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

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00073528
• Collaborator: (none)
• Enrollment: 1,286
• Locations: 278
• Arms: 2
• Actual Duration (Months): 171.4
• Patients Per Site: 4.6
• Patients Per Site Per Month: 0

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Breast Neoplasms	Drug: Lapatinib; Drug: Letrozole; Drug: Placebo	Phase 3

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).

Study Design

• Study Type: Interventional
• Actual Enrollment: 1286 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-Blind, Placebo-Controlled, Multicenter Phase III Study Comparing GW572016 and Letrozole Versus Letrozole in Subjects With Estrogen/Progesterone Receptor- Positive Advanced or Metastatic Breast Cancer
• Actual Study Start Date: Dec 9, 2003
• Actual Primary Completion Date: Jun 3, 2008
• Actual Study Completion Date: Mar 22, 2018

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo + Letrozole 2.5 mg Letrozole (2.5 mg once daily orally) with Placebo (which matched with Lapatinib tablet)	Drug: Letrozole; 2.5 mg orally once a day; Drug: Placebo; Placebo (which matched with lapatinib tablet)
Experimental: Lapatinib 1500 mg + Letrozole 2.5 mg Lapatinib (1500 mg once daily orally) with Letrozole (2.5 mg once daily orally)	Drug: Lapatinib; 1500 mg orally once a day; Other Names: GW572016 ; Drug: Letrozole; 2.5 mg orally once a day

Outcome Measures

Primary Outcome Measures

1. 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.

2. 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 Outcome Measures

1. 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.

2. 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.

3. 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.

4. 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.

5. 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.

6. 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.

7. 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.

8. 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.

9. 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.

10. 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.

11. 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.

12. 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.

13. 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.

14. 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.

15. 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.

16. 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.

17. 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.

18. 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.

19. 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.

20. 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.

21. 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.

22. 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.

23. 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.

24. 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.

25. 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.

26. 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.

27. 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.

28. 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.

29. 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.

30. 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.

31. 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+).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

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.

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

2. Post-menopausal female subjects ≥ 18 years of age.

3. ECOG Performance Status of 0 or 1;

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

5. 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.

