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

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00281658
• Collaborator: (none)
• Enrollment: 443
• Locations: 54
• Arms: 3
• Actual Duration (Months): 190.7
• Patients Per Site: 8.2
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

This is a Phase III study designed to evaluate the response (shrinkage or lack of growth) of tumors of lapatinib plus paclitaxel compared to paclitaxel plus placebo as first line metastatic treatment in women and men who have metastatic breast cancer. Patients will be evaluated for safety and efficacy. Countries include China, Hong Kong, Thailand, Brazil and Peru.

Condition or Disease	Intervention/Treatment	Phase
Neoplasms, Breast	Drug: lapatinib (GW572016) oral tablets; Drug: paclitaxel infusion	Phase 3

Detailed Description

Patients must with Her2+(ErbB2+) MBC Stage IV, newly diagnosed will receive paclitaxel+lapatinib or paclitaxel plus placebo for 6 cycles minimum. After 6 cycles continue to receive blinded monotherapy until progression. Safety evaluations include evaluating adverse events, hematology/ chemistry tests, vital signs, and cardiac muga scans. Efficacy assessments include evaluation of disease per RECIST. All patients followed for overall survival (OS).

Study conducted in regions were access to trastuzumab is limited.

Study Design

• Study Type: Interventional
• Actual Enrollment: 443 participants
• Allocation: Randomized
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: Jan 2, 2006
• Actual Primary Completion Date: Jun 18, 2010
• Actual Study Completion Date: Nov 23, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Combination Paclitaxel and Lapatinib (Blinded)	Drug: paclitaxel infusion; Paclitaxel 80 mg/m2 every 3 weeks, 4th week rest for minimum 6 months; Other Names: lapatinib (GW572016) oral tablets
Active Comparator: Paclitaxel Paclitaxel and Placebo (Blinded)	Drug: paclitaxel infusion; Paclitaxel 80 mg/m2 every 3 weeks, 4th week rest for minimum 6 months; Other Names: lapatinib (GW572016) oral tablets
Other: Monotherapy Extension Open-label monotherapy lapatinib	Drug: lapatinib (GW572016) oral tablets; 1500 mg oral daily continuously

Outcome Measures

Primary Outcome Measures

1. Overall Survival [Randomization to death (up to maximum of Month 53)]

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

Secondary Outcome Measures

1. Progression-free Survival [Randomization to disease progression or death (up to a maximum of Month 53)]

   Progression-free survival is defined as the time from randomization until the earliest date of disease progression (radiological or clinical assessment of symptomatic progression) or death due to any cause, if sooner during the randomized phase. Disease progression is based on the assessments by the investigator.

2. Overall Response (OR) [Randomization to disease progression or death (up to a maximum of Month 53)]

   OR, evaluated per Response Evaluation Criteria in Solid Tumors (RECIST), is defined as the number of participants achieving either a confirmed complete response (CR, disappearance of all target lesions) or partial response (PR, at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD) of tumor, which were based on confirmed responses from the investigator assessment of best OR during the randomized phase. Participants with unknown or missing responses were treated as non-responders.

3. Clinical Benefit [Randomization to disease progression or death (up to a maximum of Month 53)]

   Clinical benefit is defined as the number of participants achieving either a confirmed 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.

4. Duration of Response [Randomization to disease progression or death (up to a maximum of Month 53)]

   Duration of response is defined for the subset of participants with a confirmed CR or PR as the time from first documented evidence of CR or PR until the first documented sign of disease progression (radiological or clinical assessment of symptomatic progression) or death due to any cause during the randomized phase. Only participants with a confirmed CR or PR were included in this analysis. Disease progression is based on the assessments by the investigator.

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

   The original outcome measure to be analyzed was time to response; however, data are presented as the number of participants with a response at each nominal visit. Responses are based on the investigator's assessment, and only participants with a confirmed CR or PR were included in this analysis.

Eligibility Criteria

Criteria

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

Inclusion criteria:

• Signed informed consent;

• Male or female ≥18 years;

• Histologically confirmed invasive breast cancer with stage IV disease; If the disease is restricted to a solitary lesion, its neoplastic nature should be confirmed by cytology or histology.

