Trial Outcomes & Findings for Paclitaxel With / Without GW572016 (Lapatinib) As First Line Therapy For Women With Advanced Or Metastatic Breast Cancer (NCT NCT00075270)

Last Updated: 2015-05-06

Results Overview

Time to progression (TTP) is defined as the interval between the date of randomization and the earliest date of progression of disease (PD) or death due to breast cancer. The investigator assessed PD based on radiological PD (imaging data) and clinical symptomatic progress (Response Evaluation Criteria in Solid Tumors \[RECIST\] Criteria: target lesion (TL), at least a 20% increase in the sum of largest diameter (LD) of TLs or the appearance of one or more new lesions; non-TL (NTL), the appearance of one or more new lesions and/or unequivocal progression of existing NTLs). TTP was assessed in participants who died due to breast cancer or progressed, as assessed by the investigator, as well as in those who were censored and completed follow-up and those who were censored but are still being followed. For censored participants (those without a documented date of disease progression/death due to breast cancer), the date of the last radiographic assessment was used.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

580 participants

Primary outcome timeframe

Randomization until the date of disease progression or death (average of 26 weeks)

Results posted on

2015-05-06

Participant Flow

A total of 580 participants were enrolled and randomized to treatment; however one participant withdrew from the study before taking any medication. Thus, only 579 participants were included in the Intent-to-Treat Population (comprised of all randomized participants who had received at least one dose of randomized therapy \[lapatinib or placebo\]).

Participant milestones

Participant milestones
Measure	Lapatinib With Paclitaxel Participants received lapatinib 1500 milligrams (mg) orally once daily (OD) with paclitaxel 175 mg/meters squared (m\^2) intravenously (IV) over the course of 3 hours, every 3 weeks. The treatment group was stratified by sites of metastatic disease and stage of disease. Participants were treated until disease progression, unacceptable toxicity, or consent withdrawal.	Placebo With Paclitaxel Participants received matching placebo orally OD with paclitaxel (175 mg/m\^2 IV) over the course of 3 hours, every 3 weeks. The treatment group was stratified by sites of metastatic disease and stage of disease. Participants were treated until disease progression, unacceptable toxicity, or consent withdrawal.
Overall Study STARTED	291	288
Overall Study Missing	26	13
Overall Study COMPLETED	5	4
Overall Study NOT COMPLETED	286	284

Reasons for withdrawal

Reasons for withdrawal
Measure	Lapatinib With Paclitaxel Participants received lapatinib 1500 milligrams (mg) orally once daily (OD) with paclitaxel 175 mg/meters squared (m\^2) intravenously (IV) over the course of 3 hours, every 3 weeks. The treatment group was stratified by sites of metastatic disease and stage of disease. Participants were treated until disease progression, unacceptable toxicity, or consent withdrawal.	Placebo With Paclitaxel Participants received matching placebo orally OD with paclitaxel (175 mg/m\^2 IV) over the course of 3 hours, every 3 weeks. The treatment group was stratified by sites of metastatic disease and stage of disease. Participants were treated until disease progression, unacceptable toxicity, or consent withdrawal.
Overall Study Withdrawal by Subject	28	21
Overall Study Lost to Follow-up	25	28
Overall Study Protocol Violation	0	2
Overall Study Death	198	215
Overall Study Other/Unknown	9	5
Overall Study Missing	26	13

Baseline Characteristics

Paclitaxel With / Without GW572016 (Lapatinib) As First Line Therapy For Women With Advanced Or Metastatic Breast Cancer

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Lapatinib With Paclitaxel n=291 Participants Participants received lapatinib 1500 milligrams (mg) orally once daily (OD) with paclitaxel 175 mg/meters squared (m\^2) intravenously (IV) over the course of 3 hours, every 3 weeks. The treatment group was stratified by sites of metastatic disease and stage of disease. Participants were treated until disease progression, unacceptable toxicity, or consent withdrawal.	Placebo With Paclitaxel n=288 Participants Participants received matching placebo orally OD with paclitaxel (175 mg/m\^2 IV) over the course of 3 hours, every 3 weeks. The treatment group was stratified by sites of metastatic disease and stage of disease. Participants were treated until disease progression, unacceptable toxicity, or consent withdrawal.	Total n=579 Participants Total of all reporting groups
Age, Continuous	51.3 Years STANDARD_DEVIATION 10.45 • n=5 Participants	52.4 Years STANDARD_DEVIATION 10.98 • n=7 Participants	51.8 Years STANDARD_DEVIATION 10.72 • n=5 Participants
Sex: Female, Male Female	291 Participants n=5 Participants	288 Participants n=7 Participants	579 Participants n=5 Participants
Sex: Female, Male Male	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race/Ethnicity, Customized White	190 participants n=5 Participants	182 participants n=7 Participants	372 participants n=5 Participants
Race/Ethnicity, Customized Black	10 participants n=5 Participants	10 participants n=7 Participants	20 participants n=5 Participants
Race/Ethnicity, Customized Asian	30 participants n=5 Participants	35 participants n=7 Participants	65 participants n=5 Participants
Race/Ethnicity, Customized American Hispanic	54 participants n=5 Participants	53 participants n=7 Participants	107 participants n=5 Participants
Race/Ethnicity, Customized Unknown	7 participants n=5 Participants	8 participants n=7 Participants	15 participants n=5 Participants

PRIMARY outcome

Timeframe: Randomization until the date of disease progression or death (average of 26 weeks)

Population: Intent-to-Treat (ITT) Population: all randomized participants who had received at least one dose of randomized therapy (lapatinib or placebo)