6. 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Tucson	Arizona	United States	85715
2	Novartis Investigative Site	Hot Springs	Arkansas	United States	71913
3	Novartis Investigative Site	Jonesboro	Arkansas	United States	72401
4	Novartis Investigative Site	Alhambra	California	United States	91801
5	Novartis Investigative Site	Bakersfield	California	United States	93309
6	Novartis Investigative Site	Duarte	California	United States	91010
7	Novartis Investigative Site	Fountain Valley	California	United States	92708
8	Novartis Investigative Site	Fresno	California	United States	93710
9	Novartis Investigative Site	Fullerton	California	United States	92835
10	Novartis Investigative Site	La Jolla	California	United States	92093-0987
11	Novartis Investigative Site	Long Beach	California	United States	90813
12	Novartis Investigative Site	Los Angeles	California	United States	90095
13	Novartis Investigative Site	Montebello	California	United States	90640
14	Novartis Investigative Site	Northridge	California	United States	91325
15	Novartis Investigative Site	Oxnard	California	United States	93030
16	Novartis Investigative Site	Pleasant Hill	California	United States	94523
17	Novartis Investigative Site	Porterville	California	United States	93257
18	Novartis Investigative Site	Redondo Beach	California	United States	90277
19	Novartis Investigative Site	San Diego	California	United States	92120
20	Novartis Investigative Site	Santa Barbara	California	United States	93105
21	Novartis Investigative Site	Santa Maria	California	United States	93454
22	Novartis Investigative Site	Vallejo	California	United States	94589
23	Novartis Investigative Site	Vista	California	United States	92081
24	Novartis Investigative Site	Aurora	Colorado	United States	80045
25	Novartis Investigative Site	Denver	Colorado	United States	80220
26	Novartis Investigative Site	Longmont	Colorado	United States	80501
27	Novartis Investigative Site	Wheat Ridge	Colorado	United States	80033
28	Novartis Investigative Site	New Haven	Connecticut	United States	06520
29	Novartis Investigative Site	Boca Raton	Florida	United States	33428
30	Novartis Investigative Site	Boca Raton	Florida	United States	33486
31	Novartis Investigative Site	Gainesville	Florida	United States	32605
32	Novartis Investigative Site	Gainesville	Florida	United States	32610
33	Novartis Investigative Site	Hollywood	Florida	United States	33021
34	Novartis Investigative Site	Lakeland	Florida	United States	33805
35	Novartis Investigative Site	Miami	Florida	United States	33136
36	Novartis Investigative Site	Orlando	Florida	United States	32804
37	Novartis Investigative Site	Port Saint Lucie	Florida	United States	34952
38	Novartis Investigative Site	West Palm Beach	Florida	United States	33401
39	Novartis Investigative Site	Atlanta	Georgia	United States	30341
40	Novartis Investigative Site	Marietta	Georgia	United States	30060
41	Novartis Investigative Site	Savannah	Georgia	United States	31406
42	Novartis Investigative Site	Peoria	Illinois	United States	61615
43	Novartis Investigative Site	Skokie	Illinois	United States	60076
44	Novartis Investigative Site	Indianapolis	Indiana	United States	46202
45	Novartis Investigative Site	Bettendorf	Iowa	United States	52722
46	Novartis Investigative Site	Louisville	Kentucky	United States	40202
47	Novartis Investigative Site	Metairie	Louisiana	United States	70006
48	Novartis Investigative Site	New Orleans	Louisiana	United States	70121
49	Novartis Investigative Site	Worcester	Massachusetts	United States	01608
50	Novartis Investigative Site	Duluth	Minnesota	United States	55805
51	Novartis Investigative Site	Minneapolis	Minnesota	United States	55407-3799
52	Novartis Investigative Site	Robbinsdale	Minnesota	United States	55422
53	Novartis Investigative Site	Saint Louis Park	Minnesota	United States	55426
54	Novartis Investigative Site	Saint Charles	Missouri	United States	63304
55	Novartis Investigative Site	Saint Louis	Missouri	United States	63141
56	Novartis Investigative Site	Omaha	Nebraska	United States	68114
57	Novartis Investigative Site	Las Vegas	Nevada	United States	89169
58	Novartis Investigative Site	Voorhees	New Jersey	United States	08043
59	Novartis Investigative Site	Santa Fe	New Mexico	United States	87505
60	Novartis Investigative Site	Manhasset	New York	United States	11030
61	Novartis Investigative Site	Rochester	New York	United States	14623
62	Novartis Investigative Site	Chapel Hill	North Carolina	United States	27599-7305
63	Novartis Investigative Site	Greenville	North Carolina	United States	27834
64	Novartis Investigative Site	Fargo	North Dakota	United States	58103
65	Novartis Investigative Site	Canton	Ohio	United States	44718
66	Novartis Investigative Site	Hershey	Pennsylvania	United States	17033
67	Novartis Investigative Site	Philadelphia	Pennsylvania	United States	19111
68	Novartis Investigative Site	Pittsburgh	Pennsylvania	United States	15212
69	Novartis Investigative Site	West Columbia	South Carolina	United States	29210
70	Novartis Investigative Site	Germantown	Tennessee	United States	38138
71	Novartis Investigative Site	Knoxville	Tennessee	United States	37916
72	Novartis Investigative Site	Amarillo	Texas	United States	79106
73	Novartis Investigative Site	Dallas	Texas	United States	75246
74	Novartis Investigative Site	Dallas	Texas	United States	75390-9113
75	Novartis Investigative Site	Houston	Texas	United States	77025
76	Novartis Investigative Site	Irving	Texas	United States	75061
77	Novartis Investigative Site	Ogden	Utah	United States	84403
78	Novartis Investigative Site	Salt Lake City	Utah	United States	84106
79	Novartis Investigative Site	Burlington	Vermont	United States	05401
80	Novartis Investigative Site	Danville	Virginia	United States	24541
81	Novartis Investigative Site	Richmond	Virginia	United States	23230
82	Novartis Investigative Site	Seattle	Washington	United States	98104
83	Novartis Investigative Site	Tacoma	Washington	United States	98405
84	Novartis Investigative Site	Charleston	West Virginia	United States	25304
85	Novartis Investigative Site	Capital Federal	Buenos Aires	Argentina	C1426ANZ
86	Novartis Investigative Site	Buenos Aires		Argentina	1425
87	Novartis Investigative Site	Ciudad Autonoma de Buenos Aires		Argentina	C1405BWU
88	Novartis Investigative Site	Garran	Australian Capital Territory	Australia	2606
89	Novartis Investigative Site	Douglas	Queensland	Australia	4814
90	Novartis Investigative Site	Herston	Queensland	Australia	4029
91	Novartis Investigative Site	Redcliffe	Queensland	Australia	4020
92	Novartis Investigative Site	Adelaide	South Australia	Australia	5000
93	Novartis Investigative Site	Salvador	Bahía	Brazil	41825-010
94	Novartis Investigative Site	Rio de Janeiro		Brazil	20560-120
95	Novartis Investigative Site	Plovdiv		Bulgaria	4000
96	Novartis Investigative Site	Sofia		Bulgaria	1527
97	Novartis Investigative Site	Sofia		Bulgaria	1756
98	Novartis Investigative Site	Winnipeg	Manitoba	Canada	R2H 2A6
99	Novartis Investigative Site	London	Ontario	Canada	N6A 4L6
100	Novartis Investigative Site	Mississauga	Ontario	Canada	L5B 1B8
101	Novartis Investigative Site	Oshawa	Ontario	Canada	L1G 2B9
102	Novartis Investigative Site	Sudbury	Ontario	Canada	P3E 5J1
103	Novartis Investigative Site	Toronto	Ontario	Canada	M6R 1B5
104	Novartis Investigative Site	Montreal	Quebec	Canada	H1T 2M4
105	Novartis Investigative Site	Montreal	Quebec	Canada	H2L 4M1
106	Novartis Investigative Site	Montreal	Quebec	Canada	H3T 1E2
107	Novartis Investigative Site	Montreal	Quebec	Canada	H4J 1C5
108	Novartis Investigative Site	Sherbrooke	Quebec	Canada	J1H 5N4
109	Novartis Investigative Site	Quebec		Canada	G1S 4L8
110	Novartis Investigative Site	Santiago	Región Metro De Santiago	Chile	7500921
111	Novartis Investigative Site	Santiago	Región Metro De Santiago	Chile	7591046
112	Novartis Investigative Site	Bogota		Colombia
113	Novartis Investigative Site	Osijek		Croatia	31000
114	Novartis Investigative Site	Pula		Croatia	52100
115	Novartis Investigative Site	Split		Croatia	21000
116	Novartis Investigative Site	Brno		Czechia	656 53
117	Novartis Investigative Site	Ceske Budejovice		Czechia	370 87
118	Novartis Investigative Site	Praha 8		Czechia	180 00
119	Novartis Investigative Site	Aalborg		Denmark	9000
120	Novartis Investigative Site	Hillerod		Denmark	3400
121	Novartis Investigative Site	Koebenhavn Oe		Denmark	2100
122	Novartis Investigative Site	Naestved		Denmark	4700
123	Novartis Investigative Site	Odense C		Denmark	5000
124	Novartis Investigative Site	Roskilde		Denmark	4000
125	Novartis Investigative Site	Vejle		Denmark	7100
126	Novartis Investigative Site	Angers Cedex 01		France	49033
127	Novartis Investigative Site	Besancon		France	25030
128	Novartis Investigative Site	Grenoble Cedex 9		France	38043
129	Novartis Investigative Site	Lille Cedex		France	59020
130	Novartis Investigative Site	Montpellier		France	34298
131	Novartis Investigative Site	Paris Cedex 5		France	75248
132	Novartis Investigative Site	Pierre Benite Cedex		France	69495
133	Novartis Investigative Site	Toulouse Cedex9		France	31059
134	Novartis Investigative Site	Villejuif Cedex		France	94805
135	Novartis Investigative Site	Aalen	Baden-Wuerttemberg	Germany	73428
136	Novartis Investigative Site	Freiburg	Baden-Wuerttemberg	Germany	79106
137	Novartis Investigative Site	Heidelberg	Baden-Wuerttemberg	Germany	69115
138	Novartis Investigative Site	Heidenheim	Baden-Wuerttemberg	Germany	89518
139	Novartis Investigative Site	Schwetzingen	Baden-Wuerttemberg	Germany	68723
140	Novartis Investigative Site	Stuttgart	Baden-Wuerttemberg	Germany	70174
141	Novartis Investigative Site	Ulm	Baden-Wuerttemberg	Germany	89075
142	Novartis Investigative Site	Augsburg	Bayern	Germany	86150
143	Novartis Investigative Site	Bayreuth	Bayern	Germany	95445
144	Novartis Investigative Site	Erlangen	Bayern	Germany	91054
145	Novartis Investigative Site	Muenchen	Bayern	Germany	80335
146	Novartis Investigative Site	Muenchen	Bayern	Germany	80637
147	Novartis Investigative Site	Muenchen	Bayern	Germany	81377
148	Novartis Investigative Site	Regensburg	Bayern	Germany	93049
149	Novartis Investigative Site	Rehling	Bayern	Germany	86508
150	Novartis Investigative Site	Rosenheim	Bayern	Germany	83002
151	Novartis Investigative Site	Frankfurt am Main	Hessen	Germany	60590
152	Novartis Investigative Site	Frankfurt	Hessen	Germany	60596
153	Novartis Investigative Site	Wiesbaden	Hessen	Germany	65191
154	Novartis Investigative Site	Wiesbaden	Hessen	Germany	65199
155	Novartis Investigative Site	Goslar	Niedersachsen	Germany	38642
156	Novartis Investigative Site	Leer	Niedersachsen	Germany	26789
157	Novartis Investigative Site	Bonn	Nordrhein-Westfalen	Germany	53127
158	Novartis Investigative Site	Coesfeld	Nordrhein-Westfalen	Germany	48653
159	Novartis Investigative Site	Duesseldorf	Nordrhein-Westfalen	Germany	40217
160	Novartis Investigative Site	Ibbenbueren	Nordrhein-Westfalen	Germany	49477
161	Novartis Investigative Site	Muenster	Nordrhein-Westfalen	Germany	48149
162	Novartis Investigative Site	Troisdorf	Nordrhein-Westfalen	Germany	53840
163	Novartis Investigative Site	Velbert	Nordrhein-Westfalen	Germany	42551
164	Novartis Investigative Site	Altenkirchen	Rheinland-Pfalz	Germany	57610
165	Novartis Investigative Site	Chemnitz	Sachsen	Germany	09009
166	Novartis Investigative Site	Dresden	Sachsen	Germany	01219
167	Novartis Investigative Site	Kiel	Schleswig-Holstein	Germany	24103
168	Novartis Investigative Site	Kiel	Schleswig-Holstein	Germany	24105
169	Novartis Investigative Site	Pinneberg	Schleswig-Holstein	Germany	25421
170	Novartis Investigative Site	Jena	Thueringen	Germany	07743
171	Novartis Investigative Site	Berlin		Germany	10117
172	Novartis Investigative Site	Berlin		Germany	10317
173	Novartis Investigative Site	Berlin		Germany	12200
174	Novartis Investigative Site	Berlin		Germany	14195
175	Novartis Investigative Site	Hamburg		Germany	20095
176	Novartis Investigative Site	Hamburg		Germany	20259
177	Novartis Investigative Site	Hamburg		Germany	22081
178	Novartis Investigative Site	Hamburg		Germany	22457
179	Novartis Investigative Site	Hamburg		Germany	22767
180	Novartis Investigative Site	Budapest		Hungary	1032
181	Novartis Investigative Site	Budapest		Hungary	1088
182	Novartis Investigative Site	Budapest		Hungary	1096
183	Novartis Investigative Site	Kecskemet		Hungary	6000
184	Novartis Investigative Site	Kistarcsa		Hungary	2143
185	Novartis Investigative Site	Szeged		Hungary	6720
186	Novartis Investigative Site	Tatabanya		Hungary	2800
187	Novartis Investigative Site	Cork		Ireland
188	Novartis Investigative Site	Dooradoyle		Ireland
189	Novartis Investigative Site	Dublin		Ireland	4
190	Novartis Investigative Site	Dublin		Ireland	8
191	Novartis Investigative Site	Dublin		Ireland	9
192	Novartis Investigative Site	Galway		Ireland
193	Novartis Investigative Site	Tallaght, Dublin		Ireland	24
194	Novartis Investigative Site	Wilton, Cork		Ireland
195	Novartis Investigative Site	Bologna	Emilia-Romagna	Italy	40138
196	Novartis Investigative Site	Parma	Emilia-Romagna	Italy	43100
197	Novartis Investigative Site	Roma	Lazio	Italy	00133
198	Novartis Investigative Site	Roma	Lazio	Italy	00152
199	Novartis Investigative Site	Genova	Liguria	Italy	16128
200	Novartis Investigative Site	Genova	Liguria	Italy	16132
201	Novartis Investigative Site	Crema	Lombardia	Italy	26013
202	Novartis Investigative Site	Milano	Lombardia	Italy	20162
203	Novartis Investigative Site	Gyeonggi-do		Korea, Republic of	411-769
204	Novartis Investigative Site	Seodaemun-gu, Seoul		Korea, Republic of	03722
205	Novartis Investigative Site	Seoul		Korea, Republic of	135-710
206	Novartis Investigative Site	Acapulco	Guerrero	Mexico	39670
207	Novartis Investigative Site	Colima		Mexico	28010
208	Novartis Investigative Site	Durango		Mexico	34000
209	Novartis Investigative Site	Durango		Mexico	34079
210	Novartis Investigative Site	Mexico, D.F.		Mexico	14050
211	Novartis Investigative Site	Amersfoort		Netherlands	3813 TZ
212	Novartis Investigative Site	Delft		Netherlands	2625 AD
213	Novartis Investigative Site	Den Haag		Netherlands	2512 VA
214	Novartis Investigative Site	Den Haag		Netherlands	2545 CH
215	Novartis Investigative Site	Doetinchem		Netherlands	7009 BL
216	Novartis Investigative Site	Eindhoven		Netherlands	5623 EJ
217	Novartis Investigative Site	Heerlen		Netherlands	6419 PC
218	Novartis Investigative Site	Leidschendam		Netherlands	2262 BA
219	Novartis Investigative Site	Maastricht		Netherlands	6229 HX
220	Novartis Investigative Site	Nieuwegein		Netherlands	3435 CM
221	Novartis Investigative Site	Sittard-geleen		Netherlands	6162 BG
222	Novartis Investigative Site	Utrecht		Netherlands	3582 KE
223	Novartis Investigative Site	Utrecht		Netherlands	3584 CX
224	Novartis Investigative Site	Christchurch		New Zealand	8001
225	Novartis Investigative Site	Lahore		Pakistan	54000
226	Novartis Investigative Site	Lahore		Pakistan
227	Novartis Investigative Site	Rawalpindi		Pakistan	46000
228	Novartis Investigative Site	Callao		Peru	Callao 2
229	Novartis Investigative Site	Lima		Peru	Lima 34
230	Novartis Investigative Site	Bydogoszcz		Poland	85-796
231	Novartis Investigative Site	Krakow		Poland	31-115
232	Novartis Investigative Site	Poznan		Poland	61-866
233	Novartis Investigative Site	Warszawa		Poland	02-781
234	Novartis Investigative Site	Wroclaw		Poland	53-413
235	Novartis Investigative Site	Moscow		Russian Federation	107005
236	Novartis Investigative Site	Moscow		Russian Federation	115 478
237	Novartis Investigative Site	St. Petersburg		Russian Federation	197022
238	Novartis Investigative Site	St. Petersburg		Russian Federation	197758
239	Novartis Investigative Site	Capital Park		South Africa	0002
240	Novartis Investigative Site	Panorama		South Africa	7500
241	Novartis Investigative Site	Parktown		South Africa	2193
242	Novartis Investigative Site	Port Elizabeth		South Africa	6001
243	Novartis Investigative Site	Alcala De Henares (Madrid)		Spain
244	Novartis Investigative Site	Badalona		Spain	08916
245	Novartis Investigative Site	Barcelona		Spain	08036
246	Novartis Investigative Site	Elche		Spain	03203
247	Novartis Investigative Site	Girona		Spain	17007
248	Novartis Investigative Site	Leganes, Madrid		Spain	28911
249	Novartis Investigative Site	Madrid		Spain	28007
250	Novartis Investigative Site	Madrid		Spain	28034
251	Novartis Investigative Site	Madrid		Spain	28035
252	Novartis Investigative Site	Madrid		Spain	28040
253	Novartis Investigative Site	Madrid		Spain	28041
254	Novartis Investigative Site	Malaga		Spain	29010
255	Novartis Investigative Site	Mostoles		Spain	28935
256	Novartis Investigative Site	Oviedo		Spain	33006
257	Novartis Investigative Site	Palma de Mallorca		Spain	07010
258	Novartis Investigative Site	San Sebastian		Spain	20014
259	Novartis Investigative Site	Valencia		Spain	46010
260	Novartis Investigative Site	Vigo ( Pontevedra)		Spain	36204
261	Novartis Investigative Site	Zaragoza		Spain	50009
262	Novartis Investigative Site	Sfax		Tunisia	3000
263	Novartis Investigative Site	Sousse		Tunisia	4000
264	Novartis Investigative Site	Tunis		Tunisia	1004
265	Novartis Investigative Site	Tunis		Tunisia	1007
266	Novartis Investigative Site	Ankara		Turkey	06100
267	Novartis Investigative Site	Istanbul		Turkey	34865
268	Novartis Investigative Site	Istanbul		Turkey
269	Novartis Investigative Site	Chelmsford	Essex	United Kingdom	CM1 7ET
270	Novartis Investigative Site	Manchester	Lancashire	United Kingdom	M20 4BX
271	Novartis Investigative Site	Northwood	Middlesex	United Kingdom	HA6 2RN
272	Novartis Investigative Site	Sutton	Surrey	United Kingdom	SM2 5PT
273	Novartis Investigative Site	Birmingham	West Midlands	United Kingdom	B18 7QH
274	Novartis Investigative Site	Huddersfield		United Kingdom	HD3 3EA
275	Novartis Investigative Site	London		United Kingdom	NW3 2QG
276	Novartis Investigative Site	London		United Kingdom	SW17 0QT
277	Novartis Investigative Site	London		United Kingdom	SW3 6JJ
278	Novartis Investigative Site	Sheffield		United Kingdom	S10 2SJ