• Documented amplification of ErbB2 by fluorescence in situ hybridization (FISH) in primary or metastatic tumor tissue by the central laboratory for randomization into the study;

• If a taxane was administered in the neoadjuvant or adjuvant setting, progression must have occurred >12 months after completion of this treatment and the patient recovered from all associated toxicities;

• Measurable lesion(s) according to RECIST (Response Evaluation Criteria in Solid Tumors);

• Radiotherapy as palliative treatment for painful metastatic disease is permitted but must have been stopped within 2 weeks prior to initiation of any investigational treatment. All subjects must have recovered from all radiotherapy related toxicities prior to initiation of any investigational treatment. The site of radiotherapy must not be used as a site of measurable disease;

• Bisphosphonate therapy for bone metastases and is allowed; however, treatment must be initiated prior to the first dose of investigational treatment. Prophylactic use of bisphosphonates in subjects without bone disease is not permitted, except for the treatment of osteoporosis;

• For those patients whose disease is ER+ and/or PR+ the following criteria should be met:

Patients with visceral disease that requires chemotherapy (eg., patients with liver or lung metastases) Rapidly progressing or life threatening disease, as determined by the investigator Patients who received hormonal therapy and are no longer benefiting from this therapy and the hormonal treatment must have been stopped before the first dose of investigational treatment;

• Cardiac ejection fraction within institutional range of normal as measured by echocardiogram. MUGA scans will be accepted in cases where an echocardiogram cannot be performed or is inconclusive;

• ECOG Performance Status of 0 to 1;

• Life expectancy of ≥ 12 weeks;

• Able to swallow and retain oral medication;

• Archived tumor tissue available for testing;

• Women and men with potential to have children must be willing to practice acceptable methods of birth control during the study;

• Willing to complete all screening assessments as outlined in the protocol;

• Adequate organ function as defined in Table 1 Baseline Laboratory Values;

Exclusion Criteria:

• Pregnant or lactating females at anytime during the study

• Subjects with only non-measurable metastatic sites of disease per RECIST, (e.g. bone metastases, pleural effusion, or ascites, etc. (Refer to Section 5.3 Efficacy for list sites considered to be non-measurable disease.);

• Received prior chemotherapy, immunotherapy, biologic therapy, or anti-ErbB1/ErbB2 therapy for metastatic disease.

• Prior therapy with an ErbB1 and/or ErbB2 inhibitor, other than trastuzumab in the adjuvant setting. If trastuzumab was administered in the adjuvant setting, then > 12 months must have elapsed since completion of trastuzumab therapy;

• Planned concurrent anti-cancer therapy (chemotherapy, radiation therapy, immunotherapy, biologic therapy, hormonal therapy) while taking investigational treatment;

• Unresolved or unstable, serious toxicity from prior administration of another investigational drug and/or of prior cancer treatment;

• Peripheral neuropathy of Grade 2 or greater;

• Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel. Subjects with ulcerative colitis are also excluded;

• History of other malignancy. However, subjects who have been disease-free for 5 years, or subjects with a history of completely resected non-melanoma skin cancer or successfully treated in situ carcinoma, are eligible;

• Concurrent disease or condition that would make the subject inappropriate for study participation, or any serious medical disorder that would interfere with the subject's safety;

• Uncontrolled infection;

• Dementia, altered mental status, or any psychiatric condition that would prohibit the understanding or rendering of informed consent;

• Known history of uncontrolled or symptomatic angina, arrhythmias, or congestive heart failure;

• Known history or clinical evidence of central nervous system (CNS) metastases or leptomeningeal carcinomatosis;

• Concurrent treatment with prohibited medications, including herbal remedies and Chinese traditional medicines;

• Concurrent treatment with an investigational agent or participation in another clinical trial involving investigational agents;

• Used an investigational drug within 30 days or 5 half-lives, whichever is longer, preceding the first dose of investigational treatment;

• Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to paclitaxel or lapatinib or their excipients.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Salvador	Bahía	Brazil	40.050-410
2	Novartis Investigative Site	Salvador	Bahía	Brazil	40285-001
3	Novartis Investigative Site	Belo Horizonte	Minas Gerais	Brazil	30150-281
4	Novartis Investigative Site	Porto Alegre	Rio Grande Do Sul	Brazil	90610 000
5	Novartis Investigative Site	Natal	Rio Grande Du Norte	Brazil	59075-740
6	Novartis Investigative Site	Jau	São Paulo	Brazil	17210-120
7	Novartis Investigative Site	Santo Andre	São Paulo	Brazil	09060-650
8	Novartis Investigative Site	Sao Paulo	São Paulo	Brazil	01221-020
9	Novartis Investigative Site	Sao Paulo	São Paulo	Brazil	03102-002
10	Novartis Investigative Site	Guangzhou	Guangdong	China	510060
11	Novartis Investigative Site	Wuhan	Hubei	China	430030
12	Novartis Investigative Site	Nanjing	Jiangsu	China	210002
13	Novartis Investigative Site	Nanjing	Jiangsu	China	210009
14	Novartis Investigative Site	Dalian	Liaoning	China	116027
15	Novartis Investigative Site	Xi'an	Shaanxi	China	710032
16	Novartis Investigative Site	Xi'an	Shaanxi	China	710061
17	Novartis Investigative Site	Jinan	Shandong	China	250012
18	Novartis Investigative Site	Jinan	Shandong	China	250031
19	Novartis Investigative Site	Jinan	Shandong	China	250117
20	Novartis Investigative Site	Hangzhou	Zhejiang	China	310022
21	Novartis Investigative Site	Beijing		China	100021
22	Novartis Investigative Site	Beijing		China	100036
23	Novartis Investigative Site	Beijing		China	100071
24	Novartis Investigative Site	Beijing		China	100853
25	Novartis Investigative Site	Chengdu		China	610041
26	Novartis Investigative Site	Chongqing		China	400037
27	Novartis Investigative Site	Dalian		China	116011
28	Novartis Investigative Site	Fuzhou		China	350001
29	Novartis Investigative Site	Fuzhou		China	350014
30	Novartis Investigative Site	Shanghai		China	200032
31	Novartis Investigative Site	Shanghai		China	200070
32	Novartis Investigative Site	Shanghai		China	200433
33	Novartis Investigative Site	Shenyang		China	110015
34	Novartis Investigative Site	Tianjin		China	300060
35	Novartis Investigative Site	Kowloon		Hong Kong
36	Novartis Investigative Site	Pokfulam		Hong Kong
37	Novartis Investigative Site	Tuen Mun		Hong Kong
38	Novartis Investigative Site	Lahore		Pakistan	53400
39	Novartis Investigative Site	Lahore		Pakistan	54600
40	Novartis Investigative Site	Lahore		Pakistan
41	Novartis Investigative Site	Lima		Peru	Lima 34
42	Novartis Investigative Site	Kazan		Russian Federation	420029
43	Novartis Investigative Site	Moscow		Russian Federation	117997
44	Novartis Investigative Site	Moscow		Russian Federation	125101
45	Novartis Investigative Site	Moscow		Russian Federation	143423
46	Novartis Investigative Site	Rostov-na-Donu		Russian Federation	344037
47	Novartis Investigative Site	Samara		Russian Federation	443031
48	Novartis Investigative Site	Voronezh		Russian Federation	394062
49	Novartis Investigative Site	Bangkok		Thailand	10400
50	Novartis Investigative Site	Chiangmai		Thailand	50200
51	Novartis Investigative Site	Cherkasy		Ukraine	18009
52	Novartis Investigative Site	Chernihiv		Ukraine	14029
53	Novartis Investigative Site	Dnipropetrovsk		Ukraine	49055
54	Novartis Investigative Site	Zaporizhzhia		Ukraine	69040

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT00281658
• Other Study ID Numbers: EGF104535; CLAP016A2302
• First Posted: Jan 25, 2006
• Last Update Posted: Jan 25, 2022
• Last Verified: Jan 1, 2022

• 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: ErbB2 positive; Her2+; metastatic breast cancer; FISH positive; Stage IV
• Additional relevant MeSH terms: Breast Neoplasms; Paclitaxel; Lapatinib

Study Results

Participant Flow

Pre-assignment Detail	At the time of disease progression, participants had the option to be unblinded. Participants (pts) who were on placebo+paclitaxel could continue in an open-label lapatinib monotherapy extension phase until further progression or an unacceptable toxicity. All participants were followed for survival. The unblinding was performed by a third party.

