Neoplasms

All Conditions

Skin and Connective Tissue Diseases

Symptoms and General Pathology

Carcinoma

Breast Neoplasms

Disease Progression

Breast Diseases

Skin Diseases

Antineoplastic Agents

All Drugs and Chemicals

Amino Acids

Letrozole

Estrogens

Mitogens

Lapatinib

Progesterone

Aromatase Inhibitors

Enzyme Inhibitors

Estrogen Antagonists

Estrogen Receptor Antagonists

Hormones

Hormone Antagonists

Tyrosine Kinase Inhibitors

Protein Kinase Inhibitors

Tyrosine

Letrozole (2.5 mg once daily orally) with Placebo (which matched with Lapatinib tablet)

Lapatinib (1500 mg once daily orally) with Letrozole (2.5 mg once daily orally)

Placebo (which matched with lapatinib tablet)

Placebo

Novartis Pharmaceuticals

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.

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

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

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

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.

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.

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

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.

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.

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.

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 to response is defined as the time from randomization until the first documented evidence of CR (disappearance of all target lesions) or PR (at least a 30% decrease in the sume of the LD of target lesions, taking as reference the baseline sum LD) (whichever status was recorded first). The assessments of CR or PR required confirmation using bone scans.

Duration of response 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.

The confirmation criteria for the evidence of brain metastases was the incidence of lesions occurring within any part of the central nervous system (CNS) as evidenced by radiological scans. Metastases are defined as the spread of cancer from one part of the body to another.

TTP 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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Participants who had a HER2-negative tumor status based on baseline tissue with baseline serum HER2 ECD values =\<15 ng/mL but later had at least two consecutive serum HER2 ECD values \>15 ng/mL experienced seroconversion.

Time to seroconversion was defined as the time from the date of randomization until the first instance of serum HER2 (\>15 ng/mL) on two consecutive occasions.

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+).

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).

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.

Placebo + Letrozole 2.5 mg

Participants received 6 tablets of Lapatinib orally daily (250 mg lapatinib/tablet for a total of 1500 mg of lapatinib/day; approximately at the same time each day), either 1 hour (or more) before breakfast or 1 hour (or more) after breakfast. Participants also received 1 tablet of letrozole 2.5 mg orally daily, preferably with the daily dose of lapatinib.

Lapatinib 1500 mg + Letrozole 2.5 mg

Total

Age, Continuous

Sex: Female, Male

White

Black

Asian

American Hispanic

Other

Race/Ethnicity, Customized

Study Director

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.

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

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

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

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.

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

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

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

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

Overall Survival in the HER2-Positive Population

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

SDS, Soft tissue or visceral

SDS, Bone-only disease

PAET, DI =>6 months

PAET, DI <6 months

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

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

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

Unknown

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.

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.

Week 12

Week 16

Week 24 or longer

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

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

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

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

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

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

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

Overall Survival in the ITT Population

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

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

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.

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

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

Week 24

Week 28

Week 36 or longer

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

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

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

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

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

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

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

Day 1, baseline

Week 36

Week 48

Week 60

Week 72

Week 84

Week 96

Week 108

Week 120

Week 132

Week 144

Week 156

Week 168

Week 180

Week 192

Conclusion/withdrawal

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

Conclusion/WD

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

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

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

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

FACT-B total, =>8 (MID upper bound)

FACT-G, =>6 (MID upper bound)

TOI, =>6 (MID upper bound)

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

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

FISH status, Positive

FISH status, Negative

FISH status, missing

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

IHC Intensity 0

IHC Intensity 1

IHC Intensity 2

IHC Intensity 3

IHC Intensity Missing

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

>15 ng/mL, CR/PR

>15 ng/mL, SD

>15 ng/mL, PD/NE

=<15 ng/mL, CR/PR

=<15 ng/mL, SD

=<15 ng/mL, PD/NE

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

Seroconversion, No

Seroconversion, Yes

Missing

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.

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

HER2-Negative Population. Only those participants who had a HER2-negative tumor status based on baseline tissue with baseline serum HER2 ECD values =\<15 ng/mL but later had at least two consecutive serum HER2 ECD values \>15 ng/mL were assessed.

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

EGFR, 0

EGFR, 1+

EGFR, 2+

EGFR, 3+

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

On-treatment deaths

All deaths

On treatment deaths were collected from FPFT up to 30 days after study drug discontinuation, for a maximum duration of 663.9 weeks (treatment duration ranged from 0.1 to 659.9 weeks).

Deaths post treatment survival follow up were collected after the on- treatment period, up to approximately 14 years. Patients who didn't die during the on-treatment period and had not stopped study participation at the time of data cut-off (end of study) were censored.

Clinical database population; all treated patients.

All Collected Deaths

Overall Study

Recurrence

Anti-Infective Agents

Capecitabine

Everolimus

Exemestane

Anastrozole

Antimetabolites

Sirolimus

Temsirolimus

MTOR Inhibitors

Immunosuppressive Agents

Immunologic Factors

Capecitabine (1250 mg/m2 twice daily) for two weeks, followed by one week rest period in 3-weeks cycles (investigational arm).

Everolimus (10 mg daily) (investigational arm).

Everolimus (10 mg daily) with Exemestane (25 mg daily) (control arm).

Capecitabine, tablets for oral use, 1250 mg/m² twice daily for 2 weeks followed by one week rest (3-week-cycle) (locally supplied)

Exemestane, tablets for oral use, 25 mg per day in (locally supplied)

Everolimus, 5 mg tablets for oral use, 10 mg (2 x 5 mg) per day (centrally supplied)

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Study Comparing Lapatinib (GW572016) And Letrozole Versus Letrozole In Subjects With Advanced Or Metastatic Breast Cancer	NCT00073528	Breast Neoplasm...	Lapatinib Letrozole Placebo	18 Years -	Novartis
A Phase II Study of Everolimus in Combination With Exemestane Versus Everolimus Alone Versus Capecitabine in Advance Breast Cancer.	NCT01783444	Breast Cancer	Capecitabine Exemestane Everolimus	18 Years -	Novartis
A Phase II Study of Everolimus in Combination With Exemestane Versus Everolimus Alone Versus Capecitabine in Advance Breast Cancer.	NCT01783444	Breast Cancer	Capecitabine Exemestane Everolimus	18 Years -	Novartis

Spots Global Cancer Trial Database for breast cancer positive for human epidermal growth factor receptor 2