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

None provided.

More Information

Publications

• Finn RS, Press MF, Dering J, O'Rourke L, Florance A, Ellis C, Martin AM, Johnston S. Quantitative ER and PgR assessment as predictors of benefit from lapatinib in postmenopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer. Clin Cancer Res. 2014 Feb 1;20(3):736-43. doi: 10.1158/1078-0432.CCR-13-1260. Epub 2013 Nov 6.
• Johnston S, Pippen J Jr, Pivot X, Lichinitser M, Sadeghi S, Dieras V, Gomez HL, Romieu G, Manikhas A, Kennedy MJ, Press MF, Maltzman J, Florance A, O'Rourke L, Oliva C, Stein S, Pegram M. Lapatinib combined with letrozole versus letrozole and placebo as first-line therapy for postmenopausal hormone receptor-positive metastatic breast cancer. J Clin Oncol. 2009 Nov 20;27(33):5538-46. doi: 10.1200/JCO.2009.23.3734. Epub 2009 Sep 28.
• Prat A, Cheang MC, Galván P, Nuciforo P, Paré L, Adamo B, Muñoz M, Viladot M, Press MF, Gagnon R, Ellis C, Johnston S. Prognostic Value of Intrinsic Subtypes in Hormone Receptor-Positive Metastatic Breast Cancer Treated With Letrozole With or Without Lapatinib. JAMA Oncol. 2016 Oct 1;2(10):1287-1294. doi: 10.1001/jamaoncol.2016.0922.
• Schwartzberg LS, Franco SX, Florance A, O'Rourke L, Maltzman J, Johnston S. Lapatinib plus letrozole as first-line therapy for HER-2+ hormone receptor-positive metastatic breast cancer. Oncologist. 2010;15(2):122-9. doi: 10.1634/theoncologist.2009-0240. Epub 2010 Feb 15. Erratum in: Oncologist. 2010;15(3):327. Schwarzberg, Lee S [corrected to Schwartzberg, Lee S].
• Sherrill B, Amonkar MM, Sherif B, Maltzman J, O'Rourke L, Johnston S. Quality of life in hormone receptor-positive HER-2+ metastatic breast cancer patients during treatment with letrozole alone or in combination with lapatinib. Oncologist. 2010;15(9):944-53. doi: 10.1634/theoncologist.2010-0012. Epub 2010 Aug 26.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT00073528
• Other Study ID Numbers: EGF30008; CLAP016A2308; 2004-003928-35; NCT00084968
• First Posted: Nov 26, 2003
• Last Update Posted: Feb 24, 2021
• Last Verified: Feb 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Novartis Pharmaceuticals: 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
• Additional relevant MeSH terms: Breast Neoplasms; Letrozole; Lapatinib

Study Results

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).