Arm/Group Title	Lapatinib Plus Paclitaxel	Placebo Plus Paclitaxel	Lapatinib 1500 mg
Arm/Group Description	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	Matching placebo administered once daily plus paclitaxel 80 mg/m^2 administered IV weekly for 3 weeks every 4 weeks	Lapatinib 1500 mg administered once daily
Period Title: Double-blind, Randomized Phase
STARTED	222	222	0
COMPLETED	85	168	0
NOT COMPLETED	137	54	0
Period Title: Double-blind, Randomized Phase
STARTED	0	0	149
COMPLETED	0	0	48
NOT COMPLETED	0	0	101

Baseline Characteristics

Arm/Group Title	Lapatinib Plus Paclitaxel	Placebo Plus Paclitaxel	Total
Arm/Group Description	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	Matching placebo administered once daily plus paclitaxel 80 mg/m^2 administered IV weekly for 3 weeks every 4 weeks	Total of all reporting groups
Overall Participants	222	222	444
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	49.1 (10.74)	49.3 (9.75)	49.2 (10.25)
Sex: Female, Male (Count of Participants)
Female	222 100%	217 97.7%	439 98.9%
Male	0 0%	5 2.3%	5 1.1%
Race/Ethnicity, Customized (Number) [Number]
White	9 4.1%	13 5.9%	22 5%
Asian	192 86.5%	192 86.5%	384 86.5%
Hispanic	21 9.5%	16 7.2%	37 8.3%
Missing	0 0%	1 0.5%	1 0.2%
Number of participants with any visceral metastatic disease and with only non-visceral disease (Count of Participants)
Visceral	187 84.2%	186 83.8%	373 84%
Non-visceral	35 15.8%	36 16.2%	71 16%
Number of Participants with the Indicated Hormone Receptor Status (Count of Participants)
ER+ and/or PgR+ or Unknown	111 50%	113 50.9%	224 50.5%
ER- and PgR-	111 50%	109 49.1%	220 49.5%
Number of Participants with the Indicated Stage of Disease at Initial Diagnosis (Count of Participants)
Stage I to II	107 48.2%	119 53.6%	226 50.9%
Stage III	75 33.8%	68 30.6%	143 32.2%
Stage IV	30 13.5%	24 10.8%	54 12.2%
Unknown	10 4.5%	11 5%	21 4.7%
Number of Participants with the Indicated Eastern Cooperative Oncology Group Performance Status (Count of Participants)
0, Fully Active	103 46.4%	113 50.9%	216 48.6%
1, Ambulatory, Restricted Strenuous Activity	119 53.6%	109 49.1%	228 51.4%
Number of Participants with the Indicated Number of Metastatic Sites (Count of Participants)
Greater than or equal to 3	131 59%	115 51.8%	246 55.4%
Less than 3	91 41%	107 48.2%	198 44.6%
Number of Participants in the Indicated Age Groups (Count of Participants)
Greater than or equal to 65 years of age	16 7.2%	13 5.9%	29 6.5%
Less than 65 years of age	206 92.8%	209 94.1%	415 93.5%
Mean Time of Disease-Free Interval (months) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [months]	27.51 (27.481)	29.04 (34.522)	28.27 (31.174)

Outcome Measures

1. Primary Outcome

Title	Overall Survival
Description	Overall survival is defined as the time from randomization until death due to any cause.
Time Frame	Randomization to death (up to maximum of Month 53)

Outcome Measure Data

Analysis Population Description

Intent-to-Treat (ITT) Population: all randomized participants

Arm/Group Title	Lapatinib Plus Paclitaxel	Placebo Plus Paclitaxel
Arm/Group Description	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	Matching placebo administered once daily plus paclitaxel 80 mg/m^2 administered IV weekly for 3 weeks every 4 weeks
Measure Participants	222	222
Median (95% Confidence Interval) [months]	27.8	20.5