Outcome measures

Outcome measures
Measure	Lapatinib With Paclitaxel n=291 Participants Participants received lapatinib 1500 mg orally OD with paclitaxel 175 m\^2 IV over the course of 3 hours, every 3 weeks. The treatment group was stratified by sites of metastatic disease and stage of disease. Participants were treated until disease progression, unacceptable toxicity, or consent withdrawal.	Placebo With Paclitaxel n=288 Participants Participants received matching placebo orally OD with paclitaxel (175 mg/m\^2 IV) over the course of 3 hours, every 3 weeks. The treatment group was stratified by sites of metastatic disease and stage of disease. Participants were treated until disease progression, unacceptable toxicity, or consent withdrawal.
Time to Progression as Evaluated by the Investigator	29.0 weeks Interval 13.9 to 46.9	22.9 weeks Interval 12.0 to 38.3

PRIMARY outcome

Timeframe: Randomization until the date of disease progression or death (average of 26 weeks)

Population: ITT Population

Time to progression is defined as the interval between the date of randomization and the earliest date of progression of disease (PD) or death due to breast cancer. The IRC assessed PD based on radiological PD (imaging data) and clinical symptomatic progress (Response Evaluation Criteria in Solid Tumors \[RECIST\] Criteria: target lesion (TL), at least a 20% increase in the sum of largest diameter (LD) of TLs or the appearance of one or more new lesions; non-TL (NTL), the appearance of one or more new lesions and/or unequivocal progression of existing NTLs). TTP was assessed in participants who died due to breast cancer or progressed, as assessed by the independent reviewer, as well as in those who were censored and completed follow-up and those who were censored but are still being followed. For censored participants (those without a documented date of disease progression/death due to breast cancer), the date of the last radiographic assessment was used.

Outcome measures

Outcome measures
Measure	Lapatinib With Paclitaxel n=291 Participants Participants received lapatinib 1500 mg orally OD with paclitaxel 175 m\^2 IV over the course of 3 hours, every 3 weeks. The treatment group was stratified by sites of metastatic disease and stage of disease. Participants were treated until disease progression, unacceptable toxicity, or consent withdrawal.	Placebo With Paclitaxel n=288 Participants Participants received matching placebo orally OD with paclitaxel (175 mg/m\^2 IV) over the course of 3 hours, every 3 weeks. The treatment group was stratified by sites of metastatic disease and stage of disease. Participants were treated until disease progression, unacceptable toxicity, or consent withdrawal.
Time to Progression as Evaluated by the Independent Review Committee (IRC)	33.7 weeks Interval 18.7 to 69.1	26.1 weeks Interval 12.9 to 57.1

SECONDARY outcome

Timeframe: Randomization until the date of disease progression or death (average of 26 weeks)

Population: ITT Population

The percentage of participants with tumor response is defined as those participants with measurable disease who achieved either a complete response (CR) or partial response (PR). The Response Evaluation Criteria in Solid Tumors (RECIST) was used to evaluate the measurability of tumor lesions, to determine target lesion (TLs) and non-target lesion (NTLs). CR (TLs and NTLs): the disappearance of all TLs and NTLs; PR (for TLs): at least a 30% decrease in the sum of the largest diameter (LD) of TLs, taking as a reference the Baseline sum LD; PR (for NTLs): persistence of one or more lesions.

Outcome measures

Outcome measures
Measure	Lapatinib With Paclitaxel n=291 Participants Participants received lapatinib 1500 mg orally OD with paclitaxel 175 m\^2 IV over the course of 3 hours, every 3 weeks. The treatment group was stratified by sites of metastatic disease and stage of disease. Participants were treated until disease progression, unacceptable toxicity, or consent withdrawal.	Placebo With Paclitaxel n=288 Participants Participants received matching placebo orally OD with paclitaxel (175 mg/m\^2 IV) over the course of 3 hours, every 3 weeks. The treatment group was stratified by sites of metastatic disease and stage of disease. Participants were treated until disease progression, unacceptable toxicity, or consent withdrawal.
Number of Participants With Tumor Response as Evaluated by the Investigator CR	14 participants	6 participants
Number of Participants With Tumor Response as Evaluated by the Investigator PR	88 participants	67 participants

SECONDARY outcome

Timeframe: Randomization until the date of disease progression or death (average of 26 weeks)

Population: ITT Population

The percentage of participants with tumor response is defined as those participants with measurable disease who achieved either a complete response (CR) or partial response (PR). The RECIST criteria was used to evaluate the measurability of tumor lesions, to determine target lesion (TLs) and non-target lesion (NTLs). CR (TLs and NTLs): the disappearance of all TLs and NTLs; PR (for TLs): at least a 30% decrease in the sum of the largest diameter (LD) of TLs, taking as a reference the Baseline sum LD; PR (for NTLs): persistence of one or more lesions.

Outcome measures

Outcome measures
Measure	Lapatinib With Paclitaxel n=291 Participants Participants received lapatinib 1500 mg orally OD with paclitaxel 175 m\^2 IV over the course of 3 hours, every 3 weeks. The treatment group was stratified by sites of metastatic disease and stage of disease. Participants were treated until disease progression, unacceptable toxicity, or consent withdrawal.	Placebo With Paclitaxel n=288 Participants Participants received matching placebo orally OD with paclitaxel (175 mg/m\^2 IV) over the course of 3 hours, every 3 weeks. The treatment group was stratified by sites of metastatic disease and stage of disease. Participants were treated until disease progression, unacceptable toxicity, or consent withdrawal.
Number of Participants With Tumor Response as Evaluated by the Independent Review Committee CR	1 participants	1 participants
Number of Participants With Tumor Response as Evaluated by the Independent Review Committee PR	77 participants	53 participants

SECONDARY outcome

Timeframe: Randomization until the date of disease progression or death (average of 26 weeks)

Population: ITT Population

Percentage of participants. with CB is defined as the percentage of participants with evidence of CR (disappearance of all TLs and NTLs), PR (TLs: a \>=30% decrease in the sum of the LD, taking as a reference the Baseline sum LD; NTLs: persistence of \>=1 lesion), or stable disease (neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD) for \>=6 months based on RECIST criteria. PD for TL: a \>=20% increase in the sum of the LD of TLs or the appearance of \>=1 new lesion. PD for NTLs: the appearance of \>=1 new lesion and/or unequivocal progression of existing NTLs.