Arm/Group Title	Placebo + Letrozole 2.5 mg	Lapatinib 1500 mg + Letrozole 2.5 mg
Arm/Group Description	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.	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.
Period Title: Overall Study
STARTED	644	642
COMPLETED	14	14
NOT COMPLETED	630	628

Baseline Characteristics

Arm/Group Title	Placebo + Letrozole 2.5 mg	Lapatinib 1500 mg + Letrozole 2.5 mg	Total
Arm/Group Description	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.	Participants received 6 tablets of Lapatinib orally daily (250 mg lapatinib/tablet for a total of 1500 mg of lapatinib/day; approximately at the same time each day), either 1 hour (or more) before breakfast or 1 hour (or more) after breakfast. Participants also received 1 tablet of letrozole 2.5 mg orally daily, preferably with the daily dose of lapatinib.	Total of all reporting groups
Overall Participants	644	642	1286
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	63.3 (9.95)	62.8 (9.70)	63.1 (9.83)
Sex: Female, Male (Count of Participants)
Female	644 100%	642 100%	1286 100%
Male	0 0%	0 0%	0 0%
Race/Ethnicity, Customized (Number) [Number]
White	557 86.5%	529 82.4%	1086 84.4%
Black	10 1.6%	17 2.6%	27 2.1%
Asian	30 4.7%	30 4.7%	60 4.7%
American Hispanic	44 6.8%	57 8.9%	101 7.9%
Other	3 0.5%	9 1.4%	12 0.9%

Outcome Measures

1. Primary Outcome

Title	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
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Placebo + Letrozole 2.5 mg	Lapatinib 1500 mg + Letrozole 2.5 mg
Arm/Group Description	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.	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.
Measure Participants	108	111
Count of Participants [Participants]	89 13.8%	88 13.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo + Letrozole 2.5 mg, Lapatinib 1500 mg + Letrozole 2.5 mg
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.019
	Comments	p-value is from stratified log-rank test, stratifying for site of disease and time since prior adjuvant endocrine therapy at screening
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.71
	Confidence Interval	(2-Sided) 95%; 0.53 to 0.96
	Parameter Dispersion	Type: Value:
	Estimation Comments	The estimate of the treatment Hazard Ratio wase based on the log-rank test.

2. Primary Outcome

Title	Progression Free Survival (PFS) of Participants in the HER2-Positive Population as Assessed by the Investigator
Description	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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Placebo + Letrozole 2.5 mg	Lapatinib 1500 mg + Letrozole 2.5 mg
Arm/Group Description	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.	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.
Measure Participants	89	88
Median (95% Confidence Interval) [Weeks]	13.0	35.4

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo + Letrozole 2.5 mg, Lapatinib 1500 mg + Letrozole 2.5 mg
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.019
	Comments	p-value is from stratified log-rank test, stratifying for site of disease and time since prior adjuvant endocrine therapy at screening
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.71
	Confidence Interval	(2-Sided) 95%; 0.53 to 0.96
	Parameter Dispersion	Type: Value:
	Estimation Comments	The estimate of the treatment Hazard Ratio was based on the log-rank test.

3. Secondary Outcome

Title	Number of Participants With PFS in the Intent-To-Treat (ITT) Population as Assessed by the Investigator
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Placebo + Letrozole 2.5 mg	Lapatinib 1500 mg + Letrozole 2.5 mg
Arm/Group Description	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.	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.
Measure Participants	644	642
Count of Participants [Participants]	476 73.9%	413 64.3%

4. Secondary Outcome

Title	PFS in Participants in the ITT Population as Assessed by the Investigator
Description	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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Placebo + Letrozole 2.5 mg	Lapatinib 1500 mg + Letrozole 2.5 mg
Arm/Group Description	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.	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.
Measure Participants	476	413
Median (95% Confidence Interval) [Weeks]	47.0	51.7

5. Secondary Outcome

Title	Overall Survival in the HER2-Positive Population
Description	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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Placebo + Letrozole 2.5 mg	Lapatinib 1500 mg + Letrozole 2.5 mg
Arm/Group Description	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.	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.
Measure Participants	108	111
Median (95% Confidence Interval) [Weeks]	140.3	144.7

6. Secondary Outcome

Title	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
Description	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

Outcome Measure Data

Analysis Population Description

HER2-Positive Population

Arm/Group Title	Placebo + Letrozole 2.5 mg	Lapatinib 1500 mg + Letrozole 2.5 mg
Arm/Group Description	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.	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.
Measure Participants	108	111
Number (95% Confidence Interval) [Percent response rate]	14.8	27.9

7. Secondary Outcome

Title	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
Description	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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Placebo + Letrozole 2.5 mg	Lapatinib 1500 mg + Letrozole 2.5 mg
Arm/Group Description	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.	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.
Measure Participants	75	93
SDS, Soft tissue or visceral	14 2.2%	31 4.8%
SDS, Bone-only disease	0 0%	0 0%
PAET, DI =>6 months	12 1.9%	24 3.7%
PAET, DI <6 months	2 0.3%	7 1.1%

8. Secondary Outcome

Title	Clinical Benefit (CB) in the HER2-Positive Population as Assessed by the Investigator
Description	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

Outcome Measure Data

Analysis Population Description

HER2-Positive Population

Arm/Group Title	Placebo + Letrozole 2.5 mg	Lapatinib 1500 mg + Letrozole 2.5 mg
Arm/Group Description	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.	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.
Measure Participants	108	111
Number (95% Confidence Interval) [Months]	28.7	47.7

9. Secondary Outcome

Title	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.
Description	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

Outcome Measure Data

Analysis Population Description

HER2-Positive Population

Arm/Group Title	Placebo + Letrozole 2.5 mg	Lapatinib 1500 mg + Letrozole 2.5 mg
Arm/Group Description	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.	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.
Measure Participants	108	111
CR	4 0.6%	5 0.8%
PR	12 1.9%	26 4%
SD	35 5.4%	44 6.9%
PD	49 7.6%	30 4.7%
Unknown	8 1.2%	6 0.9%

10. Secondary Outcome

Title	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.
Description	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

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	Placebo + Letrozole 2.5 mg	Lapatinib 1500 mg + Letrozole 2.5 mg
Arm/Group Description	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.	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.
Measure Participants	644	642
CR	26 4%	28 4.4%
PR	153 23.8%	168 26.2%
SD	243 37.7%	280 43.6%
PD	174 27%	113 17.6%
Unknown	48 7.5%	53 8.3%

11. Secondary Outcome

Title	Number of Participants With the Indicated Time to Response for CR or PR in the HER2-Positive Population as Assessed by the Investigator
Description	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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Placebo + Letrozole 2.5 mg	Lapatinib 1500 mg + Letrozole 2.5 mg
Arm/Group Description	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.	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.
Measure Participants	16	31
Week 12	11 1.7%	23 3.6%
Week 16	1 0.2%	3 0.5%
Week 24 or longer	4 0.6%	5 0.8%

12. Secondary Outcome

Title	Duration of Response for the Participants With CR or PR in the HER2-Positive Population as Assessed by the Investigator
Description	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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Placebo + Letrozole 2.5 mg	Lapatinib 1500 mg + Letrozole 2.5 mg
Arm/Group Description	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.	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.
Measure Participants	16	31
Median (Inter-Quartile Range) [weeks]	84.4	47.4