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lapatinib Plus Paclitaxel, Placebo Plus Paclitaxel
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.0005
	Comments	two-sided p-value
	Method	Wald Chi-squared
	Comments	Adjusted for hormonal status, metastatic disease site, initial diagnosis stage, ECOG status, number of metastatic sites, age and disease-free interval
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.64
	Confidence Interval	(2-Sided) 95%; 0.49 to 0.82
	Parameter Dispersion	Type: Value:
	Estimation Comments	Adjusted HR based on Cox Regression model

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Lapatinib Plus Paclitaxel, Placebo Plus Paclitaxel
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.0124
	Comments	two-sided p-value
	Method	Log Rank
	Comments	Stratified log-rank test, stratifying for metastatic disease sites and hormonal status
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.74
	Confidence Interval	() 95%; 0.58 to 0.94
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Progression-free Survival
Description	Progression-free survival is defined as the time from randomization until the earliest date of disease progression (radiological or clinical assessment of symptomatic progression) or death due to any cause, if sooner during the randomized phase. Disease progression is based on the assessments by the investigator.
Time Frame	Randomization to disease progression or death (up to a maximum of Month 53)

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	Lapatinib Plus Paclitaxel	Placebo Plus Paclitaxel
Arm/Group Description	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	Matching placebo administered once daily plus paclitaxel 80 mg/m^2 administered IV weekly for 3 weeks every 4 weeks
Measure Participants	222	222
Median (95% Confidence Interval) [months]	9.7	6.5

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lapatinib Plus Paclitaxel, Placebo Plus Paclitaxel
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.52
	Confidence Interval	(2-Sided) 95%; 0.42 to 0.64
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Overall Response (OR)
Description	OR, evaluated per Response Evaluation Criteria in Solid Tumors (RECIST), is defined as the number of participants achieving either a confirmed complete response (CR, disappearance of all target lesions) or partial response (PR, at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD) of tumor, which were based on confirmed responses from the investigator assessment of best OR during the randomized phase. Participants with unknown or missing responses were treated as non-responders.
Time Frame	Randomization to disease progression or death (up to a maximum of Month 53)

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	Lapatinib Plus Paclitaxel	Placebo Plus Paclitaxel
Arm/Group Description	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	Matching placebo administered once daily plus paclitaxel 80 mg/m^2 administered IV weekly for 3 weeks every 4 weeks
Measure Participants	222	222
Number [participants]	154 69.4%	110 49.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lapatinib Plus Paclitaxel, Placebo Plus Paclitaxel
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.30
	Confidence Interval	() 95%; 1.54 to 3.47
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Clinical Benefit
Description	Clinical benefit is defined as the number of participants achieving either a confirmed 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.
Time Frame	Randomization to disease progression or death (up to a maximum of Month 53)

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	Lapatinib Plus Paclitaxel	Placebo Plus Paclitaxel
Arm/Group Description	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	Matching placebo administered once daily plus paclitaxel 80 mg/m^2 administered IV weekly for 3 weeks every 4 weeks
Measure Participants	222	222
Number [participants]	166 74.8%	124 55.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lapatinib Plus Paclitaxel, Placebo Plus Paclitaxel
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.34
	Confidence Interval	() 95%; 1.54 to 3.58
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Duration of Response
Description	Duration of response is defined for the subset of participants with a confirmed CR or PR as the time from first documented evidence of CR or PR until the first documented sign of disease progression (radiological or clinical assessment of symptomatic progression) or death due to any cause during the randomized phase. Only participants with a confirmed CR or PR were included in this analysis. Disease progression is based on the assessments by the investigator.
Time Frame	Randomization to disease progression or death (up to a maximum of Month 53)

Outcome Measure Data

Analysis Population Description

Participants in the ITT Population with a confirmed CR or PR

Arm/Group Title	Lapatinib Plus Paclitaxel	Placebo Plus Paclitaxel
Arm/Group Description	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	Matching placebo administered once daily plus paclitaxel 80 mg/m^2 administered IV weekly for 3 weeks every 4 weeks
Measure Participants	154	110
Median (95% Confidence Interval) [months]	9.3	5.8