Outcome measures

Outcome measures
Measure	Lapatinib With Paclitaxel n=291 Participants Participants received lapatinib 1500 mg orally OD with paclitaxel 175 m\^2 IV over the course of 3 hours, every 3 weeks. The treatment group was stratified by sites of metastatic disease and stage of disease. Participants were treated until disease progression, unacceptable toxicity, or consent withdrawal.	Placebo With Paclitaxel n=288 Participants Participants received matching placebo orally OD with paclitaxel (175 mg/m\^2 IV) over the course of 3 hours, every 3 weeks. The treatment group was stratified by sites of metastatic disease and stage of disease. Participants were treated until disease progression, unacceptable toxicity, or consent withdrawal.
Percentage of Participants With Clinical Benefit (CB) as Assessed by the Investigator	40.5 Percentage of participants	31.9 Percentage of participants

SECONDARY outcome

Timeframe: Weeks 6, 12, 18, 24, 30, 36, 42, 48, 54, 60, 66, and 72

Population: ITT Population

Time to response (TTR) is defined as the time from randomization until the first documented evidence of CR (disappearance of all TLs and NTLs) or PR (for TLs: a \>=30% decrease in the sum of the LD of TLs, taking as a reference the Baseline sum LD; for NTLs: the persistence of \>=1 lesion) (whichever status was recorded first). TTR data are displayed as the number of participants achieving a CR or PR by the indicated week. The investigator evaluated the TTR, and the analysis was based on responses confirmed at a repeat assessment, with the TTR taken as the first time the response was observed.

Outcome measures

Outcome measures
Measure	Lapatinib With Paclitaxel n=291 Participants Participants received lapatinib 1500 mg orally OD with paclitaxel 175 m\^2 IV over the course of 3 hours, every 3 weeks. The treatment group was stratified by sites of metastatic disease and stage of disease. Participants were treated until disease progression, unacceptable toxicity, or consent withdrawal.	Placebo With Paclitaxel n=288 Participants Participants received matching placebo orally OD with paclitaxel (175 mg/m\^2 IV) over the course of 3 hours, every 3 weeks. The treatment group was stratified by sites of metastatic disease and stage of disease. Participants were treated until disease progression, unacceptable toxicity, or consent withdrawal.
Number of Participants With a Response of CR or PR by the Indicated Study Week Week 6	3 participants	0 participants
Number of Participants With a Response of CR or PR by the Indicated Study Week Week 12	83 participants	55 participants
Number of Participants With a Response of CR or PR by the Indicated Study Week Week 18	86 participants	57 participants
Number of Participants With a Response of CR or PR by the Indicated Study Week Week 24	98 participants	69 participants
Number of Participants With a Response of CR or PR by the Indicated Study Week Week 30	98 participants	69 participants
Number of Participants With a Response of CR or PR by the Indicated Study Week Week 36	101 participants	71 participants
Number of Participants With a Response of CR or PR by the Indicated Study Week Week 42	102 participants	72 participants
Number of Participants With a Response of CR or PR by the Indicated Study Week Week 48	102 participants	72 participants
Number of Participants With a Response of CR or PR by the Indicated Study Week Week 54	102 participants	72 participants
Number of Participants With a Response of CR or PR by the Indicated Study Week Week 60	102 participants	72 participants
Number of Participants With a Response of CR or PR by the Indicated Study Week Week 66	102 participants	72 participants
Number of Participants With a Response of CR or PR by the Indicated Study Week Week 72	102 participants	73 participants

SECONDARY outcome

Timeframe: From the time of the first documented complete or partial response until the first documented evidence of progression or death (average of 26 weeks)

Population: ITT Population. Only participants who had a CR or PR were evaluated.

The investigator evaluated the DOR for the subset of participants who showed a CR (disappearance of all TLs and NTLs) or PR (TLs: a \>=30% decrease in the sum of the LD of TLs, taking as a reference the Baseline sum LD; NTLs: persistence of \>=1 lesion). DOR is defined as the time from the first documented evidence of PR or CR until the first documented sign of PD (TL: a \>=20% increase in the sum of the LD of TLs or the appearance of \>=1 new lesion; NTL: the appearance of \>=1 new lesion and/or unequivocal progression of existing NTLs) or death due to breast cancer, if sooner.

Outcome measures

Outcome measures
Measure	Lapatinib With Paclitaxel n=102 Participants Participants received lapatinib 1500 mg orally OD with paclitaxel 175 m\^2 IV over the course of 3 hours, every 3 weeks. The treatment group was stratified by sites of metastatic disease and stage of disease. Participants were treated until disease progression, unacceptable toxicity, or consent withdrawal.	Placebo With Paclitaxel n=73 Participants Participants received matching placebo orally OD with paclitaxel (175 mg/m\^2 IV) over the course of 3 hours, every 3 weeks. The treatment group was stratified by sites of metastatic disease and stage of disease. Participants were treated until disease progression, unacceptable toxicity, or consent withdrawal.
Duration of Response (DOR)	28.3 weeks Interval 22.3 to 50.0	27.1 weeks Interval 18.1 to 46.3

SECONDARY outcome

Timeframe: Randomization until the date of disease progression or death (average of 26 weeks)

Population: ITT Population. PFS was assessed in par. who died or progressed, as well as in those who were censored and completed follow-up and those who were censored but are still being followed. For censored par. (those without a documented date of disease progression/death due to any cause), the date of the last radiographic assessment was used.

PFS is defined as the interval between the date of randomization and the earliest date of progression disease (PD) or death due to any cause, if sooner. For TLs, progressive disease is defined as at least a 20% increase in the sum of the LD of TLs or the appearance of 1 or more new lesions. For NTLs, progressive disease is defined as the appearance of 1 or more new lesions and/or unequivocal progression of existing NTLs. par., participants.

