Continued HER2 Suppression With Lapatinib Plus Trastuzumab Versus Trastuzumab Alone

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT00968968
• Collaborator: (none)
• Enrollment: 37
• Locations: 116
• Arms: 2
• Actual Duration (Months): 98.3
• Patients Per Site: 0.3
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

This was a randomized, open-label, multi-center Phase III study evaluating the efficacy and safety of lapatinib in combination with trastuzumab versus trastuzumab alone as continued HER2 suppression therapy in women with HER2-positive metastatic breast cancer (MBC). Eligible subjects should have completed 12 to 24 weeks of first- or second-line treatment with trastuzumab plus chemotherapy, experienced either complete disappearance of all metastatic lesions, or persistence of metastatic disease (stable disease) without unequivocal progression or the occurrence of new lesions, and been indicated to continue to receive trastuzumab alone as maintenance therapy. Eligible subjects who entered the LPT112515 study on first-line treatment should not have known history of central nervous system (CNS) metastases; subjects who entered the study on second-line treatment should not have known history of CNS metastases or have stable (asymptomatic and off steroids ≥3 months) CNS metastases. The primary objective of this study was to compare progression-free survival (PFS) in subjects with HER2-positive MBC randomized to receive treatment with lapatinib plus trastuzumab versus those randomized to receive trastuzumab alone. The secondary objectives included overall survival, clinical benefit response rate (CR, PR or SD ≥24 weeks) and the qualitative and quantitative adverse event profile of the 2 treatment arms. It was estimated that 280 subjects (140 per group) would be required to observe 193 PFS events.

Condition or Disease	Intervention/Treatment	Phase
Cancer	Drug: Lapatinib; Biological: Trastuzumab	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 37 participants
• Allocation: Randomized
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Randomized, Phase III, Open-label Study of Lapatinib Plus Trastuzumab Versus Trastuzumab as Continued HER2 Suppression Therapy After Completion of First- or Second-line Trastuzumab Plus Chemotherapy in Subjects With HER2-positive Metastatic Breast Cancer
• Actual Study Start Date: Jan 20, 2010
• Actual Primary Completion Date: Feb 21, 2014
• Actual Study Completion Date: Mar 30, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm 1: Lapatinib plus Trastuzumab	Drug: Lapatinib; Oral Lapatinib 1000 mg once daily. Lapatinib was a small molecule, reversible inhibitor targeting HER2 tyrosine kinase receptor.; Biological: Trastuzumab; IV Trastuzumab 6 mg/kg every three weeks. Trastuzumab was a humanized, monoclonal antibody directed against the extracellular domain of the HER2 tyrosine kinase receptor.
Active Comparator: Arm 2: Trastuzumab	Biological: Trastuzumab; IV Trastuzumab 6 mg/kg every three weeks. Trastuzumab was a humanized, monoclonal antibody directed against the extracellular domain of the HER2 tyrosine kinase receptor.

Outcome Measures

Primary Outcome Measures

1. Progression-free Survival [Time from randomization until disease progression or death, approximately 4 years]

   Progression-free survival (PFS) with lapatinib plus trastuzumab versus trastuzumab alone. Progression-free survival (PFS) is defined as the time from randomization to the earliest date of disease progression (with radiological evidence) or death from any cause, or to last contact date up to 21Feb2014. Disease Progression was defined using Response Evaluation Criteria In Solid Tumors (RECIST v1.1), a 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum diameters recorded since the treatment started (the sum must have an absolute increase from nadir of 5mm), or an unequivocal progression of existing non-target lesions, or the appearance of new lesions.

Secondary Outcome Measures

1. Overall Survival [Time from randomization until death, approximately 4 years]

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

2. Best Overall Response [approximately 4 years]

   The best overall response was the best response from the start of the treatment until disease progression/recurrence and was determined programmatically using investigators assessment of responses of target lesion, non-target lesion and new lesions based on RECIST v1.1. Complete Response (CR) = disappearance of all target lesion and non-target lesions if applicable, and no new lesion; Partial Response (PR) = ≥30% decrease in the sum of the longest diameter of target lesions and non-target lesion was neither complete response nor progressive disease (Non-CR/Non-PD) or not evaluable (NE); SD = Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD; PD = ≥ 20% increase from nadir of the target lesions or appearance of new lesion. CR and PR were confirmed responses. Confirmed CR - at least two determinations of CR at least 4 weeks apart before PD; Confirmed PR - at least two determinations of PR or better at least 4 weeks apart before PD.