6. Secondary Outcome

Title	Number of Participants With a CR or PR at Weeks 8, 12, 16, 24, 32, 40, 48, 56, 64, and 72
Description	The original outcome measure to be analyzed was time to response; however, data are presented as the number of participants with a response at each nominal visit. Responses are based on the investigator's assessment, and only participants with a confirmed CR or PR were included in this analysis.
Time Frame	Weeks 8, 12, 16, 24, 32, 40, 48, 56, 64, and 72

Outcome Measure Data

Analysis Population Description

Participants in the ITT Population with a confirmed CR or PR

Arm/Group Title	Lapatinib Plus Paclitaxel	Placebo Plus Paclitaxel
Arm/Group Description	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	Matching placebo administered once daily plus paclitaxel 80 mg/m^2 administered IV weekly for 3 weeks every 4 weeks
Measure Participants	154	110
Week 8	94 42.3%	61 27.5%
Week 12	40 18%	28 12.6%
Week 16	6 2.7%	11 5%
Week 24	7 3.2%	8 3.6%
Week 32	3 1.4%	2 0.9%
Week 40	0 0%	0 0%
Week 48	1 0.5%	0 0%
Week 56	1 0.5%	0 0%
Week 64	1 0.5%	0 0%
Week 72	1 0.5%	0 0%