Outcome measures

Outcome measures
Measure	Lapatinib With Paclitaxel n=291 Participants Participants received lapatinib 1500 mg orally OD with paclitaxel 175 m\^2 IV over the course of 3 hours, every 3 weeks. The treatment group was stratified by sites of metastatic disease and stage of disease. Participants were treated until disease progression, unacceptable toxicity, or consent withdrawal.	Placebo With Paclitaxel n=288 Participants Participants received matching placebo orally OD with paclitaxel (175 mg/m\^2 IV) over the course of 3 hours, every 3 weeks. The treatment group was stratified by sites of metastatic disease and stage of disease. Participants were treated until disease progression, unacceptable toxicity, or consent withdrawal.
Progression-Free Survival (PFS)	25.1 weeks Interval 21.9 to 32.1	22.6 weeks Interval 21.0 to 25.4

SECONDARY outcome

Timeframe: Randomization until the date of disease progression or death (average of 26 weeks)

Population: ITT Population

PFS is defined as the interval between the date of randomization and the earliest date of disease progression or death due to any cause, if sooner. Six months PFS is defined as PFS at six months from the time of randomization. Raw data for 6 months PFS are not available; thus, data are presented as the number of participants who progressed or died at or prior to 6 months. For TLs, progressive disease is defined asat least a 20% increase in the sum of the LD of TLs or the appearance of 1 or more new lesions. For NTLs, progressive disease is defined as the appearance of 1 or more new lesions and/or unequivocal progression of existing NTLs. PFS was assessed in participants who died or progressed, as well as in those who were censored and completed follow-up and those who were censored but are still being followed. For censored participants (those without a documented date of disease progression/death due to breast cancer), the date of the last radiographic assessment was used.

Outcome measures

Outcome measures
Measure	Lapatinib With Paclitaxel n=291 Participants Participants received lapatinib 1500 mg orally OD with paclitaxel 175 m\^2 IV over the course of 3 hours, every 3 weeks. The treatment group was stratified by sites of metastatic disease and stage of disease. Participants were treated until disease progression, unacceptable toxicity, or consent withdrawal.	Placebo With Paclitaxel n=288 Participants Participants received matching placebo orally OD with paclitaxel (175 mg/m\^2 IV) over the course of 3 hours, every 3 weeks. The treatment group was stratified by sites of metastatic disease and stage of disease. Participants were treated until disease progression, unacceptable toxicity, or consent withdrawal.
Number of Participants Who Progressed or Died at or Prior to 6 Months, as a Measure of Six Months Progression-free Survival (PFS)	133 participants	153 participants

SECONDARY outcome

Timeframe: Randomization until the date of death due to any cause (average of 24 months)

Population: ITT population. Overall survival was assessed in participants who died as well as in those who were censored and completed follow-up and those who were censored but are still being followed. For censored participants (those still alive), the date of the last contact was used.

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

Outcome measures

Outcome measures
Measure	Lapatinib With Paclitaxel n=291 Participants Participants received lapatinib 1500 mg orally OD with paclitaxel 175 m\^2 IV over the course of 3 hours, every 3 weeks. The treatment group was stratified by sites of metastatic disease and stage of disease. Participants were treated until disease progression, unacceptable toxicity, or consent withdrawal.	Placebo With Paclitaxel n=288 Participants Participants received matching placebo orally OD with paclitaxel (175 mg/m\^2 IV) over the course of 3 hours, every 3 weeks. The treatment group was stratified by sites of metastatic disease and stage of disease. Participants were treated until disease progression, unacceptable toxicity, or consent withdrawal.
Overall Survival	23.82 months Interval 19.88 to 26.18	20.17 months Interval 17.84 to 23.92

SECONDARY outcome

Timeframe: Baseline (Day 1); Weeks 9, 21, 33, and 45; Withdrawal

Population: ITT Population. Only participants contributing data at the indicated time points were analyzed. Only observed data were collected, and score analyses were conducted using the last observation carried forward (LOCF) method: the last available on-therapy observation for a participant was used to estimate missing data points.

The FACT-B questionnaire was designed to measure multidimensional quality of life (QOL) in participants with breast cancer. The physical and functional well-being subscale scores range from 0 to 28, based on 7 questions (each scored from 0 \[not at all\] to 4 \[very much\] for all subscales); the emotional and social/family well-being (1 question optional) subscale scores range from 0 to 24 (based on 6 questions), and the additional concerns subscale score ranges from 0 to 40, based on 10 questions. The FACT-B Total Score (0 \[better QOL\] to 144 \[worse QOL\]) is the sum of the subscale scores.

Outcome measures

Outcome measures
Measure	Lapatinib With Paclitaxel n=208 Participants Participants received lapatinib 1500 mg orally OD with paclitaxel 175 m\^2 IV over the course of 3 hours, every 3 weeks. The treatment group was stratified by sites of metastatic disease and stage of disease. Participants were treated until disease progression, unacceptable toxicity, or consent withdrawal.	Placebo With Paclitaxel n=230 Participants Participants received matching placebo orally OD with paclitaxel (175 mg/m\^2 IV) over the course of 3 hours, every 3 weeks. The treatment group was stratified by sites of metastatic disease and stage of disease. Participants were treated until disease progression, unacceptable toxicity, or consent withdrawal.
Change From Baseline in Functional Assessment of Cancer Therapy-Breast Cancer (FACT-B) Questionnaire Scores Week 9, n=208, 230	-1.1 Scores on a scale Standard Deviation 16.09	-2.3 Scores on a scale Standard Deviation 16.27
Change From Baseline in Functional Assessment of Cancer Therapy-Breast Cancer (FACT-B) Questionnaire Scores Week 21, n=126, 125	1.0 Scores on a scale Standard Deviation 16.63	-1.3 Scores on a scale Standard Deviation 17.13
Change From Baseline in Functional Assessment of Cancer Therapy-Breast Cancer (FACT-B) Questionnaire Scores Week 33, n=72, 64	1.4 Scores on a scale Standard Deviation 17.39	-2.0 Scores on a scale Standard Deviation 12.75
Change From Baseline in Functional Assessment of Cancer Therapy-Breast Cancer (FACT-B) Questionnaire Scores Week 45, n=35, 38	2.3 Scores on a scale Standard Deviation 22.05	-1.4 Scores on a scale Standard Deviation 10.79
Change From Baseline in Functional Assessment of Cancer Therapy-Breast Cancer (FACT-B) Questionnaire Scores Withdrawal, n=190, 212	-5.0 Scores on a scale Standard Deviation 19.53	-8.4 Scores on a scale Standard Deviation 17.99

SECONDARY outcome

Timeframe: Baseline (Day 1); Weeks 9, 21, 33, and 45; Withdrawal

Population: ITT Population. Only participants contributing data at the indicated time points were analyzed. Only observed data were collected, and score analyses were conducted using the LOCF method.