13. Secondary Outcome

Title	Number of Participants With Evidence of Brain Metastases in the HER2-Positive Population
Description	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

Outcome Measure Data

Analysis Population Description

HER2-Positive Population

Arm/Group Title	Placebo + Letrozole 2.5 mg	Lapatinib 1500 mg + Letrozole 2.5 mg
Arm/Group Description	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.	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.
Measure Participants	108	111
Number [participants]	2 0.3%	1 0.2%

14. Secondary Outcome

Title	Time to Progression (TTP) for the HER2-Positive Population as Assessed by the Investigator
Description	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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Placebo + Letrozole 2.5 mg	Lapatinib 1500 mg + Letrozole 2.5 mg
Arm/Group Description	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.	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.
Measure Participants	89	87
Median (95% Confidence Interval) [weeks]	13.0	35.4

15. Secondary Outcome

Title	Overall Survival in the ITT Population
Description	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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Placebo + Letrozole 2.5 mg	Lapatinib 1500 mg + Letrozole 2.5 mg
Arm/Group Description	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.	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.
Measure Participants	234	240
Median (95% Confidence Interval) [weeks]	176.3	170.9

16. Secondary Outcome

Title	Overall Tumor Response (OR) for Participants With Measurable and Non-measurable Disease, Including Bone Scans, in the ITT Population as Assessed by the Investigator
Description	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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Placebo + Letrozole 2.5 mg	Lapatinib 1500 mg + Letrozole 2.5 mg
Arm/Group Description	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.	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.
Measure Participants	644	642
Number [percentage of participants]	27.8 4.3%	30.5 4.8%

17. Secondary Outcome

Title	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
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Placebo + Letrozole 2.5 mg	Lapatinib 1500 mg + Letrozole 2.5 mg
Arm/Group Description	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.	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.
Measure Participants	486	480
SDS, Soft tissue or visceral	170 26.4%	190 29.6%
PAET, DI =>6 months	151 23.4%	168 26.2%
PAET, DI <6 months	19 3%	22 3.4%

18. Secondary Outcome

Title	Clinical Benefit (CB) in the ITT Population as Assessed by the Investigator
Description	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

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	Placebo + Letrozole 2.5 mg	Lapatinib 1500 mg + Letrozole 2.5 mg
Arm/Group Description	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.	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.
Measure Participants	644	642
Number [percentage of participants]	50.6 7.9%	55.8 8.7%

19. Secondary Outcome

Title	Number of Participants With the Indicated Time to Response for CR or PR in the ITT Population as Assessed by the Investigator
Description	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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Placebo + Letrozole 2.5 mg	Lapatinib 1500 mg + Letrozole 2.5 mg
Arm/Group Description	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.	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.
Measure Participants	179	196
Week 12	76 11.8%	94 14.6%
Week 16	21 3.3%	18 2.8%
Week 24	28 4.3%	28 4.4%
Week 28	17 2.6%	14 2.2%
Week 36 or longer	37 5.7%	42 6.5%

20. Secondary Outcome

Title	Duration of Response for the Participants With CR or PR in the ITT Population as Assessed by the Investigator
Description	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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Placebo + Letrozole 2.5 mg	Lapatinib 1500 mg + Letrozole 2.5 mg
Arm/Group Description	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.	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.
Measure Participants	179	196
Median (Inter-Quartile Range) [weeks]	72.6	60.1

21. Secondary Outcome

Title	Number of Participants With Evidence of Brain Metastases From the ITT Population
Description	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

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	Placebo + Letrozole 2.5 mg	Lapatinib 1500 mg + Letrozole 2.5 mg
Arm/Group Description	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.	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.
Measure Participants	644	642
Number [participants]	4 0.6%	6 0.9%

22. Secondary Outcome

Title	TTP for Participants From the ITT Population as Assessed by the Investigator
Description	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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Placebo + Letrozole 2.5 mg	Lapatinib 1500 mg + Letrozole 2.5 mg
Arm/Group Description	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.	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.
Measure Participants	469	409
Median (95% Confidence Interval) [weeks]	47.0	51.7

23. Secondary Outcome

Title	Number of Participants Completing the Functional Assessment of Cancer Therapy-breast (FACT-B) Questionnaire at the Scheduled Visits
Description	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

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	Placebo + Letrozole 2.5 mg	Lapatinib 1500 mg + Letrozole 2.5 mg
Arm/Group Description	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.	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.
Measure Participants	644	642
Day 1, baseline	605 93.9%	605 94.2%
Week 12	460 71.4%	476 74.1%
Week 24	350 54.3%	382 59.5%
Week 36	291 45.2%	294 45.8%
Week 48	254 39.4%	243 37.9%
Week 60	199 30.9%	183 28.5%
Week 72	181 28.1%	153 23.8%
Week 84	144 22.4%	119 18.5%
Week 96	117 18.2%	98 15.3%
Week 108	80 12.4%	62 9.7%
Week 120	59 9.2%	56 8.7%
Week 132	43 6.7%	43 6.7%
Week 144	33 5.1%	33 5.1%
Week 156	22 3.4%	21 3.3%
Week 168	15 2.3%	11 1.7%
Week 180	11 1.7%	5 0.8%
Week 192	6 0.9%	1 0.2%
Conclusion/withdrawal	327 50.8%	359 55.9%

24. Secondary Outcome

Title	Adjusted Mean Change From Baseline for the FACT-B Total Score Using Observed Data
Description	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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Placebo + Letrozole 2.5 mg	Lapatinib 1500 mg + Letrozole 2.5 mg
Arm/Group Description	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.	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.
Measure Participants	61	78
Week 12	1.5	3.3
Week 24	3.8	1.9
Week 36	3.3	1.4
Week 48	2.9	0.3
Conclusion/WD	-9.4	-9.0

25. Secondary Outcome

Title	Adjusted Mean Change From Baseline for the Functional Assessment of Cancer Therapy-General (FACT-G) Score Using Observed Data
Description	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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Placebo + Letrozole 2.5 mg	Lapatinib 1500 mg + Letrozole 2.5 mg
Arm/Group Description	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.	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.
Measure Participants	63	79
Week 12	1.6	1.5
Week 24	2.2	0.6
Week 36	2.6	0.9
Week 48	2.0	-0.9
Conclusion/WD	-7.8	-8.5

26. Secondary Outcome

Title	Adjusted Mean Change From Baseline for the Trial Outcome Index (TOI) Score Using Observed Data
Description	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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Placebo + Letrozole 2.5 mg	Lapatinib 1500 mg + Letrozole 2.5 mg
Arm/Group Description	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.	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.
Measure Participants	62	77
Week 12	-0.3	2.7
Week 24	3.9	2.0
Week 36	3.3	0.8
Week 48	2.2	-0.7
Conclusion/WD	-6.2	-6.4

27. Secondary Outcome

Title	Number of Participants Classified as QOL Responders Based on the FACT-B, FACT-G, and TOI Total Scores
Description	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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Placebo + Letrozole 2.5 mg	Lapatinib 1500 mg + Letrozole 2.5 mg
Arm/Group Description	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.	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.
Measure Participants	87	99
FACT-B total, =>8 (MID upper bound)	29 4.5%	33 5.1%
FACT-G, =>6 (MID upper bound)	29 4.5%	38 5.9%
TOI, =>6 (MID upper bound)	29 4.5%	33 5.1%

28. Secondary Outcome

Title	Number of Participants With Clinical Benefit Categorized by HER2 Fluorescence in Situ Hybridization (FISH) Status
Description	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

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	Placebo + Letrozole 2.5 mg	Lapatinib 1500 mg + Letrozole 2.5 mg
Arm/Group Description	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.	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.
Measure Participants	644	642
FISH status, Positive	28 4.3%	49 7.6%
FISH status, Negative	237 36.8%	245 38.2%
FISH status, missing	61 9.5%	64 10%

29. Secondary Outcome

Title	Number of Participants With Clinical Benefit Categorized by HER2 ImmunoHistoChemistry (IHC) Intensity
Description	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