3. Clinical Benefit Response Rate (CR, PR or SD ≥24 Weeks) [approximately 4 years]

   Clinical Benefit Rate (CBR) was defined as the percentage of patients achieving either a confirmed CR or PR at any time or maintaining SD for at least 24 weeks while on study, according to the investigator assessment of response per RECIST 1.1 criteria. Confirmed CR - at least two determinations of CR at least 4 weeks apart before PD; Confirmed PR - at least two determinations of PR or better at least 4 weeks apart before PD.

4. Adverse Event Profile of the Two Treatment Arms [From first dose of study treatment until 30 days after the last dose of study treatment, approximately 8 years.]

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Signed the informed consent form (ICF)

• Female, ≥18 years of age

• Histologically verified breast cancer with distant metastases (metastatic breast cancer)

• Documentation of HER2 overexpression or gene amplification in the invasive component of either the primary tumor or metastatic disease site defined as:

• 3+ by IHC and/or

• HER2/neu gene amplification by fluorescence, chromogenic or silver in situ hybridization [FISH, CISH or SISH; >6 HER2/neu gene copies per nucleus or a FISH, CISH or SISH HER2 gene copies to chromosome 17 signal ratio of ≥2.0]

• Completed 12 to 24 weeks of first- or second-line treatment with trastuzumab in combination with chemotherapy

• Either complete disappearance of all lesions, or persistence of metastatic disease (stable disease) without unequivocal progression or the occurrence of new lesions

• Documentation of lesion response during the course of therapy received prior to randomization (i.e., improvement or no worsening of tumor burden; the absence of new lesions)

• Measurable disease is not required for study participation

• No known or suspected (associated neurological signs and symptoms) brain metastases (including leptomeningeal involvement)

• Stable brain metastasis (defined as asymptomatic and off steroids ≥3 months) are permitted in subjects on second-line treatment (completed 12-24 weeks of second-line treatment with trastuzumab plus chemotherapy)

• Baseline of Left Ventricular Ejection Fraction (LVEF) ≥50% measured by echocardiography (ECHO) or multi-gated acquisition scan (MUGA)

• Completion of screening assessments

• Have adequate marrow and organ function

Exclusion Criteria:

• History of other malignancy. Subjects who have been disease-free for 5 years or subjects with a history of completely resected non-melanoma skin cancer (basal or squamous) are eligible

• Eastern Cooperative Oncology Group (ECOG) Performance Status >2

• Concurrent anti-cancer treatment, except anti-hormonal therapy for subjects with hormone receptor positive breast cancer

• Concurrent treatment with an investigational agent

• Prior treatment with anti-HER2 therapy, except trastuzumab or lapatinib

• Concurrent treatment with protocol-defined prohibited medications (refer to protocol for details)

• Serious cardiac illness or medical condition including but not confined to:

• Uncontrolled arrhythmias

• Uncontrolled or symptomatic angina

• History of congestive heart failure (CHF)

• Myocardial infarction <6 months from study entry

• Acute or current active (requiring anti-viral therapy) hepatic or biliary disease (with the exception of subjects with Gilbert's syndrome, asymptomatic gallstones, liver metastases or stable chronic liver disease per investigator assessment)

• Concurrent disease or condition that may interfere with study participation, or any serious medical disorder that would interfere with the subject's safety (for example, active or uncontrolled infection or any psychiatric condition prohibiting understanding or rendering of informed consent)

• Women of childbearing potential, including women whose last menstrual period was <12 months ago (unless surgically sterile) who are unable or unwilling to use adequate contraceptive measures during the study treatment period. Adequate contraception includes intra-uterine device, barrier methods with spermicide, or oral contraceptives (unless clinically contraindicated for the subject population or per local practice, refer to protocol for further details)

• Pregnant or lactating females

• Any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels.

• Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to any of the study agents or their excipients that, in the opinion of the Investigator or GSK medical monitor , contra-indicates participation

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Chandler	Arizona	United States	85224
2	Novartis Investigative Site	Flagstaff	Arizona	United States	86001
3	Novartis Investigative Site	Gilbert	Arizona	United States	85297
4	Novartis Investigative Site	Mesa	Arizona	United States	85202
5	Novartis Investigative Site	Mesa	Arizona	United States	85206
6	Novartis Investigative Site	Sedona	Arizona	United States	86336
7	Novartis Investigative Site	Tucson	Arizona	United States	85724
8	Novartis Investigative Site	Bakersfield	California	United States	93309
9	Novartis Investigative Site	Beverly Hills	California	United States	90211
10	Novartis Investigative Site	Fullerton	California	United States	92835
11	Novartis Investigative Site	La Jolla	California	United States	92037
12	Novartis Investigative Site	La Jolla	California	United States	92093-0987
13	Novartis Investigative Site	Long Beach	California	United States	90813
14	Novartis Investigative Site	Los Angeles	California	United States	90095- 7187
15	Novartis Investigative Site	San Diego	California	United States	92103-8411
16	Novartis Investigative Site	San Pablo	California	United States	94806
17	Novartis Investigative Site	Santa Maria	California	United States	93454
18	Novartis Investigative Site	Hollywood	Florida	United States	33021
19	Novartis Investigative Site	Hudson	Florida	United States	34667
20	Novartis Investigative Site	New Port Richey	Florida	United States	34655
21	Novartis Investigative Site	Augusta	Georgia	United States	30901
22	Novartis Investigative Site	Augusta	Georgia	United States	30909
23	Novartis Investigative Site	Dublin	Georgia	United States	31021
24	Novartis Investigative Site	Arlington Heights	Illinois	United States	60005
25	Novartis Investigative Site	Chicago	Illinois	United States	60611
26	Novartis Investigative Site	Evanston	Illinois	United States	60201
27	Novartis Investigative Site	Glenview	Illinois	United States	60025
28	Novartis Investigative Site	Highland Park	Illinois	United States	60035
29	Novartis Investigative Site	Joliet	Illinois	United States	60435
30	Novartis Investigative Site	Niles	Illinois	United States	60714
31	Novartis Investigative Site	Peoria	Illinois	United States	61615
32	Novartis Investigative Site	Peoria	Illinois	United States	61636
33	Novartis Investigative Site	Peoria	Illinois	United States	61637
34	Novartis Investigative Site	Skokie	Illinois	United States	60076
35	Novartis Investigative Site	Winfield	Illinois	United States	60190
36	Novartis Investigative Site	Goshen	Indiana	United States	46526
37	Novartis Investigative Site	Mishawaka	Indiana	United States	46545
38	Novartis Investigative Site	Columbia	Maryland	United States	21044
39	Novartis Investigative Site	Silver Spring	Maryland	United States	20910
40	Novartis Investigative Site	Boston	Massachusetts	United States	02114
41	Novartis Investigative Site	Boston	Massachusetts	United States	02215
42	Novartis Investigative Site	Brownstown	Michigan	United States	48183
43	Novartis Investigative Site	Dearborn	Michigan	United States	48126
44	Novartis Investigative Site	Detroit	Michigan	United States	48202
45	Novartis Investigative Site	West Bloomfield	Michigan	United States	48322
46	Novartis Investigative Site	Burnsville	Minnesota	United States	55337
47	Novartis Investigative Site	Coon Rapids	Minnesota	United States	55433
48	Novartis Investigative Site	Edina	Minnesota	United States	55435
49	Novartis Investigative Site	Fridley	Minnesota	United States	55432
50	Novartis Investigative Site	Maplewood	Minnesota	United States	55109
51	Novartis Investigative Site	Minneapolis	Minnesota	United States	55404
52	Novartis Investigative Site	Saint Paul	Minnesota	United States	55102
53	Novartis Investigative Site	Woodbury	Minnesota	United States	55125
54	Novartis Investigative Site	Columbia	Missouri	United States	65201
55	Novartis Investigative Site	Jefferson City	Missouri	United States	65109
56	Novartis Investigative Site	Billings	Montana	United States	59102