The FACT-G questionnaire was designed to measure multidimensional QOL in participants with cancer and includes subscales for physical, social/family, emotional, and functional well-being. The physical, social/family, and functional well-being subscale scores range from 0 to 28, based on responses to 7 questions (each question scored from 0 \[not at all\] to 4 \[very much\]); the emotional well-being subscale score ranges from 0 to 24, based on responses to 6 questions. The FACT-G Total Score (ranging from 0 \[better QOL\] to 108 \[worse QOL\]) is the sum of the subscale scores.

Outcome measures

Outcome measures
Measure	Lapatinib With Paclitaxel n=213 Participants Participants received lapatinib 1500 mg orally OD with paclitaxel 175 m\^2 IV over the course of 3 hours, every 3 weeks. The treatment group was stratified by sites of metastatic disease and stage of disease. Participants were treated until disease progression, unacceptable toxicity, or consent withdrawal.	Placebo With Paclitaxel n=232 Participants Participants received matching placebo orally OD with paclitaxel (175 mg/m\^2 IV) over the course of 3 hours, every 3 weeks. The treatment group was stratified by sites of metastatic disease and stage of disease. Participants were treated until disease progression, unacceptable toxicity, or consent withdrawal.
Change From Baseline in Functional Assessment of Cancer Therapy-General (FACT-G) Questionnaire Scores Week 9, n=213, 232	-0.7 Scores on a scale Standard Deviation 13.35	-1.3 Scores on a scale Standard Deviation 13.26
Change From Baseline in Functional Assessment of Cancer Therapy-General (FACT-G) Questionnaire Scores Week 21, n=127, 125	0.4 Scores on a scale Standard Deviation 13.97	-0.2 Scores on a scale Standard Deviation 14.38
Change From Baseline in Functional Assessment of Cancer Therapy-General (FACT-G) Questionnaire Scores Week 33, n=71, 65	1.1 Scores on a scale Standard Deviation 14.80	-1.7 Scores on a scale Standard Deviation 10.81
Change From Baseline in Functional Assessment of Cancer Therapy-General (FACT-G) Questionnaire Scores Week 45, n=34, 39	0.9 Scores on a scale Standard Deviation 17.68	-1.6 Scores on a scale Standard Deviation 10.41
Change From Baseline in Functional Assessment of Cancer Therapy-General (FACT-G) Questionnaire Scores Withdrawal, n=193, 214	-4.4 Scores on a scale Standard Deviation 16.11	-7.5 Scores on a scale Standard Deviation 15.02

SECONDARY outcome

Timeframe: Baseline (Day 1); Weeks 9, 21, 33, and 45; Withdrawal

Population: ITT Population. Only participants contributing data at the indicated time points were analyzed. Only observed data were collected, and score analyses were conducted using the LOCF method.

The TOI questionnaire was designed to measure multidimensional QOL in participants with cancer and includes subscales for physical, functional well-being, and additional cancer concerns. The physical and functional well-being subscale scores range from 0 to 28, based on 7 questions (each question scored from 0 \[not at all\] to 4 \[very much\]); the breast cancer unweighted subscale scores range from 0 to 36, based on 9 questions. The total TOI score (ranging from 0 \[better QOL\] to 92 \[worse QOL\]) is the sum of the TOI subscale scores.

Outcome measures

Outcome measures
Measure	Lapatinib With Paclitaxel n=208 Participants Participants received lapatinib 1500 mg orally OD with paclitaxel 175 m\^2 IV over the course of 3 hours, every 3 weeks. The treatment group was stratified by sites of metastatic disease and stage of disease. Participants were treated until disease progression, unacceptable toxicity, or consent withdrawal.	Placebo With Paclitaxel n=232 Participants Participants received matching placebo orally OD with paclitaxel (175 mg/m\^2 IV) over the course of 3 hours, every 3 weeks. The treatment group was stratified by sites of metastatic disease and stage of disease. Participants were treated until disease progression, unacceptable toxicity, or consent withdrawal.
Change From Baseline in Trial Outcome Index (TOI) Questionnaire Scores Week 9, n=208, 232	-2.3 Scores on a scale Standard Deviation 12.32	-2.6 Scores on a scale Standard Deviation 11.88
Change From Baseline in Trial Outcome Index (TOI) Questionnaire Scores Week 21, n=126, 125	-0.5 Scores on a scale Standard Deviation 11.99	-2.7 Scores on a scale Standard Deviation 12.42
Change From Baseline in Trial Outcome Index (TOI) Questionnaire Scores Week 33, n=72, 65	-0.1 Scores on a scale Standard Deviation 12.83	-2.9 Scores on a scale Standard Deviation 9.05
Change From Baseline in Trial Outcome Index (TOI) Questionnaire Scores Week 45, n=36, 38	1.5 Scores on a scale Standard Deviation 15.91	-2.8 Scores on a scale Standard Deviation 8.98
Change From Baseline in Trial Outcome Index (TOI) Questionnaire Scores Withdrawal, n=190, 212	-4.4 Scores on a scale Standard Deviation 14.30	-6.1 Scores on a scale Standard Deviation 12.84

SECONDARY outcome

Timeframe: Baseline

Population: ITT Population

The Press Laboratory collected tumor tissues of participants for ErbB2 testing. ErbB2 testing is done to detect breast cancer and predict its likely outcome. All samples were analyzed by the Press Laboratory. Participants were categorized as ErbB2 positive (overexpression of the ErbB2 gene), ErbB2 negative, and assay not done (which included participants with no available samples and those with inconclusive results). ErbB2 status is determined by immunohistochemistry (ICH) assay and fluorescence in situ hybridization (FISH) testing. Negative ErbB2 status is defined as 0 or 1+ by IHC, or as 2+ by IHC and FISH.

