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Breast Neoplasms

Breast Diseases

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Amino Acids

Paclitaxel

Albumin-Bound Paclitaxel

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Lapatinib

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Antimitotic Agents

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Open Label - Combination Therapy (Lapatinib and Paclitaxel)

Lapatinib (GW572016) oral tablets

Paclitaxel 80 mg/m2 every 3 weeks, 4th week rest for minimum 6 months

Paclitaxel infusion

Placebo

Novartis Pharmaceuticals

This was a randomized, double-blind, placebo-controlled, multicenter, Phase III study to evaluate and compare the efficacy and safety of Lapatinib + Paclitaxel versus Placebo + Paclitaxel in men and women with ErbB2 amplified metastatic (Stage IV) breast cancer who had not received prior therapy for metastatic disease.

Subjects were randomized to receive either Lapatinib (1500 mg once daily) + Paclitaxel (80 mg/m2 IV weekly for 3 weeks every 4 weeks) or Placebo (once daily) + Paclitaxel (80 mg/m2 IV weekly for 3 weeks every 4 weeks).

Subjects who progressed while on study and were on the placebo+paclitaxel arm were permitted to enter an extension phase of open label monotherapy therapy with lapatinib or open label combination therapy with lapatinib+paclitaxel and followed for response, progression and survival.

Based on the positive results in the primary analysis, Protocol Amendment 02 (dated 09 May 2011) discontinued further entry into the lapatinib monotherapy extension phase, and ongoing subjects taking placebo were permitted to replace it with open label lapatinib therapy (with or without continued paclitaxel therapy).

Following the primary Overall Survival (OS) analysis and subsequent implementation of Protocol Amendment 03, subjects who were still receiving active treatment entered the Long-term follow-up (LTFU) phase of the study. Reporting requirements in the LTFU phase were limited to Adverse events of special interest (AESI), Serious adverse events (SAEs) and pregnancy, and the subjects continued to receive treatment until the occurrence of unacceptable toxicity or disease progression (as determined by the investigator) or permanent withdrawal from treatment for any reason. Subjects who were no longer receiving active treatment were withdrawn from the study.

Study In Women And Men With Metastatic Breast Cancer That Have Overexpression Of ErbB2

A Randomized, Multicenter, Double-Blind, Placebo-Controlled, Phase III Study of Lapatinib (GW572016) in Combination With Paclitaxel Versus Paclitaxel Plus Placebo in Subjects With ErbB2 Amplified 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

Overall Survival (OS) was defined as the interval of time (in months) between the date of randomization and the date of death due to any cause.

Progression-free survival (PFS) during the randomized phase was defined as the interval of time (in months) between the date of randomization and the earlier of date of disease progression (radiological or clinical assessment of symptomatic progression), or date of death due to any cause.

Overall response rate (ORR) during the randomized phase was evaluated per Response Evaluation Criteria in Solid Tumors (RECIST v1.1) and defined as the percentage of subjects achieving either a Complete Response (CR) or a Partial Response (PR). Participants with unknown or missing responses were treated as non-responders.

Clinical benefit rate (CBR) was defined as the percentage of subjects with evidence of CR or PR or stable disease (neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease \[at least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of \>=1 new lesions\], taking as reference the smallest sum LD since treatment start) of \>=24 weeks, based on confirmed responses from the investigator assessment of best overall response during the randomized phase.

For subjects who show CR or PR, duration of response (DOR) was defined to be the time from first documented evidence of PR or CR until the first documented sign of disease progression (radiological or clinical assessment of symptomatic progression) or death due to any cause, if sooner during the randomized phase.

The original outcome measure to be analyzed was Time to response (TTR) during the randomized phase defined as the time from randomization until first documented evidence of PR or CR (whichever status was recorded first); however, data were presented as the number of participants with a response at each nominal visit. Responses were based on the investigator's assessment, and only participants with a confirmed CR or PR were included in this analysis.

Phosphatidylinositol 3-kinase (PI3K) pathway deregulation (that is PIK3CA mutations and/or phosphatase and tensin homolog (PTEN) loss) was studied to evaluate the predictive and prognostic value of PIK3CA mutations and/or PTEN low in HER2-positive patients receiving first-line treatment with paclitaxel alone or in combination with lapatinib. A PIK3CA mutation test kit was used to assess mutation status on genomic deoxyribonucleic acid (DNA) isolated from tumor tissue.

