 9 Participants |
| Lapatinib 1500 mg + Letrozole 2.5 mg | 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 | 17 Participants |
| Lapatinib 1500 mg + Letrozole 2.5 mg | 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 | 13 Participants |
| Lapatinib 1500 mg + Letrozole 2.5 mg | 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 | 23 Participants |
| Lapatinib 1500 mg + Letrozole 2.5 mg | 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 | 12 Participants |
Secondary
Number of Participants With the Indicated Best Response From the Participants With Measurable and Non-measurable Disease, Including Bone Scans, in the HER2-Positive Population as Assessed by the Investigator.
CR: disappearance of all target lesions. PR: at least a 30% decrease in the sum of the LD of target lesions, taking as reference the baseline sum LD. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as a reference the smallest sum LD since the baseline measurement. The best overall response is defined as the best response recorded from the start of treatment until disease progression/recurrence. PD: presence of target lesions, non-target lesions, and/or new lesions.
Time frame: Up to 46 months
Population: HER2-Positive Population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo + Letrozole 2.5 mg | 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 |
| Placebo + Letrozole 2.5 mg | 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 |
| Placebo + Letrozole 2.5 mg | 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 |
| Placebo + Letrozole 2.5 mg | 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 |
| Placebo + Letrozole 2.5 mg | 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 |
| Lapatinib 1500 mg + Letrozole 2.5 mg | 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 | 6 Participants |
| Lapatinib 1500 mg + Letrozole 2.5 mg | 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 | 5 Participants |
| Lapatinib 1500 mg + Letrozole 2.5 mg | 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 | 26 Participants |
| Lapatinib 1500 mg + Letrozole 2.5 mg | 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 | 44 Participants |
| Lapatinib 1500 mg + Letrozole 2.5 mg | 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 | 30 Participants |
Secondary
Number of Participants With the Indicated Best Response From the Participants With Measurable and Non-measurable Disease, Including Bone Scans, in the ITT Population as Assessed by the Investigator.
CR: disappearance of all target lesions. PR: at least a 30% decrease in the sum of the LD of target lesions, taking as reference the baseline sum LD. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as a reference the smallest sum LD since the baseline measurement. The best overall response is defined as the best response recorded from the start of treatment until disease progression/recurrence. PD: presence of target lesions, non-target lesions, and/or new lesions.
Time frame: Up to 46 months
Population: ITT Population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo + Letrozole 2.5 mg | 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 |
| Placebo + Letrozole 2.5 mg | 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 |
| Placebo + Letrozole 2.5 mg | 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 |
| Placebo + Letrozole 2.5 mg | 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 |
| Placebo + Letrozole 2.5 mg | 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 |
| Lapatinib 1500 mg + Letrozole 2.5 mg | 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 | 53 Participants |
| Lapatinib 1500 mg + Letrozole 2.5 mg | 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 | 28 Participants |
| Lapatinib 1500 mg + Letrozole 2.5 mg | 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 | 168 Participants |
| Lapatinib 1500 mg + Letrozole 2.5 mg | 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 | 280 Participants |
| Lapatinib 1500 mg + Letrozole 2.5 mg | 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 | 113 Participants |
Secondary
Number of Participants With the Indicated Expression of Tumor by Epidermal Growth Factor Receptor (ErbB1/HER1/EGFR) at Baseline
EGFR is a cell surface receptor tyrosine kinase expressed in certain types of tumors. Depending upon the staining intensity, EGFR was graded as follows: 0=absence of membrane staining above background in all tumor cells; EGFR-positive=staining is defined as any IHC staining of tumor cell membranes above background level, whether it is complete or incomplete circumferential staining (1+, 2+, 3+).