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	Placebo + Letrozole 2.5 mg	Lapatinib 1500 mg + Letrozole 2.5 mg
Arm/Group Description	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.	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.
Measure Participants	644	642
IHC Intensity 0	74 11.5%	106 16.5%
IHC Intensity 1	108 16.8%	106 16.5%
IHC Intensity 2	94 14.6%	85 13.2%
IHC Intensity 3	16 2.5%	26 4%
IHC Intensity Missing	34 5.3%	35 5.5%

30. Secondary Outcome

Title	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
Description	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

Outcome Measure Data

Analysis Population Description

HER2-Positive Population

Arm/Group Title	Placebo + Letrozole 2.5 mg	Lapatinib 1500 mg + Letrozole 2.5 mg
Arm/Group Description	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.	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.
Measure Participants	108	111
>15 ng/mL, CR/PR	3 0.5%	9 1.4%
>15 ng/mL, SD	11 1.7%	13 2%
>15 ng/mL, PD/NE	39 6.1%	12 1.9%
=<15 ng/mL, CR/PR	12 1.9%	17 2.6%
=<15 ng/mL, SD	23 3.6%	30 4.7%
=<15 ng/mL, PD/NE	16 2.5%	23 3.6%

31. Secondary Outcome

Title	Number of HER2-Negative Participants at Baseline With and Without Seroconversion to a Status of HER2 Positive
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Placebo + Letrozole 2.5 mg	Lapatinib 1500 mg + Letrozole 2.5 mg
Arm/Group Description	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.	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.
Measure Participants	474	478
Seroconversion, No	323 50.2%	140 21.8%
Seroconversion, Yes	52 8.1%	219 34.1%
Missing	99 15.4%	119 18.5%

32. Secondary Outcome

Title	Time to Seroconversion for Participants Who Were HER2 Negative at Baseline But Became HER2 Positive
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Placebo + Letrozole 2.5 mg	Lapatinib 1500 mg + Letrozole 2.5 mg
Arm/Group Description	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.	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.
Measure Participants	52	219
Median (95% Confidence Interval) [Weeks]	NA	36.1

33. Secondary Outcome

Title	Number of Participants With the Indicated Expression of Tumor by Epidermal Growth Factor Receptor (ErbB1/HER1/EGFR) at Baseline
Description	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

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	Placebo + Letrozole 2.5 mg	Lapatinib 1500 mg + Letrozole 2.5 mg
Arm/Group Description	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.	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.
Measure Participants	644	642
EGFR, 0	513 79.7%	522 81.3%
EGFR, 1+	43 6.7%	45 7%
EGFR, 2+	17 2.6%	12 1.9%
EGFR, 3+	3 0.5%	1 0.2%

34. Post-Hoc Outcome

Title	All Collected Deaths
Description	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)

Outcome Measure Data

Analysis Population Description

Clinical database population; all treated patients.

Arm/Group Title	Placebo + Letrozole 2.5 mg	Lapatinib 1500 mg + Letrozole 2.5 mg
Arm/Group Description	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.	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.
Measure Participants	624	654
On-treatment deaths	23 3.6%	18 2.8%
All deaths	484 75.2%	488 76%