Phosphatidylinositol 3-kinase (PI3K) pathway deregulation (that is PIK3CA mutations and/or phosphatase and tensin homolog (PTEN) loss) was studied to evaluate the predictive and prognostic value of PIK3CA mutations and/or PTEN low in HER2-positive patients receiving first-line treatment with paclitaxel alone or in combination with lapatinib. Immunohistochemistry (IHC) staining in an analytically validated assay was used in the assessment of PTEN protein expression on tumor tissue. Staining intensity was allocated a score of 0, 1+, 2+ or 3+. Tumors scored IHC 0 were considered as exhibiting an absence of PTEN expression whereas those scored ICH 1+, 2+ or 3+ were considered as exhibiting any PTEN expression, being 3+ the highest expression.

ORR was evaluated per RECIST v1.1 and defined as the percentage of subjects achieving either CR or PR. Phosphatidylinositol 3-kinase (PI3K) pathway deregulation (that is PIK3CA mutations and/or phosphatase and tensin homolog (PTEN) loss) was studied to evaluate the predictive and prognostic value of PIK3CA mutations and/or PTEN low in HER2-positive patients receiving first-line treatment with paclitaxel alone or in combination with lapatinib. A PIK3CA mutation test kit was used to assess mutation status on genomic deoxyribonucleic acid (DNA) isolated from tumor tissue.

ORR was evaluated per RECIST v1.1 and defined as the percentage of subjects achieving either CR or PR. Phosphatidylinositol 3-kinase (PI3K) pathway deregulation (that is PIK3CA mutations and/or phosphatase and tensin homolog (PTEN) loss) was studied to evaluate the predictive and prognostic value of PIK3CA mutations and/or PTEN low in HER2-positive patients receiving first-line treatment with paclitaxel alone or in combination with lapatinib. Immunohistochemistry (IHC) staining in an analytically validated assay was used in the assessment of PTEN protein expression on tumor tissue. Staining intensity was allocated a score of 0, 1+, 2+ or 3+. Tumors scored IHC 0 were considered as exhibiting an absence of PTEN expression whereas those scored ICH 1+, 2+ or 3+ were considered as exhibiting any PTEN expression, being 3+ the highest expression. Tumors scored IHC 0/1+ were considered PTEN low.

CBR was evaluated per RECIST v1.1 and defined as the percentage of subjects achieving CR or PR or stable disease. Phosphatidylinositol 3-kinase (PI3K) pathway deregulation (that is PIK3CA mutations and/or phosphatase and tensin homolog (PTEN) loss) was studied to evaluate the predictive and prognostic value of PIK3CA mutations and/or PTEN low in HER2-positive patients receiving first-line treatment with paclitaxel alone or in combination with lapatinib. A PIK3CA mutation test kit was used to assess mutation status on genomic deoxyribonucleic acid (DNA) isolated from tumor tissue.

CBR was evaluated per RECIST v1.1 and defined as the percentage of subjects achieving CR or PR or stable disease. Phosphatidylinositol 3-kinase (PI3K) pathway deregulation (that is PIK3CA mutations and/or phosphatase and tensin homolog (PTEN) loss) was studied to evaluate the predictive and prognostic value of PIK3CA mutations and/or PTEN low in HER2-positive patients receiving first-line treatment with paclitaxel alone or in combination with lapatinib. Immunohistochemistry (IHC) staining in an analytically validated assay was used in the assessment of PTEN protein expression on tumor tissue. Staining intensity was allocated a score of 0, 1+, 2+ or 3+. Tumors scored IHC 0 were considered as exhibiting an absence of PTEN expression whereas those scored ICH 1+, 2+ or 3+ were considered as exhibiting any PTEN expression, being 3+ the highest expression. Tumors scored IHC 0/1+ were considered PTEN low.

Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.