Time frame: Baseline
Population: ITT Population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo + Letrozole 2.5 mg | Number of Participants With the Indicated Expression of Tumor by Epidermal Growth Factor Receptor (ErbB1/HER1/EGFR) at Baseline | EGFR, 0 | 513 Participants |
| Placebo + Letrozole 2.5 mg | Number of Participants With the Indicated Expression of Tumor by Epidermal Growth Factor Receptor (ErbB1/HER1/EGFR) at Baseline | EGFR, 1+ | 43 Participants |
| Placebo + Letrozole 2.5 mg | Number of Participants With the Indicated Expression of Tumor by Epidermal Growth Factor Receptor (ErbB1/HER1/EGFR) at Baseline | EGFR, 2+ | 17 Participants |
| Placebo + Letrozole 2.5 mg | Number of Participants With the Indicated Expression of Tumor by Epidermal Growth Factor Receptor (ErbB1/HER1/EGFR) at Baseline | EGFR, 3+ | 3 Participants |
| Lapatinib 1500 mg + Letrozole 2.5 mg | Number of Participants With the Indicated Expression of Tumor by Epidermal Growth Factor Receptor (ErbB1/HER1/EGFR) at Baseline | EGFR, 3+ | 1 Participants |
| Lapatinib 1500 mg + Letrozole 2.5 mg | Number of Participants With the Indicated Expression of Tumor by Epidermal Growth Factor Receptor (ErbB1/HER1/EGFR) at Baseline | EGFR, 0 | 522 Participants |
| Lapatinib 1500 mg + Letrozole 2.5 mg | Number of Participants With the Indicated Expression of Tumor by Epidermal Growth Factor Receptor (ErbB1/HER1/EGFR) at Baseline | EGFR, 2+ | 12 Participants |
| Lapatinib 1500 mg + Letrozole 2.5 mg | Number of Participants With the Indicated Expression of Tumor by Epidermal Growth Factor Receptor (ErbB1/HER1/EGFR) at Baseline | EGFR, 1+ | 45 Participants |
Secondary
Number of Participants With the Indicated Time to Response for CR or PR in the HER2-Positive Population as Assessed by the Investigator
Time to response is defined as the time from randomization until the first documented evidence of CR (disappearance of all target lesions) or PR (at least a 30% decrease in the sume of the LD of target lesions, taking as reference the baseline sum LD) (whichever status was recorded first). The assessments of CR or PR required confirmation using bone scans.
Time frame: Up to 46 months
Population: HER2-Positive Population. Only those participants with CR or PR were assessed.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo + Letrozole 2.5 mg | 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 |
| Placebo + Letrozole 2.5 mg | 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 |
| Placebo + Letrozole 2.5 mg | 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 |
| Lapatinib 1500 mg + Letrozole 2.5 mg | 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 | 23 Participants |
| Lapatinib 1500 mg + Letrozole 2.5 mg | 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 | 3 Participants |
| Lapatinib 1500 mg + Letrozole 2.5 mg | 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 | 5 Participants |
Secondary
Number of Participants With the Indicated Time to Response for CR or PR in the ITT Population as Assessed by the Investigator
Time to response is defined as the time from randomization until the first documented evidence of CR (disappearance of all target lesions) or PR (at least a 30% decrease in the sume of the LD of target lesions, taking as reference the baseline sum LD) (whichever status was recorded first). The assessments of CR or PR required confirmation using bone scans.
Time frame: Up to 46 months
Population: ITT Population. Only those participants with CR or PR were assessed.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo + Letrozole 2.5 mg | 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 |
| Placebo + Letrozole 2.5 mg | 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 |
| Placebo + Letrozole 2.5 mg | 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 |
| Placebo + Letrozole 2.5 mg | 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 |
| Placebo + Letrozole 2.5 mg | 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 |
| Lapatinib 1500 mg + Letrozole 2.5 mg | 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 | 42 participants |
| Lapatinib 1500 mg + Letrozole 2.5 mg | Number of Participants With the Indicated Time to Response for CR or PR in the ITT Population as Assessed by the Investigator | Week 12 | 94 participants |
| Lapatinib 1500 mg + Letrozole 2.5 mg | Number of Participants With the Indicated Time to Response for CR or PR in the ITT Population as Assessed by the Investigator | Week 16 | 18 participants |
| Lapatinib 1500 mg + Letrozole 2.5 mg | 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 |
| Lapatinib 1500 mg + Letrozole 2.5 mg | Number of Participants With the Indicated Time to Response for CR or PR in the ITT Population as Assessed by the Investigator | Week 28 | 14 participants |
Secondary
Overall Survival in the HER2-Positive Population
Overall survival was defined as the time from randomization until death due to any cause.
Time frame: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo + Letrozole 2.5 mg | Overall Survival in the HER2-Positive Population | 140.3 Weeks |
| Lapatinib 1500 mg + Letrozole 2.5 mg | Overall Survival in the HER2-Positive Population | 144.7 Weeks |
Secondary
Overall Survival in the ITT Population
Overall survival was defined as the time from randomization until death due to any cause.
Time frame: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo + Letrozole 2.5 mg | Overall Survival in the ITT Population | 176.3 weeks |
| Lapatinib 1500 mg + Letrozole 2.5 mg | Overall Survival in the ITT Population | 170.9 weeks |
Secondary
Overall Tumor Response (OR) for Participants With Measurable and Non-measurable Disease, Including Bone Scans, in the HER2-Positive Population as Assessed by the Investigator
OR is defined as the percentage of participants achieving either a confirmed complete response (CR) or partial response (PR). Response was assessed via Response Evaluation criteria in Solid Tumors (RECIST). The percentage of participants with response was calculated by using the formula: 100 \* (number of participants with CR + number of participants with PR)/total number of participants. CR: disappearance of all target lesions. PR: at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as a reference the baseline sum LD.