Outcome measures

Outcome measures
Measure	Lapatinib With Paclitaxel n=291 Participants Participants received lapatinib 1500 mg orally OD with paclitaxel 175 m\^2 IV over the course of 3 hours, every 3 weeks. The treatment group was stratified by sites of metastatic disease and stage of disease. Participants were treated until disease progression, unacceptable toxicity, or consent withdrawal.	Placebo With Paclitaxel n=288 Participants Participants received matching placebo orally OD with paclitaxel (175 mg/m\^2 IV) over the course of 3 hours, every 3 weeks. The treatment group was stratified by sites of metastatic disease and stage of disease. Participants were treated until disease progression, unacceptable toxicity, or consent withdrawal.
Number of Participants With the Indicated ErbB2 Status at Baseline Positive	52 participants	39 participants
Number of Participants With the Indicated ErbB2 Status at Baseline Negative	199 participants	202 participants
Number of Participants With the Indicated ErbB2 Status at Baseline Assay not done	40 participants	47 participants

SECONDARY outcome

Timeframe: Baseline

Population: ITT Population. Only participants contributing data at the indicated time points were analyzed. Only observed data were collected, and score analyses were conducted using the LOCF method.

The Press Laboratory collected tumor tissues of participants for biomarker testing. All samples were analyzed by the Press Laboratory. The ratio of ErbB2 gene signals to chromosome 17 signals, which indicates the progression of breast cancer, was calculated. Low levels of amplification (few copies) may have a ratio of 2-5, whereas high levels of amplification may have a ratio \>10.

Outcome measures

Outcome measures
Measure	Lapatinib With Paclitaxel n=220 Participants Participants received lapatinib 1500 mg orally OD with paclitaxel 175 m\^2 IV over the course of 3 hours, every 3 weeks. The treatment group was stratified by sites of metastatic disease and stage of disease. Participants were treated until disease progression, unacceptable toxicity, or consent withdrawal.	Placebo With Paclitaxel n=200 Participants Participants received matching placebo orally OD with paclitaxel (175 mg/m\^2 IV) over the course of 3 hours, every 3 weeks. The treatment group was stratified by sites of metastatic disease and stage of disease. Participants were treated until disease progression, unacceptable toxicity, or consent withdrawal.
ErbB2 Ratio	2.23 ratio of signals Standard Deviation 2.301	2.14 ratio of signals Standard Deviation 2.214

SECONDARY outcome

Timeframe: Screening (Day -1)

Population: ITT Population

The Press Laboratory tested tumor tissue samples (taken at Screening, prior to randomization to study treatment) to determine intra-tumoral expression levels of ErbB1, ErbB2, and other analytes associated with these pathways by IHC, the process of detecting antigens (e.g., proteins) in cells of a tissue section. The IHC assessment is expressed as: 0, no staining (no cancer cells); 1+, faint staining; 2+, weak to moderate complete staining; 3+, strong complete staining (many cancer cells). A status of "Assay not done" was assigned to participants with no available samples and to those with inconclusive results. If strong staining is observed, breast cancer that has high levels of HER2 expression (overexpression) is indicated. If moderate/weak staining is observed (IHC=2+), breast cancer that has low/moderate expression levels is indicated. When no staining is observed (IHC=0), breast cancer HER2 expression may be below the level of detection of the assay.

Outcome measures

Outcome measures
Measure	Lapatinib With Paclitaxel n=291 Participants Participants received lapatinib 1500 mg orally OD with paclitaxel 175 m\^2 IV over the course of 3 hours, every 3 weeks. The treatment group was stratified by sites of metastatic disease and stage of disease. Participants were treated until disease progression, unacceptable toxicity, or consent withdrawal.	Placebo With Paclitaxel n=288 Participants Participants received matching placebo orally OD with paclitaxel (175 mg/m\^2 IV) over the course of 3 hours, every 3 weeks. The treatment group was stratified by sites of metastatic disease and stage of disease. Participants were treated until disease progression, unacceptable toxicity, or consent withdrawal.
Number of Participants With the Indicated Immunohistochemistry (IHC) Results at Screening 0	139 participants	139 participants
Number of Participants With the Indicated Immunohistochemistry (IHC) Results at Screening 1+	50 participants	51 participants
Number of Participants With the Indicated Immunohistochemistry (IHC) Results at Screening 2+	15 participants	22 participants
Number of Participants With the Indicated Immunohistochemistry (IHC) Results at Screening 3+	40 participants	28 participants
Number of Participants With the Indicated Immunohistochemistry (IHC) Results at Screening Assay not done	47 participants	48 participants

SECONDARY outcome

Timeframe: Baseline

Population: ITT Population

The Press Laboratory tested participants who were 2+ (weak to moderate complete staining) or 3+ (strong complete staining) for ErbB2 overexpression by IHC for ErbB2 gene amplification using the FISH assay. The results of the FISH assay can be ErbB2 gene "amplification" (increased number of copies of the ErbB2 gene) or "non-amplification" (not many copies of the ErbB2 gene). A status of "Assay not done" was assigned to those participants with no available samples and to those with inconclusive results (e.g., due to hybridization or staining problems).