Adverse Events

Adverse Event Reporting Description	Serious adverse events and adverse events were collected in the Safety Population, comprised of all randomized participants who received at least one dose of investigational product.
Arm/Group Title	Lapatinib Plus Paclitaxel		Placebo Plus Paclitaxel		Lapatinib 1500 mg
Arm/Group Description	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		Matching placebo administered once daily plus paclitaxel 80 mg/m^2 administered IV weekly for 3 weeks every 4 weeks		Lapatinib 1500 mg administered once daily. This is not a comparative treatment arm.
All Cause Mortality
	Lapatinib Plus Paclitaxel		Placebo Plus Paclitaxel		Lapatinib 1500 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Lapatinib Plus Paclitaxel		Placebo Plus Paclitaxel		Lapatinib 1500 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	66/222 (29.7%)		30/221 (13.6%)		7/149 (4.7%)
Blood and lymphatic system disorders
Neutropenia	36/222 (16.2%)		10/221 (4.5%)		0/149 (0%)
Leukopenia	7/222 (3.2%)		1/221 (0.5%)		0/149 (0%)
Febrile neutropenia	6/222 (2.7%)		1/221 (0.5%)		0/149 (0%)
Granulocytopenia	4/222 (1.8%)		0/221 (0%)		0/149 (0%)
Cardiac disorders
Left ventricular dysfunction	3/222 (1.4%)		0/221 (0%)		0/149 (0%)
Cardiac failure chronic	0/222 (0%)		1/221 (0.5%)		0/149 (0%)
Gastrointestinal disorders
Diarrhoea	10/222 (4.5%)		0/221 (0%)		1/149 (0.7%)
Vomiting	1/222 (0.5%)		1/221 (0.5%)		0/149 (0%)
Adominal pain	1/222 (0.5%)		0/221 (0%)		0/149 (0%)
Pancreatitis acute	1/222 (0.5%)		0/221 (0%)		0/149 (0%)
Stomatitis	0/222 (0%)		0/221 (0%)		1/149 (0.7%)
General disorders
Pyrexia	3/222 (1.4%)		0/221 (0%)		1/149 (0.7%)
Fatigue	1/222 (0.5%)		0/221 (0%)		0/149 (0%)
Microlithiasis	1/222 (0.5%)		0/221 (0%)		0/149 (0%)
Multi-organ failure	0/222 (0%)		1/221 (0.5%)		0/149 (0%)
Non-cardiac chest pain	0/222 (0%)		1/221 (0.5%)		0/149 (0%)
Hepatobiliary disorders
Cholecystitis	0/222 (0%)		1/221 (0.5%)		0/149 (0%)
Hepatic function abnormal	0/222 (0%)		1/221 (0.5%)		1/149 (0.7%)
Hepatobiliary disease	0/222 (0%)		1/221 (0.5%)		0/149 (0%)
Hepatotoxicity	0/222 (0%)		1/221 (0.5%)		0/149 (0%)
Immune system disorders
Anaphylactic reaction	0/222 (0%)		0/221 (0%)		1/149 (0.7%)
Infections and infestations
Cellulitis	2/222 (0.9%)		0/221 (0%)		0/149 (0%)
Escherichia bacteraemia	1/222 (0.5%)		0/221 (0%)		0/149 (0%)
Lung infection	1/222 (0.5%)		0/221 (0%)		0/149 (0%)
Pharyngitis	1/222 (0.5%)		0/221 (0%)		0/149 (0%)
Pneumonia	0/222 (0%)		1/221 (0.5%)		1/149 (0.7%)
Pyelonephritis acute	1/222 (0.5%)		0/221 (0%)		0/149 (0%)
Septic shock	0/222 (0%)		1/221 (0.5%)		0/149 (0%)
Urinary tract infection	1/222 (0.5%)		0/221 (0%)		0/149 (0%)
Viral infection	0/222 (0%)		1/221 (0.5%)		1/149 (0.7%)
Injury, poisoning and procedural complications
Femur fracture	0/222 (0%)		2/221 (0.9%)		0/149 (0%)
Investigations
Ejection fraction decreased	13/222 (5.9%)		3/221 (1.4%)		0/149 (0%)
Haemoglobin decreased	1/222 (0.5%)		0/221 (0%)		0/149 (0%)
Neutrophil count decreased	1/222 (0.5%)		0/221 (0%)		0/149 (0%)
Metabolism and nutrition disorders
Hypokalaemia	1/222 (0.5%)		1/221 (0.5%)		0/149 (0%)
Hyperglycaemia	1/222 (0.5%)		0/221 (0%)		0/149 (0%)
Nervous system disorders
Intracranial pressure increased	0/222 (0%)		1/221 (0.5%)		0/149 (0%)
Presyncope	0/222 (0%)		1/221 (0.5%)		0/149 (0%)
Psychiatric disorders
Completed suicide	0/222 (0%)		1/221 (0.5%)		0/149 (0%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	1/222 (0.5%)		2/221 (0.9%)		0/149 (0%)
Interstitial lung disease	0/222 (0%)		1/221 (0.5%)		0/149 (0%)
Laryngeal oedema	1/222 (0.5%)		0/221 (0%)		0/149 (0%)
Pleural effusion	0/222 (0%)		1/221 (0.5%)		0/149 (0%)
Pulmonary embolism	0/222 (0%)		0/221 (0%)		1/149 (0.7%)
Respiratory failure	0/222 (0%)		0/221 (0%)		1/149 (0.7%)