Lapatinib 1500 milligrams (mg) administered once daily plus paclitaxel 80 mg/meters squared (m\^2) administered intravenously (IV) weekly for 3 weeks every 4 weeks

Lapatinib 1500 mg + Paclitaxel

Matching placebo administered once daily plus paclitaxel 80 mg/m\^2 administered IV weekly for 3 weeks every 4 weeks

Placebo + Paclitaxel

Open Label - Monotherapy

Open Label - Combination Therapy

Total

Age, Continuous

Sex: Female, Male

White

Asian

Hispanic

Other

Race/Ethnicity, Customized

Metastasis is defined as the spread of a tumor or cancerous cells from the primary site to one or more sites elsewhere in the body. Visceral metastasis is defined as the spread of cancer to viscera, the internal organs of the body, specifically those within the chest (as the heart or lungs) or abdomen (as the liver, pancreas, or intestines). Non-visceral organs are defined as any organ not considered visceral.

Number of participants with any visceral metastatic disease and with only non-visceral disease

Cancer cells have hormone receptor expression of Estrogen Receptor (ER) and/or Progesterone Receptor (PR) and are thus considered to be ER+ and/or PgR+ cells, respectively.

Number of Participants with the Indicated Hormone Receptor Status

The stage of cancer is a description of the extent to which the cancer has spread. Stage I cancer is localized; Stage II cancer has not started to spread into the surrounding tissue, but the tumor is larger than in Stage I; Stage III cancer is locally advanced and/or involves local lymph nodes; Stage IV cancer has spread to other organs.

Number of Participants with the Indicated Stage of Disease at Initial Diagnosis

Eastern Cooperative Oncology Group (ECOG) Performance Status classifies participants according to their functional impairment, and scores indicate: 0, fully active; 1, ambulatory, restricted strenuous activity; 2, ambulatory, no work activity; 3, partially confined to bed; 4, totally confined in bed; 5, death. Participants were required to have a baseline ECOG performance status of 0 or 1 for study participation.

Number of Participants with the Indicated Eastern Cooperative Oncology Group Performance Status

Tumor cells move from the primary site to other sites in the body, where they continue to multiply and eventually form another clinically detectable tumor; thus, the site becomes metastatic. The table indicates number of metastatic sites.

Number of Participants with the Indicated Number of Metastatic Sites

The disease-free interval was defined as the time from initial diagnosis to metastases

Mean Time of Disease-Free Interval

The data collected for China patients after 01JUL2019 were excluded from analysis due to local regulations in China.

Study Director

Primary OS analysis cut-off date = 18-Jun-2010

Intent-to-Treat (ITT) Population. The ITT population was comprised of all randomized subjects and was based on the treatment to which the subject was randomized.

Overall Survival (OS) at 53 Months

Final OS analysis cut-0ff date = 23-Nov-2021

Overall Survival (OS) at 190 Months

Progression-free Survival (PFS) by Investigator Assessment

Overall Response Rate (ORR) by Investigator Assessment

Clinical Benefit Rate (CBR)

Subset of participants in the Intent-to-Treat (ITT) Population with a confirmed CR or PR

Duration of Response (DOR)

Week 8

Week 12

Week 16

Week 24

Week 32

Week 40

Week 48

Week 56

Week 64

Week 72

Participants in the Intent-to-Treat (ITT) Population with a confirmed CR or PR

Number of Participants With a CR or PR at Weeks 8, 12, 16, 24, 32, 40, 48, 56, 64, and 72

Participants in the Intent-to-Treat (ITT) Population with tumors evaluable for PIK3CA mutations

Number of Tumors Evaluable for PIK3CA Mutations

Participants in the Intent-to-Treat (ITT) Population with tumors evaluable for PTEN

Number of Participants With Tumors Evaluable for PTEN

PIK3CA mutation

PIK3CA wild-type

Participants in the Intent-to-Treat (ITT) Population with tumors evaluable for PIK3CA mutations (PIK3CA mutation and PIK3CA wild type)

Predictive Effect of PIK3CA Mutations Status on Overall Response Rate (ORR)

PTEN low

Without PTEN low

Participants in the Intent-to-Treat (ITT) Population with PTEN low and without PTEN low

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Study In Women And Men With Metastatic Breast Cancer That Have Overexpression Of ErbB2	NCT00281658	Neoplasms, Brea...	Lapatinib (GW57... Paclitaxel infu... Placebo	18 Years -	Novartis
Study In Women And Men With Metastatic Breast Cancer That Have Overexpression Of ErbB2	NCT00281658	Neoplasms, Brea...	Lapatinib (GW57... Paclitaxel infu... Placebo	18 Years -	Novartis

Spots Global Cancer Trial Database for lapatinib (gw572016) oral tablets