Outcome measures

Outcome measures
Measure	Lapatinib With Paclitaxel n=291 Participants Participants received lapatinib 1500 mg orally OD with paclitaxel 175 m\^2 IV over the course of 3 hours, every 3 weeks. The treatment group was stratified by sites of metastatic disease and stage of disease. Participants were treated until disease progression, unacceptable toxicity, or consent withdrawal.	Placebo With Paclitaxel n=288 Participants Participants received matching placebo orally OD with paclitaxel (175 mg/m\^2 IV) over the course of 3 hours, every 3 weeks. The treatment group was stratified by sites of metastatic disease and stage of disease. Participants were treated until disease progression, unacceptable toxicity, or consent withdrawal.
Number of Participants With the Indicated ErbB2 Fluorescence in Situ Hybridization (FISH) Results Amplified	45 participants	35 participants
Number of Participants With the Indicated ErbB2 Fluorescence in Situ Hybridization (FISH) Results Non-amplified	175 participants	165 participants
Number of Participants With the Indicated ErbB2 Fluorescence in Situ Hybridization (FISH) Results Assay not done	71 participants	88 participants

SECONDARY outcome

Timeframe: Screening (Day-1) and Withdrawal (up to Study Week 129)

Population: ITT Population. Only participants contributing data at the indicated time points were analyzed. Only observed data were collected, and score analyses were conducted using the LOCF method.

The Quest Laboratory collected blood samples for quantitative determination of serum ErbB1. The results of serum monitoring were used to compare tumor response rates following randomized therapy.

Outcome measures

Outcome measures
Measure	Lapatinib With Paclitaxel n=269 Participants Participants received lapatinib 1500 mg orally OD with paclitaxel 175 m\^2 IV over the course of 3 hours, every 3 weeks. The treatment group was stratified by sites of metastatic disease and stage of disease. Participants were treated until disease progression, unacceptable toxicity, or consent withdrawal.	Placebo With Paclitaxel n=265 Participants Participants received matching placebo orally OD with paclitaxel (175 mg/m\^2 IV) over the course of 3 hours, every 3 weeks. The treatment group was stratified by sites of metastatic disease and stage of disease. Participants were treated until disease progression, unacceptable toxicity, or consent withdrawal.
Serum ErbB1 Concentration Screening, n=269, 265	58.6 Nanograms per milliliter (ng/mL) Standard Deviation 20.30	59.5 Nanograms per milliliter (ng/mL) Standard Deviation 44.20
Serum ErbB1 Concentration Withdrawal, n=145, 157	59.0 Nanograms per milliliter (ng/mL) Standard Deviation 30.22	61.5 Nanograms per milliliter (ng/mL) Standard Deviation 16.74

SECONDARY outcome

Timeframe: Screening (Day-1) and Withdrawal (up to Study Week 129)

Population: ITT Population. Only participants contributing data at the indicated time points were analyzed. Only observed data were collected, and score analyses were conducted using the LOCF method.

The Quest Laboratory collected blood samples for quantitative determination of serum ErbB2. The results of serum monitoring were used to compare tumor response rates following randomized therapy.

Outcome measures

Outcome measures
Measure	Lapatinib With Paclitaxel n=270 Participants Participants received lapatinib 1500 mg orally OD with paclitaxel 175 m\^2 IV over the course of 3 hours, every 3 weeks. The treatment group was stratified by sites of metastatic disease and stage of disease. Participants were treated until disease progression, unacceptable toxicity, or consent withdrawal.	Placebo With Paclitaxel n=265 Participants Participants received matching placebo orally OD with paclitaxel (175 mg/m\^2 IV) over the course of 3 hours, every 3 weeks. The treatment group was stratified by sites of metastatic disease and stage of disease. Participants were treated until disease progression, unacceptable toxicity, or consent withdrawal.
Serum ErbB2 Concentration Screening, n=270, 265	37.67 ng/mL Standard Deviation 95.883	36.19 ng/mL Standard Deviation 87.629
Serum ErbB2 Concentration Withdrawal, n=145, 158	37.31 ng/mL Standard Deviation 98.257	39.95 ng/mL Standard Deviation 96.327

SECONDARY outcome

Timeframe: Baseline (Day 1) until 30 days after the last dose of randomized therapy (average of 26 weeks)

Population: Safety Population: all randomized participants who received at least one dose of investigational product (based on the actual treatment received if this differed from that to which the participant was randomized). Two participants randomized to the placebo group actually received lapatinib.

The severity of adverse events was graded per the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE), Version 3. Grades 1 through 5 have unique clinical descriptions of severity for each AE based on the following general guideline: Grade 1, Mild AE; Grade 2, Moderate AE; Grade 3, Severe AE; Grade 4, Life-threatening or disabling AE; Grade 5, death related to AE.