Adverse Events

Time Frame	Adverse events were collected from First Patient First Treatment (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).
Adverse Event Reporting Description	Any sign or symptom that occurs during the study treatment and 30 days post treatment follow up. Maximum exposure to Lapatinib = 612 weeks (Lapatinib + Letrozole treatment group). Maximum exposure to Letrozole = 659.7 weeks (Placebo + Letrozole treatment group) and 612 weeks (Lapatinib + Letrozole treatment group).
Arm/Group Title	Placebo + Letrozole 2.5 mg		Lapatinib 1500 mg + Letrozole 2.5 mg
Arm/Group Description	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.		Participants received 6 tablets of Lapatinib orally daily (250 mg lapatinib/tablet for a total of 1500 mg of lapatinib/day; approximately at the same time each day), either 1 hour (or more) before breakfast or 1 hour (or more) after breakfast. Participants also received 1 tablet of letrozole 2.5 mg orally daily, preferably with the daily dose of lapatinib.
All Cause Mortality
	Placebo + Letrozole 2.5 mg		Lapatinib 1500 mg + Letrozole 2.5 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	23/624 (3.7%)		18/654 (2.8%)
Serious Adverse Events
	Placebo + Letrozole 2.5 mg		Lapatinib 1500 mg + Letrozole 2.5 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	103/624 (16.5%)		150/654 (22.9%)
Blood and lymphatic system disorders
Anaemia	2/624 (0.3%)		5/654 (0.8%)
Febrile neutropenia	0/624 (0%)		3/654 (0.5%)
Jaundice	0/624 (0%)		1/654 (0.2%)
Leukocytosis	0/624 (0%)		1/654 (0.2%)
Thrombocytopenia	0/624 (0%)		2/654 (0.3%)
Cardiac disorders
Arrhythmia	2/624 (0.3%)		0/654 (0%)
Atrial fibrillation	2/624 (0.3%)		1/654 (0.2%)
Cardiac failure	2/624 (0.3%)		1/654 (0.2%)
Dyspnoea	5/624 (0.8%)		6/654 (0.9%)
Left ventricular dysfunction	1/624 (0.2%)		7/654 (1.1%)
Left ventricular failure	1/624 (0.2%)		0/654 (0%)
Palpitations	1/624 (0.2%)		0/654 (0%)
Pericardial effusion	1/624 (0.2%)		1/654 (0.2%)
Pericarditis	1/624 (0.2%)		0/654 (0%)
Peripheral swelling	1/624 (0.2%)		0/654 (0%)
Sinus tachycardia	0/624 (0%)		1/654 (0.2%)
Supraventricular tachycardia	3/624 (0.5%)		1/654 (0.2%)
Ear and labyrinth disorders
Deafness bilateral	1/624 (0.2%)		0/654 (0%)
Endocrine disorders
Carcinoid tumour	0/624 (0%)		1/654 (0.2%)
Hypercalcaemia	2/624 (0.3%)		0/654 (0%)
Inappropriate antidiuretic hormone secretion	0/624 (0%)		1/654 (0.2%)
Eye disorders
Eye injury	1/624 (0.2%)		0/654 (0%)
Visual impairment	1/624 (0.2%)		0/654 (0%)
Gastrointestinal disorders
Abdominal pain	3/624 (0.5%)		3/654 (0.5%)
Abdominal strangulated hernia	0/624 (0%)		1/654 (0.2%)
Ascites	0/624 (0%)		3/654 (0.5%)
Clostridium difficile colitis	0/624 (0%)		1/654 (0.2%)
Colitis	1/624 (0.2%)		1/654 (0.2%)
Colon cancer	0/624 (0%)		1/654 (0.2%)
Constipation	2/624 (0.3%)		0/654 (0%)
Diarrhoea	2/624 (0.3%)		15/654 (2.3%)
Gastric ulcer	0/624 (0%)		1/654 (0.2%)
Gastric ulcer perforation	1/624 (0.2%)		0/654 (0%)
Ileus	1/624 (0.2%)		0/654 (0%)
Intestinal obstruction	1/624 (0.2%)		1/654 (0.2%)
Nausea	4/624 (0.6%)		5/654 (0.8%)
Oral infection	0/624 (0%)		1/654 (0.2%)
Pancreatitis	0/624 (0%)		1/654 (0.2%)
Pancreatitis haemorrhagic	1/624 (0.2%)		0/654 (0%)
Peritonitis bacterial	0/624 (0%)		1/654 (0.2%)
Rectal prolapse	0/624 (0%)		1/654 (0.2%)
Small intestinal obstruction	1/624 (0.2%)		1/654 (0.2%)
Vomiting	7/624 (1.1%)		9/654 (1.4%)
General disorders
Asthenia	1/624 (0.2%)		2/654 (0.3%)
Chest pain	3/624 (0.5%)		4/654 (0.6%)
Complication associated with device	1/624 (0.2%)		0/654 (0%)
Decreased appetite	2/624 (0.3%)		1/654 (0.2%)
Fatigue	0/624 (0%)		1/654 (0.2%)
General physical health deterioration	1/624 (0.2%)		1/654 (0.2%)
Malaise	1/624 (0.2%)		1/654 (0.2%)
Multiple organ dysfunction syndrome	0/624 (0%)		1/654 (0.2%)
Non-cardiac chest pain	0/624 (0%)		1/654 (0.2%)
Pyrexia	4/624 (0.6%)		4/654 (0.6%)
Hepatobiliary disorders
Bile duct stone	1/624 (0.2%)		0/654 (0%)
Cholecystitis	0/624 (0%)		1/654 (0.2%)
Cholecystitis acute	0/624 (0%)		1/654 (0.2%)
Gallbladder disorder	0/624 (0%)		1/654 (0.2%)
Gallbladder pain	0/624 (0%)		1/654 (0.2%)
Hepatic function abnormal	0/624 (0%)		2/654 (0.3%)
Immune system disorders
Crohn's disease	1/624 (0.2%)		0/654 (0%)
Dermatomyositis	0/624 (0%)		1/654 (0.2%)
Infections and infestations
Diverticulitis	0/624 (0%)		1/654 (0.2%)
Erysipelas	2/624 (0.3%)		4/654 (0.6%)
Furuncle	0/624 (0%)		1/654 (0.2%)
Gastroenteritis	2/624 (0.3%)		0/654 (0%)
Infection	1/624 (0.2%)		1/654 (0.2%)
Localised infection	1/624 (0.2%)		0/654 (0%)
Lower respiratory tract infection	0/624 (0%)		2/654 (0.3%)
Lung infection	0/624 (0%)		2/654 (0.3%)
Pneumonia	4/624 (0.6%)		3/654 (0.5%)
Pyelonephritis	2/624 (0.3%)		1/654 (0.2%)
Sepsis	1/624 (0.2%)		1/654 (0.2%)
Septic shock	0/624 (0%)		2/654 (0.3%)
Tooth abscess	1/624 (0.2%)		0/654 (0%)
Tooth infection	1/624 (0.2%)		0/654 (0%)
Urinary tract infection	1/624 (0.2%)		6/654 (0.9%)
Urosepsis	0/624 (0%)		1/654 (0.2%)
Vulval abscess	0/624 (0%)		1/654 (0.2%)
Injury, poisoning and procedural complications
Accidental poisoning	1/624 (0.2%)		0/654 (0%)
Catheter site infection	1/624 (0.2%)		0/654 (0%)
Head injury	0/624 (0%)		1/654 (0.2%)
Hepatotoxicity	2/624 (0.3%)		1/654 (0.2%)
Overdose	0/624 (0%)		1/654 (0.2%)
Pelvic fracture	0/624 (0%)		1/654 (0.2%)
Post procedural complication	1/624 (0.2%)		0/654 (0%)
Post procedural infection	0/624 (0%)		1/654 (0.2%)
Road traffic accident	1/624 (0.2%)		0/654 (0%)
Synovial rupture	1/624 (0.2%)		0/654 (0%)
Toxic skin eruption	0/624 (0%)		1/654 (0.2%)
Toxicity to various agents	0/624 (0%)		1/654 (0.2%)
Upper limb fracture	1/624 (0.2%)		0/654 (0%)
Uterine perforation	0/624 (0%)		1/654 (0.2%)
Wound infection	0/624 (0%)		1/654 (0.2%)
Wrist fracture	0/624 (0%)		1/654 (0.2%)
Investigations
Alanine aminotransferase increased	0/624 (0%)		1/654 (0.2%)
Aspartate aminotransferase increased	1/624 (0.2%)		0/654 (0%)
Blood alkaline phosphatase increased	1/624 (0.2%)		1/654 (0.2%)
Blood urea increased	0/624 (0%)		1/654 (0.2%)
Ejection fraction decreased	8/624 (1.3%)		17/654 (2.6%)
Gamma-glutamyltransferase increased	0/624 (0%)		1/654 (0.2%)
Hepatic enzyme increased	0/624 (0%)		1/654 (0.2%)
Metabolism and nutrition disorders
Dehydration	2/624 (0.3%)		7/654 (1.1%)
Diabetes mellitus	1/624 (0.2%)		0/654 (0%)
Electrolyte imbalance	0/624 (0%)		1/654 (0.2%)
Hyperglycaemia	1/624 (0.2%)		1/654 (0.2%)
Hyperuricaemia	0/624 (0%)		2/654 (0.3%)
Hypocalcaemia	1/624 (0.2%)		0/654 (0%)
Hypoglycaemia	1/624 (0.2%)		0/654 (0%)
Hypokalaemia	2/624 (0.3%)		0/654 (0%)
Hyponatraemia	0/624 (0%)		1/654 (0.2%)
Iron deficiency anaemia	0/624 (0%)		1/654 (0.2%)
Musculoskeletal and connective tissue disorders
Ankle fracture	0/624 (0%)		1/654 (0.2%)
Arthralgia	0/624 (0%)		2/654 (0.3%)
Arthritis	1/624 (0.2%)		0/654 (0%)
Back pain	7/624 (1.1%)		2/654 (0.3%)
Bone pain	1/624 (0.2%)		1/654 (0.2%)
Cervical vertebral fracture	1/624 (0.2%)		0/654 (0%)
Femoral neck fracture	0/624 (0%)		1/654 (0.2%)
Femur fracture	1/624 (0.2%)		3/654 (0.5%)
Flank pain	1/624 (0.2%)		0/654 (0%)
Fracture	0/624 (0%)		1/654 (0.2%)
Gait disturbance	1/624 (0.2%)		0/654 (0%)