57	Novartis Investigative Site	Henderson	Nevada	United States	89052
58	Novartis Investigative Site	Henderson	Nevada	United States	89074
59	Novartis Investigative Site	Las Vegas	Nevada	United States	89128
60	Novartis Investigative Site	Las Vegas	Nevada	United States	89148
61	Novartis Investigative Site	Las Vegas	Nevada	United States	89169
62	Novartis Investigative Site	Cary	North Carolina	United States	27518
63	Novartis Investigative Site	Elizabeth City	North Carolina	United States	27909
64	Novartis Investigative Site	Greensboro	North Carolina	United States	27403
65	Novartis Investigative Site	Raleigh	North Carolina	United States	27607
66	Novartis Investigative Site	Raleigh	North Carolina	United States	27614
67	Novartis Investigative Site	Washington	North Carolina	United States	27889
68	Novartis Investigative Site	Abington	Pennsylvania	United States	19001
69	Novartis Investigative Site	Philadelphia	Pennsylvania	United States	19106
70	Novartis Investigative Site	Radnor	Pennsylvania	United States	19087
71	Novartis Investigative Site	Abilene	Texas	United States	79606-5208
72	Novartis Investigative Site	Beaumont	Texas	United States	77701
73	Novartis Investigative Site	Bedford	Texas	United States	76022
74	Novartis Investigative Site	Dallas	Texas	United States	75230
75	Novartis Investigative Site	El Paso	Texas	United States	79902
76	Novartis Investigative Site	El Paso	Texas	United States	79915
77	Novartis Investigative Site	Fort Worth	Texas	United States	76104
78	Novartis Investigative Site	Fort Worth	Texas	United States	76132
79	Novartis Investigative Site	Garland	Texas	United States	75042
80	Novartis Investigative Site	Grapevine	Texas	United States	76051
81	Novartis Investigative Site	Houston	Texas	United States	77024
82	Novartis Investigative Site	Kerrville	Texas	United States	78028
83	Novartis Investigative Site	Odessa	Texas	United States	79761
84	Novartis Investigative Site	Plano	Texas	United States	75075
85	Novartis Investigative Site	Plano	Texas	United States	75093
86	Novartis Investigative Site	San Antonio	Texas	United States	78217
87	Novartis Investigative Site	San Antonio	Texas	United States	78258-3912
88	Novartis Investigative Site	Bountiful	Utah	United States	84010
89	Novartis Investigative Site	Layton	Utah	United States	84041
90	Novartis Investigative Site	Murray	Utah	United States	84157-7000
91	Novartis Investigative Site	Provo	Utah	United States	84604
92	Novartis Investigative Site	Salt Lake City	Utah	United States	84102
93	Novartis Investigative Site	Salt Lake City	Utah	United States	84106
94	Novartis Investigative Site	Sandy	Utah	United States	84094
95	Novartis Investigative Site	Arlington	Virginia	United States	22205
96	Novartis Investigative Site	Chesapeake	Virginia	United States	23320
97	Novartis Investigative Site	Fairfax	Virginia	United States	22031
98	Novartis Investigative Site	Gainesville	Virginia	United States	20155
99	Novartis Investigative Site	Hampton	Virginia	United States	23666
100	Novartis Investigative Site	Leesburg	Virginia	United States	20176
101	Novartis Investigative Site	Newport News	Virginia	United States	23606
102	Novartis Investigative Site	Norfolk	Virginia	United States	23502
103	Novartis Investigative Site	Virginia Beach	Virginia	United States	23456
104	Novartis Investigative Site	Williamsburg	Virginia	United States	23185
105	Novartis Investigative Site	Edmonds	Washington	United States	98026
106	Novartis Investigative Site	Federal Way	Washington	United States	98003
107	Novartis Investigative Site	Gig Harbor	Washington	United States	98332
108	Novartis Investigative Site	Lakewood	Washington	United States	98499
109	Novartis Investigative Site	Puyallup	Washington	United States	98372
110	Novartis Investigative Site	Seattle	Washington	United States	98104
111	Novartis Investigative Site	Seattle	Washington	United States	98133
112	Novartis Investigative Site	Tacoma	Washington	United States	98405
113	Novartis Investigative Site	Halifax	Nova Scotia	Canada	B3H 1V7
114	Novartis Investigative Site	Brampton	Ontario	Canada	L6R 3J7
115	Novartis Investigative Site	Oshawa	Ontario	Canada	L1G 2B9
116	Novartis Investigative Site	Rimouski	Quebec	Canada	G5L 5T1