Time frame: Up to 46 months
Population: HER2-Positive Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo + Letrozole 2.5 mg | 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 |
| Lapatinib 1500 mg + Letrozole 2.5 mg | 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 | 27.9 Percent response rate |
Secondary
Overall Tumor Response (OR) for Participants With Measurable and Non-measurable Disease, Including Bone Scans, in the ITT Population as Assessed by the Investigator
OR is defined as the percentage of participants achieving either a confirmed complete response (CR) or partial response (PR). Response was assessed via Response Evaluation criteria in Solid Tumors (RECIST). The percentage of participants with response was calculated by using the formula: 100 \* (number of participants with CR + number of participants with PR)/total number of participants. CR: disappearance of all target lesions. PR: at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as a reference the baseline sum LD.
Time frame: Up to 46 months
Population: ITT Population. Only those participants who achieved either a confirmed CR or PR were assessed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo + Letrozole 2.5 mg | 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 |
| Lapatinib 1500 mg + Letrozole 2.5 mg | Overall Tumor Response (OR) for Participants With Measurable and Non-measurable Disease, Including Bone Scans, in the ITT Population as Assessed by the Investigator | 30.5 percentage of participants |
Secondary
PFS in Participants in the ITT Population as Assessed by the Investigator
PFS is defined as the time from randomization until the earliest date of disease progression or death due to any cause, if sooner. The date of documented disease progression is defined as the date of radiological disease progression as assessed by the investigator based on imaging data and also by the clinical assessment of symptomatic progression. Per RECIST 1.0, disease progression is defined as a 20% increase in the sum of the LD of target lesions, taking as a reference the smallest sum LD recorded since the treatment started, or the appearance of 1 or more new lesions.
Time frame: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo + Letrozole 2.5 mg | PFS in Participants in the ITT Population as Assessed by the Investigator | 47.0 Weeks |
| Lapatinib 1500 mg + Letrozole 2.5 mg | PFS in Participants in the ITT Population as Assessed by the Investigator | 51.7 Weeks |
Secondary
Time to Progression (TTP) for the HER2-Positive Population as Assessed by the Investigator
TTP is defined as the interval between the date of randomization and the earliest date of disease progression or death due to breast cancer. Disease progression was based on the assessments by the Investigator.
Time frame: Up to 46 months
Population: HER2-Positive Population. Only those participants who experienced disease progression or died due to breast cancer were assessed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo + Letrozole 2.5 mg | Time to Progression (TTP) for the HER2-Positive Population as Assessed by the Investigator | 13.0 weeks |
| Lapatinib 1500 mg + Letrozole 2.5 mg | Time to Progression (TTP) for the HER2-Positive Population as Assessed by the Investigator | 35.4 weeks |
Secondary
Time to Seroconversion for Participants Who Were HER2 Negative at Baseline But Became HER2 Positive
Time to seroconversion was defined as the time from the date of randomization until the first instance of serum HER2 (\>15 ng/mL) on two consecutive occasions.
Time frame: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo + Letrozole 2.5 mg | Time to Seroconversion for Participants Who Were HER2 Negative at Baseline But Became HER2 Positive | NA Weeks |
| Lapatinib 1500 mg + Letrozole 2.5 mg | Time to Seroconversion for Participants Who Were HER2 Negative at Baseline But Became HER2 Positive | 36.1 Weeks |
Secondary
TTP for Participants From the ITT Population as Assessed by the Investigator
TTP is defined as the interval between the date of randomization and the earliest date of disease progression or death due to breast cancer. Disease progression was based on the assessments by the Investigator.
Time frame: Up to 46 months
Population: ITT Population. Only those participants who experienced disease progression or died due to breast cancer were assessed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo + Letrozole 2.5 mg | TTP for Participants From the ITT Population as Assessed by the Investigator | 47.0 weeks |
| Lapatinib 1500 mg + Letrozole 2.5 mg | TTP for Participants From the ITT Population as Assessed by the Investigator | 51.7 weeks |
Post Hoc
All Collected Deaths
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.
Time frame: up to 663 weeks (on-treatment), up to approximately 14 years (study duration)
Population: Clinical database population; all treated patients.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo + Letrozole 2.5 mg | All Collected Deaths | On-treatment deaths | 23 Participants |
| Placebo + Letrozole 2.5 mg | All Collected Deaths | All deaths | 484 Participants |
| Lapatinib 1500 mg + Letrozole 2.5 mg | All Collected Deaths | All deaths | 488 Participants |
| Lapatinib 1500 mg + Letrozole 2.5 mg | All Collected Deaths | On-treatment deaths | 18 Participants |