Hip fracture	2/624 (0.3%)		0/654 (0%)
Humerus fracture	0/624 (0%)		1/654 (0.2%)
Hypercreatinaemia	0/624 (0%)		1/654 (0.2%)
Musculoskeletal chest pain	1/624 (0.2%)		0/654 (0%)
Musculoskeletal pain	0/624 (0%)		1/654 (0.2%)
Neck pain	0/624 (0%)		2/654 (0.3%)
Osteoarthritis	0/624 (0%)		2/654 (0.3%)
Pain in extremity	0/624 (0%)		1/654 (0.2%)
Pathological fracture	1/624 (0.2%)		1/654 (0.2%)
Rhabdomyolysis	0/624 (0%)		1/654 (0.2%)
Spinal compression fracture	0/624 (0%)		1/654 (0.2%)
Spinal fracture	1/624 (0.2%)		0/654 (0%)
Tibia fracture	0/624 (0%)		1/654 (0.2%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acute leukaemia	0/624 (0%)		1/654 (0.2%)
Breast cancer metastatic	0/624 (0%)		1/654 (0.2%)
Lymphoma	1/624 (0.2%)		0/654 (0%)
Ovarian cyst	0/624 (0%)		1/654 (0.2%)
Plasma cell myeloma	0/624 (0%)		1/654 (0.2%)
Renal cell carcinoma	0/624 (0%)		2/654 (0.3%)
Transitional cell carcinoma	0/624 (0%)		1/654 (0.2%)
Nervous system disorders
Ataxia	1/624 (0.2%)		0/654 (0%)
Cerebellar haemorrhage	1/624 (0.2%)		0/654 (0%)
Cerebrovascular accident	1/624 (0.2%)		1/654 (0.2%)
Cerebrovascular disorder	0/624 (0%)		1/654 (0.2%)
Cognitive disorder	1/624 (0.2%)		0/654 (0%)
Confusional state	1/624 (0.2%)		1/654 (0.2%)
Dementia Alzheimer's type	1/624 (0.2%)		0/654 (0%)
Depressed level of consciousness	0/624 (0%)		1/654 (0.2%)
Dizziness	1/624 (0.2%)		0/654 (0%)
Encephalopathy	1/624 (0.2%)		0/654 (0%)
Facial paralysis	0/624 (0%)		1/654 (0.2%)
Facial paresis	1/624 (0.2%)		0/654 (0%)
Headache	2/624 (0.3%)		0/654 (0%)
Hemiparesis	2/624 (0.3%)		0/654 (0%)
Ischaemic stroke	1/624 (0.2%)		0/654 (0%)
Meningioma	1/624 (0.2%)		0/654 (0%)
Paraparesis	1/624 (0.2%)		0/654 (0%)
Syncope	1/624 (0.2%)		3/654 (0.5%)
Product Issues
Device breakage	1/624 (0.2%)		0/654 (0%)
Device dislocation	0/624 (0%)		1/654 (0.2%)
Psychiatric disorders
Anxiety	0/624 (0%)		1/654 (0.2%)
Hallucination, visual	1/624 (0.2%)		0/654 (0%)
Renal and urinary disorders
Acute kidney injury	0/624 (0%)		1/654 (0.2%)
Hepatorenal failure	0/624 (0%)		1/654 (0.2%)
Hydronephrosis	1/624 (0.2%)		1/654 (0.2%)
Hypercreatininaemia	1/624 (0.2%)		0/654 (0%)
Nephrolithiasis	0/624 (0%)		1/654 (0.2%)
Pelvi-ureteric obstruction	1/624 (0.2%)		0/654 (0%)
Pelvic pain	1/624 (0.2%)		0/654 (0%)
Renal failure	1/624 (0.2%)		2/654 (0.3%)
Renal impairment	1/624 (0.2%)		0/654 (0%)
Reproductive system and breast disorders
Breast abscess	0/624 (0%)		1/654 (0.2%)
Breast cellulitis	1/624 (0.2%)		1/654 (0.2%)
Ovarian enlargement	0/624 (0%)		1/654 (0.2%)
Respiratory, thoracic and mediastinal disorders
Acute pulmonary oedema	0/624 (0%)		1/654 (0.2%)
Cardio-respiratory arrest	1/624 (0.2%)		0/654 (0%)
Epistaxis	1/624 (0.2%)		0/654 (0%)
Haemothorax	0/624 (0%)		1/654 (0.2%)
Hypoxia	0/624 (0%)		2/654 (0.3%)
Idiopathic pulmonary fibrosis	0/624 (0%)		1/654 (0.2%)
Interstitial lung disease	0/624 (0%)		1/654 (0.2%)
Pleural effusion	1/624 (0.2%)		2/654 (0.3%)
Pleuritic pain	0/624 (0%)		1/654 (0.2%)
Pneumothorax	1/624 (0.2%)		1/654 (0.2%)
Pulmonary embolism	3/624 (0.5%)		3/654 (0.5%)
Respiratory tract infection	1/624 (0.2%)		0/654 (0%)
Tachypnoea	0/624 (0%)		1/654 (0.2%)
Skin and subcutaneous tissue disorders
Cellulitis	0/624 (0%)		5/654 (0.8%)
Erythema	0/624 (0%)		1/654 (0.2%)
Excessive granulation tissue	0/624 (0%)		1/654 (0.2%)
Herpes zoster	0/624 (0%)		1/654 (0.2%)
Incision site cellulitis	0/624 (0%)		1/654 (0.2%)
Infected skin ulcer	1/624 (0.2%)		0/654 (0%)
Malignant melanoma	0/624 (0%)		1/654 (0.2%)
Paronychia	0/624 (0%)		1/654 (0.2%)
Pruritus	0/624 (0%)		1/654 (0.2%)
Rash	0/624 (0%)		1/654 (0.2%)
Rash papular	0/624 (0%)		1/654 (0.2%)
Vascular disorders
Acute myocardial infarction	1/624 (0.2%)		0/654 (0%)
Angina unstable	0/624 (0%)		1/654 (0.2%)
Deep vein thrombosis	2/624 (0.3%)		2/654 (0.3%)
Gastrointestinal haemorrhage	1/624 (0.2%)		2/654 (0.3%)
Haematemesis	0/624 (0%)		2/654 (0.3%)
Haematochezia	1/624 (0.2%)		0/654 (0%)
Haematoma	0/624 (0%)		1/654 (0.2%)
Haemoptysis	0/624 (0%)		2/654 (0.3%)
Haemorrhoids thrombosed	1/624 (0.2%)		0/654 (0%)
Hypertension	1/624 (0.2%)		1/654 (0.2%)
Hypotension	1/624 (0.2%)		0/654 (0%)
Lymphoedema	2/624 (0.3%)		0/654 (0%)
Melaena	0/624 (0%)		1/654 (0.2%)
Myocardial infarction	1/624 (0.2%)		1/654 (0.2%)
Pulmonary hypertension	0/624 (0%)		1/654 (0.2%)
Rectal haemorrhage	0/624 (0%)		2/654 (0.3%)
Superior vena cava syndrome	0/624 (0%)		1/654 (0.2%)
Thrombophlebitis	0/624 (0%)		1/654 (0.2%)
Thrombosis	1/624 (0.2%)		0/654 (0%)
Uterine haemorrhage	0/624 (0%)		1/654 (0.2%)
Other (Not Including Serious) Adverse Events
	Placebo + Letrozole 2.5 mg		Lapatinib 1500 mg + Letrozole 2.5 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	481/624 (77.1%)		589/654 (90.1%)
Blood and lymphatic system disorders
Anaemia	28/624 (4.5%)		52/654 (8%)
Cardiac disorders
Dyspnoea	68/624 (10.9%)		58/654 (8.9%)
Gastrointestinal disorders
Abdominal pain	28/624 (4.5%)		48/654 (7.3%)
Abdominal pain upper	16/624 (2.6%)		36/654 (5.5%)
Constipation	64/624 (10.3%)		45/654 (6.9%)
Diarrhoea	109/624 (17.5%)		393/654 (60.1%)
Dyspepsia	28/624 (4.5%)		56/654 (8.6%)
Nausea	123/624 (19.7%)		190/654 (29.1%)
Stomatitis	8/624 (1.3%)		34/654 (5.2%)
Vomiting	69/624 (11.1%)		101/654 (15.4%)
General disorders
Asthenia	62/624 (9.9%)		76/654 (11.6%)
Decreased appetite	55/624 (8.8%)		80/654 (12.2%)
Fatigue	98/624 (15.7%)		124/654 (19%)
Mucosal inflammation	11/624 (1.8%)		37/654 (5.7%)
Pyrexia	32/624 (5.1%)		42/654 (6.4%)
Infections and infestations
Nasopharyngitis	44/624 (7.1%)		50/654 (7.6%)
Upper respiratory tract infection	32/624 (5.1%)		31/654 (4.7%)
Urinary tract infection	44/624 (7.1%)		35/654 (5.4%)
Investigations
Alanine aminotransferase increased	28/624 (4.5%)		58/654 (8.9%)
Aspartate aminotransferase increased	24/624 (3.8%)		54/654 (8.3%)
Blood alkaline phosphatase increased	15/624 (2.4%)		34/654 (5.2%)
Weight decreased	13/624 (2.1%)		35/654 (5.4%)
Metabolism and nutrition disorders
Oedema peripheral	46/624 (7.4%)		28/654 (4.3%)
Musculoskeletal and connective tissue disorders
Arthralgia	135/624 (21.6%)		112/654 (17.1%)
Back pain	91/624 (14.6%)		99/654 (15.1%)
Bone pain	48/624 (7.7%)		26/654 (4%)
Muscle spasms	22/624 (3.5%)		33/654 (5%)
Musculoskeletal chest pain	34/624 (5.4%)		30/654 (4.6%)
Musculoskeletal pain	49/624 (7.9%)		52/654 (8%)
Myalgia	41/624 (6.6%)		26/654 (4%)
Pain in extremity	65/624 (10.4%)		67/654 (10.2%)
Nervous system disorders
Dizziness	46/624 (7.4%)		44/654 (6.7%)
Headache	79/624 (12.7%)		84/654 (12.8%)
Insomnia	50/624 (8%)		41/654 (6.3%)
Respiratory, thoracic and mediastinal disorders
Cough	89/624 (14.3%)		71/654 (10.9%)
Epistaxis	9/624 (1.4%)		61/654 (9.3%)
Skin and subcutaneous tissue disorders
Acne	4/624 (0.6%)		39/654 (6%)
Alopecia	39/624 (6.3%)		74/654 (11.3%)
Dry skin	25/624 (4%)		82/654 (12.5%)
Erythema	9/624 (1.4%)		33/654 (5%)
Nail disorder	6/624 (1%)		63/654 (9.6%)
Paronychia	1/624 (0.2%)		39/654 (6%)
Pruritus	50/624 (8%)		76/654 (11.6%)
Rash	56/624 (9%)		223/654 (34.1%)
Vascular disorders
Hot flush	80/624 (12.8%)		65/654 (9.9%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

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