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: NCT00968968
• Other Study ID Numbers: 112515; CLAP016A2306
• First Posted: Aug 31, 2009
• Last Update Posted: Jun 10, 2019
• Last Verified: Jun 1, 2019

• 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: carcinoma, breast lump, Pagets disease, breast cancer positive for human epidermal growth factor receptor 2, breast cancer progression, estrogen-receptor
• Additional relevant MeSH terms: Trastuzumab; Lapatinib

Study Results

Participant Flow

Recruitment Details	A total of 37 subjects with HER2-positive metastatic breast cancer were enrolled.
Pre-assignment Detail	Subjects enrolled in the study were randomized 1:1 to either of the arms.

Arm/Group Title	Lapatinib + Trastuzumab	Trastuzumab
Arm/Group Description	Lapatinib 1000 mg oral once daily plus intravenous (iv) trastuzumab 6 mg/kg once every 3 weeks.	Trastuzumab iv 6 mg/kg once every 3 weeks
Period Title: Overall Study
STARTED	20	17
COMPLETED	4	3
NOT COMPLETED	16	14

Baseline Characteristics

Arm/Group Title	Lapatinib + Trastuzumab	Trastuzumab	Total
Arm/Group Description	Lapatinib 1000 mg oral once daily plus intravenous (iv) trastuzumab 6 mg/kg once every 3 weeks.	Trastuzumab iv 6 mg/kg once every 3 weeks	Total of all reporting groups
Overall Participants	20	17	37
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	54.3 (12.70)	59.1 (9.44)	56.5 (11.43)
Sex: Female, Male (Count of Participants)
Female	20 100%	17 100%	37 100%
Male	0 0%	0 0%	0 0%
Race/Ethnicity, Customized (Count of Participants)
Hispanic or Latino	1 5%	0 0%	1 2.7%
Not Hispanic or Latino	19 95%	17 100%	36 97.3%

Outcome Measures

1. Primary Outcome

Title	Progression-free Survival
Description	Progression-free survival (PFS) with lapatinib plus trastuzumab versus trastuzumab alone. Progression-free survival (PFS) is defined as the time from randomization to the earliest date of disease progression (with radiological evidence) or death from any cause, or to last contact date up to 21Feb2014. Disease Progression was defined using Response Evaluation Criteria In Solid Tumors (RECIST v1.1), a 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum diameters recorded since the treatment started (the sum must have an absolute increase from nadir of 5mm), or an unequivocal progression of existing non-target lesions, or the appearance of new lesions.
Time Frame	Time from randomization until disease progression or death, approximately 4 years

Outcome Measure Data

Analysis Population Description

Intent-to-treat population: All randomized subjects and based on the treatment to which the subject was randomized.

Arm/Group Title	Lapatinib + Trastuzumab	Trastuzumab
Arm/Group Description	Lapatinib 1000 mg oral once daily plus intravenous (iv) trastuzumab 6 mg/kg once every 3 weeks.	Trastuzumab iv 6 mg/kg once every 3 weeks
Measure Participants	20	17
Median (95% Confidence Interval) [months]	25	2

2. Secondary Outcome

Title	Overall Survival
Description	Overall Survival is defined as the interval of time (in months) between the date of randomization and the date of death due to any cause.
Time Frame	Time from randomization until death, approximately 4 years

Outcome Measure Data

Analysis Population Description

Intent-to-treat population: All randomized subjects and based on the treatment to which the subject was randomized.