Outcome measures

Outcome measures
Measure	Lapatinib With Paclitaxel n=293 Participants Participants received lapatinib 1500 mg orally OD with paclitaxel 175 m\^2 IV over the course of 3 hours, every 3 weeks. The treatment group was stratified by sites of metastatic disease and stage of disease. Participants were treated until disease progression, unacceptable toxicity, or consent withdrawal.	Placebo With Paclitaxel n=286 Participants Participants received matching placebo orally OD with paclitaxel (175 mg/m\^2 IV) over the course of 3 hours, every 3 weeks. The treatment group was stratified by sites of metastatic disease and stage of disease. Participants were treated until disease progression, unacceptable toxicity, or consent withdrawal.
Number of Participants With the Indicated Adverse Events (AEs) With a Maximum Toxicity Grade of 3 or 4 Diarrhea; Grade 3	43 participants	4 participants
Number of Participants With the Indicated Adverse Events (AEs) With a Maximum Toxicity Grade of 3 or 4 Diarrhea; Grade 4	1 participants	0 participants
Number of Participants With the Indicated Adverse Events (AEs) With a Maximum Toxicity Grade of 3 or 4 Alopecia; Grade 3	10 participants	15 participants
Number of Participants With the Indicated Adverse Events (AEs) With a Maximum Toxicity Grade of 3 or 4 Alopecia; Grade 4	0 participants	0 participants
Number of Participants With the Indicated Adverse Events (AEs) With a Maximum Toxicity Grade of 3 or 4 Rash; Grade 3	15 participants	1 participants
Number of Participants With the Indicated Adverse Events (AEs) With a Maximum Toxicity Grade of 3 or 4 Rash; Grade 4	0 participants	0 participants
Number of Participants With the Indicated Adverse Events (AEs) With a Maximum Toxicity Grade of 3 or 4 Nausea; Grade 3	7 participants	2 participants
Number of Participants With the Indicated Adverse Events (AEs) With a Maximum Toxicity Grade of 3 or 4 Nausea; Grade 4	0 participants	0 participants
Number of Participants With the Indicated Adverse Events (AEs) With a Maximum Toxicity Grade of 3 or 4 Myalgia; Grade 3	6 participants	2 participants
Number of Participants With the Indicated Adverse Events (AEs) With a Maximum Toxicity Grade of 3 or 4 Myalgia; Grade 4	0 participants	0 participants
Number of Participants With the Indicated Adverse Events (AEs) With a Maximum Toxicity Grade of 3 or 4 Neutropenia; Grade 3	30 participants	20 participants
Number of Participants With the Indicated Adverse Events (AEs) With a Maximum Toxicity Grade of 3 or 4 Neutropenia; Grade 4	23 participants	14 participants
Number of Participants With the Indicated Adverse Events (AEs) With a Maximum Toxicity Grade of 3 or 4 Vomiting; Grade 3	5 participants	4 participants
Number of Participants With the Indicated Adverse Events (AEs) With a Maximum Toxicity Grade of 3 or 4 Vomiting; Grade 4	0 participants	0 participants
Number of Participants With the Indicated Adverse Events (AEs) With a Maximum Toxicity Grade of 3 or 4 Arthralgia; Grade 3	7 participants	4 participants
Number of Participants With the Indicated Adverse Events (AEs) With a Maximum Toxicity Grade of 3 or 4 Arthralgia; Grade 4	0 participants	0 participants
Number of Participants With the Indicated Adverse Events (AEs) With a Maximum Toxicity Grade of 3 or 4 Fatigue; Grade 3	5 participants	5 participants
Number of Participants With the Indicated Adverse Events (AEs) With a Maximum Toxicity Grade of 3 or 4 Fatigue; Grade 4	0 participants	0 participants
Number of Participants With the Indicated Adverse Events (AEs) With a Maximum Toxicity Grade of 3 or 4 Asthenia; Grade 3	1 participants	4 participants
Number of Participants With the Indicated Adverse Events (AEs) With a Maximum Toxicity Grade of 3 or 4 Asthenia; Grade 4	1 participants	0 participants
Number of Participants With the Indicated Adverse Events (AEs) With a Maximum Toxicity Grade of 3 or 4 Neuropathy; Grade 3	7 participants	3 participants
Number of Participants With the Indicated Adverse Events (AEs) With a Maximum Toxicity Grade of 3 or 4 Neuropathy; Grade 4	0 participants	0 participants
Number of Participants With the Indicated Adverse Events (AEs) With a Maximum Toxicity Grade of 3 or 4 Decreased appetite; Grade 3	1 participants	0 participants
Number of Participants With the Indicated Adverse Events (AEs) With a Maximum Toxicity Grade of 3 or 4 Decreased appetite; Grade 4	0 participants	0 participants
Number of Participants With the Indicated Adverse Events (AEs) With a Maximum Toxicity Grade of 3 or 4 Pain in extremity; Grade 3	2 participants	3 participants
Number of Participants With the Indicated Adverse Events (AEs) With a Maximum Toxicity Grade of 3 or 4 Pain in extremity; Grade 4	2 participants	0 participants
Number of Participants With the Indicated Adverse Events (AEs) With a Maximum Toxicity Grade of 3 or 4 Peripheral sensory neuropathy; Grade 3	6 participants	4 participants
Number of Participants With the Indicated Adverse Events (AEs) With a Maximum Toxicity Grade of 3 or 4 Peripheral sensory neuropathy; Grade 4	0 participants	0 participants
Number of Participants With the Indicated Adverse Events (AEs) With a Maximum Toxicity Grade of 3 or 4 Pruritis; Grade 3	2 participants	0 participants
Number of Participants With the Indicated Adverse Events (AEs) With a Maximum Toxicity Grade of 3 or 4 Pruritis; Grade 4	0 participants	0 participants
Number of Participants With the Indicated Adverse Events (AEs) With a Maximum Toxicity Grade of 3 or 4 Paraesthesia; Grade 3	2 participants	1 participants
Number of Participants With the Indicated Adverse Events (AEs) With a Maximum Toxicity Grade of 3 or 4 Paraesthesia; Grade 4	0 participants	0 participants
Number of Participants With the Indicated Adverse Events (AEs) With a Maximum Toxicity Grade of 3 or 4 Constipation; Grade 3	0 participants	0 participants
Number of Participants With the Indicated Adverse Events (AEs) With a Maximum Toxicity Grade of 3 or 4 Constipation; Grade 4	0 participants	0 participants
Number of Participants With the Indicated Adverse Events (AEs) With a Maximum Toxicity Grade of 3 or 4 Cough; Grade 3	1 participants	1 participants
Number of Participants With the Indicated Adverse Events (AEs) With a Maximum Toxicity Grade of 3 or 4 Cough; Grade 4	0 participants	0 participants

Adverse Events

Lapatinib With Paclitaxel

Serious events: 103 serious events

Other events: 287 other events

Deaths: 0 deaths

Placebo With Paclitaxel

Serious events: 63 serious events

Other events: 278 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

GSK Response Center

GlaxoSmithKline

Phone: 866-435-7343

Results disclosure agreements

Principal investigator is a sponsor employee GSK agreements may vary with individual investigators, but will not prohibit any investigator from publishing. GSK supports the publication of results from all centers of a multi-center trial but requests that reports based on single-site data not precede the primary publication of the entire clinical trial.
Publication restrictions are in place

Restriction type: OTHER