Vascular disorders
Deep vein thrombosis	0/222 (0%)		1/221 (0.5%)		0/149 (0%)
Other (Not Including Serious) Adverse Events
	Lapatinib Plus Paclitaxel		Placebo Plus Paclitaxel		Lapatinib 1500 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	219/222 (98.6%)		206/221 (93.2%)		132/149 (88.6%)
Blood and lymphatic system disorders
Neutropenia	168/222 (75.7%)		103/221 (46.6%)		8/149 (5.4%)
Leukopenia	113/222 (50.9%)		74/221 (33.5%)		10/149 (6.7%)
Anemia	50/222 (22.5%)		22/221 (10%)		0/149 (0%)
Granulocytopenia	17/222 (7.7%)		15/221 (6.8%)		0/149 (0%)
Gastrointestinal disorders
Diarrhea	171/222 (77%)		64/221 (29%)		40/149 (26.8%)
Nausea	66/222 (29.7%)		41/221 (18.6%)		0/149 (0%)
Vomiting	48/222 (21.6%)		26/221 (11.8%)		0/149 (0%)
Abdominal pain	17/222 (7.7%)		10/221 (4.5%)		0/149 (0%)
Constipation	8/222 (3.6%)		18/221 (8.1%)		0/149 (0%)
Dyspepsia	11/222 (5%)		8/221 (3.6%)		0/149 (0%)
Mouth ulceration	16/222 (7.2%)		0/221 (0%)		0/149 (0%)
Abdominal pain upper	13/222 (5.9%)		2/221 (0.9%)		0/149 (0%)
Abdominal distension	12/222 (5.4%)		3/221 (1.4%)		0/149 (0%)
General disorders
Fatigue	47/222 (21.2%)		35/221 (15.8%)		0/149 (0%)
Pyrexia	29/222 (13.1%)		30/221 (13.6%)		0/149 (0%)
Oedema	8/222 (3.6%)		16/221 (7.2%)		8/149 (5.4%)
Asthenia	15/222 (6.8%)		6/221 (2.7%)		0/149 (0%)
Mucosal inflammation	18/222 (8.1%)		3/221 (1.4%)		0/149 (0%)
Hepatobiliary disorders
Hepatic function abnormal	17/222 (7.7%)		9/221 (4.1%)		0/149 (0%)
Hyperbilirubinemia	12/222 (5.4%)		2/221 (0.9%)		0/149 (0%)
Infections and infestations
Upper respiratory tract infection	20/222 (9%)		12/221 (5.4%)		0/149 (0%)
Nasopharyngitis	11/222 (5%)		11/221 (5%)		0/149 (0%)
Pharyngitis	9/222 (4.1%)		11/221 (5%)		0/149 (0%)
Paronychia	17/222 (7.7%)		1/221 (0.5%)		0/149 (0%)
Investigations
Alanine aminotransferase increased	24/222 (10.8%)		17/221 (7.7%)		9/149 (6%)
Aspartate aminotransferase increased	19/222 (8.6%)		16/221 (7.2%)		8/149 (5.4%)
Hemoglobin decreased	22/222 (9.9%)		4/221 (1.8%)		0/149 (0%)
Blood alkaline phosphatase increased	11/222 (5%)		10/221 (4.5%)		0/149 (0%)
White blood cell decreased	10/222 (4.5%)		10/221 (4.5%)		0/149 (0%)
Metabolism and nutrition disorders
Decreased Appetite	70/222 (31.5%)		41/221 (18.6%)		0/149 (0%)
Musculoskeletal and connective tissue disorders
Myalgia	30/222 (13.5%)		23/221 (10.4%)		0/149 (0%)
Arthralgia	18/222 (8.1%)		14/221 (6.3%)		0/149 (0%)
Musculoskeletal pain	10/222 (4.5%)		6/221 (2.7%)		0/149 (0%)
Nervous system disorders
Neuropathy peripheral	30/222 (13.5%)		30/221 (13.6%)		15/149 (10.1%)
Hypoaesthesia	18/222 (8.1%)		25/221 (11.3%)		16/149 (10.7%)
Headache	20/222 (9%)		20/221 (9%)		0/149 (0%)
Dizziness	19/222 (8.6%)		10/221 (4.5%)		0/149 (0%)
Peripheral sensory neuropathy	12/222 (5.4%)		12/221 (5.4%)		0/149 (0%)
Psychiatric disorders
Insomnia	12/222 (5.4%)		17/221 (7.7%)		0/149 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	22/222 (9.9%)		19/221 (8.6%)		0/149 (0%)
Dyspnea	13/222 (5.9%)		12/221 (5.4%)		0/149 (0%)
Skin and subcutaneous tissue disorders
Alopecia	102/222 (45.9%)		113/221 (51.1%)		61/149 (40.9%)
Rash	130/222 (58.6%)		52/221 (23.5%)		58/149 (38.9%)
Nail disorder	25/222 (11.3%)		3/221 (1.4%)		10/149 (6.7%)
Pruritus	21/222 (9.5%)		6/221 (2.7%)		8/149 (5.4%)
Dry skin	15/222 (6.8%)		3/221 (1.4%)		0/149 (0%)

Limitations/Caveats

Some participants (PAR) are captured as withdrawing from the study due to death. Per protocol, PAR who died were considered to be study completers and did not withdraw from the study; for the purposes of this report, they are classified as withdrawn.

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Certain Agreements

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

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.