Arm/Group Title	Lapatinib + Trastuzumab	Trastuzumab
Arm/Group Description	Lapatinib 1000 mg oral once daily plus intravenous (iv) trastuzumab 6 mg/kg once every 3 weeks.	Trastuzumab iv 6 mg/kg once every 3 weeks
Measure Participants	20	17
Median (95% Confidence Interval) [Months]	NA	NA

3. Secondary Outcome

Title	Best Overall Response
Description	The best overall response was the best response from the start of the treatment until disease progression/recurrence and was determined programmatically using investigators assessment of responses of target lesion, non-target lesion and new lesions based on RECIST v1.1. Complete Response (CR) = disappearance of all target lesion and non-target lesions if applicable, and no new lesion; Partial Response (PR) = ≥30% decrease in the sum of the longest diameter of target lesions and non-target lesion was neither complete response nor progressive disease (Non-CR/Non-PD) or not evaluable (NE); SD = Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD; PD = ≥ 20% increase from nadir of the target lesions or appearance of new lesion. CR and PR were confirmed responses. Confirmed CR - at least two determinations of CR at least 4 weeks apart before PD; Confirmed PR - at least two determinations of PR or better at least 4 weeks apart before PD.
Time Frame	approximately 4 years

Outcome Measure Data

Analysis Population Description

Intent-to-treat population: All randomized subjects and based on the treatment to which the subject was randomized

Arm/Group Title	Lapatinib + Trastuzumab	Trastuzumab
Arm/Group Description	Lapatinib 1000 mg oral once daily plus intravenous (iv) trastuzumab 6 mg/kg once every 3 weeks.	Trastuzumab iv 6 mg/kg once every 3 weeks
Measure Participants	20	17
Complete response (CR)	0 0%	0 0%
Partial response (PR)	2 10%	0 0%
Stable disease (SD)	1 5%	2 11.8%
Non - CR/Non - PD	4 20%	3 17.6%
Progressive disease (PD)	1 5%	7 41.2%
Not evaluable (NE)	12 60%	5 29.4%

4. Secondary Outcome

Title	Clinical Benefit Response Rate (CR, PR or SD ≥24 Weeks)
Description	Clinical Benefit Rate (CBR) was defined as the percentage of patients achieving either a confirmed CR or PR at any time or maintaining SD for at least 24 weeks while on study, according to the investigator assessment of response per RECIST 1.1 criteria. Confirmed CR - at least two determinations of CR at least 4 weeks apart before PD; Confirmed PR - at least two determinations of PR or better at least 4 weeks apart before PD.
Time Frame	approximately 4 years

Outcome Measure Data

Analysis Population Description

Intent-to-treat population: All randomized subjects and based on the treatment to which the subject was randomized

Arm/Group Title	Lapatinib + Trastuzumab	Trastuzumab
Arm/Group Description	Lapatinib 1000 mg oral once daily plus intravenous (iv) trastuzumab 6 mg/kg once every 3 weeks.	Trastuzumab iv 6 mg/kg once every 3 weeks
Measure Participants	20	17
Number (95% Confidence Interval) [Percentages of participants]	10 50%	0 0%

5. Secondary Outcome

Title	Adverse Event Profile of the Two Treatment Arms
Time Frame	From first dose of study treatment until 30 days after the last dose of study treatment, approximately 8 years.

Outcome Measure Data

Analysis Population Description

Safety population: All subjects who received any dose of lapatinib + trastuzumab or trastuzumab.

Arm/Group Title	Lapatinib + Trastuzumab	Trastuzumab
Arm/Group Description	Lapatinib 1000 mg oral once daily plus intravenous (iv) trastuzumab 6 mg/kg once every 3 weeks.	Trastuzumab iv 6 mg/kg once every 3 weeks
Measure Participants	18	16
Any AEs	18 90%	16 94.1%
AEs related to study treatment	16 80%	7 41.2%
AEs leading to discont. of study treatment	3 15%	0 0%
AE leading to dose reduction	0 0%	0 0%
AE leading to dose interruption/delay	11 55%	2 11.8%
Any SAE	7 35%	4 23.5%
SAEs related to study treatment	3 15%	1 5.9%
Fatal SAEs	0 0%	0 0%
Fatal SAEs related to study treatment	0 0%	0 0%

Adverse Events

Time Frame	Adverse Events and Serious Adverse Events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 8.5 years.
Adverse Event Reporting Description	From first dose of study treatment until 30 days after the last dose of study treatment
Arm/Group Title	Lapatinib + Trastuzumab		Trastuzumab		All Subjects
Arm/Group Description	Lapatinib 1000 mg oral once daily plus intravenous (iv) trastuzumab 6 mg/kg once every 3 weeks.		Trastuzumab iv 6 mg/kg once every 3 weeks		All Subjects
All Cause Mortality
	Lapatinib + Trastuzumab		Trastuzumab		All Subjects
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/18 (0%)		0/17 (0%)		0/35 (0%)
Serious Adverse Events
	Lapatinib + Trastuzumab		Trastuzumab		All Subjects
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/18 (38.9%)		4/17 (23.5%)		11/35 (31.4%)
Cardiac disorders
Pericardial effusion	1/18 (5.6%)		0/17 (0%)		1/35 (2.9%)
Endocrine disorders
Goitre	1/18 (5.6%)		0/17 (0%)		1/35 (2.9%)
Gastrointestinal disorders
Pancreatitis acute	1/18 (5.6%)		0/17 (0%)		1/35 (2.9%)
Volvulus	1/18 (5.6%)		0/17 (0%)		1/35 (2.9%)
Hepatobiliary disorders
Cholecystitis acute	0/18 (0%)		1/17 (5.9%)		1/35 (2.9%)
Cholelithiasis	1/18 (5.6%)		0/17 (0%)		1/35 (2.9%)
Infections and infestations
Appendicitis	1/18 (5.6%)		0/17 (0%)		1/35 (2.9%)
Cellulitis	0/18 (0%)		2/17 (11.8%)		2/35 (5.7%)
Peritonsillar abscess	1/18 (5.6%)		0/17 (0%)		1/35 (2.9%)
Tonsillitis	1/18 (5.6%)		0/17 (0%)		1/35 (2.9%)
Investigations
Alanine aminotransferase increased	1/18 (5.6%)		0/17 (0%)		1/35 (2.9%)
Aspartate aminotransferase increased	1/18 (5.6%)		0/17 (0%)		1/35 (2.9%)
Ejection fraction decreased	0/18 (0%)		1/17 (5.9%)		1/35 (2.9%)
Respiratory, thoracic and mediastinal disorders
Pleural effusion	1/18 (5.6%)		0/17 (0%)		1/35 (2.9%)
Pneumonitis	1/18 (5.6%)		0/17 (0%)		1/35 (2.9%)
Respiratory failure	1/18 (5.6%)		0/17 (0%)		1/35 (2.9%)
Other (Not Including Serious) Adverse Events
	Lapatinib + Trastuzumab		Trastuzumab		All Subjects
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	18/18 (100%)		16/17 (94.1%)		34/35 (97.1%)
Blood and lymphatic system disorders
Anaemia	1/18 (5.6%)		0/17 (0%)		1/35 (2.9%)
Iron deficiency anaemia	1/18 (5.6%)		0/17 (0%)		1/35 (2.9%)
Neutropenia	0/18 (0%)		1/17 (5.9%)		1/35 (2.9%)
Cardiac disorders
Atrial fibrillation	1/18 (5.6%)		0/17 (0%)		1/35 (2.9%)
Diastolic dysfunction	1/18 (5.6%)		0/17 (0%)		1/35 (2.9%)
Left atrial enlargement	1/18 (5.6%)		0/17 (0%)		1/35 (2.9%)
Left ventricular dysfunction	0/18 (0%)		1/17 (5.9%)		1/35 (2.9%)
Pericardial effusion	1/18 (5.6%)		0/17 (0%)		1/35 (2.9%)
Ventricular hypertrophy	1/18 (5.6%)		0/17 (0%)		1/35 (2.9%)
Ear and labyrinth disorders
Middle ear effusion	1/18 (5.6%)		0/17 (0%)		1/35 (2.9%)
Motion sickness	0/18 (0%)		1/17 (5.9%)		1/35 (2.9%)
Vertigo	0/18 (0%)		1/17 (5.9%)		1/35 (2.9%)
Eye disorders
Blepharospasm	0/18 (0%)		1/17 (5.9%)		1/35 (2.9%)
Conjunctival haemorrhage	0/18 (0%)		1/17 (5.9%)		1/35 (2.9%)
Eye irritation	1/18 (5.6%)		0/17 (0%)		1/35 (2.9%)
Eye swelling	1/18 (5.6%)		0/17 (0%)		1/35 (2.9%)
Lacrimation increased	1/18 (5.6%)		0/17 (0%)		1/35 (2.9%)
Photopsia	1/18 (5.6%)		0/17 (0%)		1/35 (2.9%)
Retinal detachment	0/18 (0%)		1/17 (5.9%)		1/35 (2.9%)
Vision blurred	3/18 (16.7%)		0/17 (0%)		3/35 (8.6%)
Visual impairment	1/18 (5.6%)		0/17 (0%)		1/35 (2.9%)
Gastrointestinal disorders
Abdominal discomfort	1/18 (5.6%)		0/17 (0%)		1/35 (2.9%)
Abdominal distension	1/18 (5.6%)		0/17 (0%)		1/35 (2.9%)
Abdominal pain	3/18 (16.7%)		0/17 (0%)		3/35 (8.6%)
Abdominal pain upper	1/18 (5.6%)		2/17 (11.8%)		3/35 (8.6%)
Constipation	1/18 (5.6%)		1/17 (5.9%)		2/35 (5.7%)
Diarrhoea	15/18 (83.3%)		5/17 (29.4%)		20/35 (57.1%)
Dry mouth	2/18 (11.1%)		0/17 (0%)		2/35 (5.7%)
Dyspepsia	2/18 (11.1%)		0/17 (0%)		2/35 (5.7%)
Dysphagia	2/18 (11.1%)		0/17 (0%)		2/35 (5.7%)
Gastrooesophageal reflux disease	2/18 (11.1%)		1/17 (5.9%)		3/35 (8.6%)
Gingival pain	1/18 (5.6%)		0/17 (0%)		1/35 (2.9%)
Haemorrhoids	1/18 (5.6%)		0/17 (0%)		1/35 (2.9%)
Mouth ulceration	1/18 (5.6%)		0/17 (0%)		1/35 (2.9%)
Nausea	12/18 (66.7%)		4/17 (23.5%)		16/35 (45.7%)
Oral discomfort	1/18 (5.6%)		0/17 (0%)		1/35 (2.9%)
Oral pain	1/18 (5.6%)		0/17 (0%)		1/35 (2.9%)
Proctalgia	1/18 (5.6%)		0/17 (0%)		1/35 (2.9%)
Stomatitis	3/18 (16.7%)		1/17 (5.9%)		4/35 (11.4%)
Tongue ulceration	1/18 (5.6%)		0/17 (0%)		1/35 (2.9%)
Vomiting	7/18 (38.9%)		3/17 (17.6%)		10/35 (28.6%)
General disorders
Asthenia	2/18 (11.1%)		0/17 (0%)		2/35 (5.7%)
Catheter site bruise	1/18 (5.6%)		0/17 (0%)		1/35 (2.9%)
Catheter site erythema	1/18 (5.6%)		0/17 (0%)		1/35 (2.9%)
Chills	1/18 (5.6%)		0/17 (0%)		1/35 (2.9%)
Fatigue	8/18 (44.4%)		1/17 (5.9%)		9/35 (25.7%)
Infusion site pain	0/18 (0%)		1/17 (5.9%)		1/35 (2.9%)
Non-cardiac chest pain	1/18 (5.6%)		0/17 (0%)		1/35 (2.9%)
Oedema peripheral	2/18 (11.1%)		1/17 (5.9%)		3/35 (8.6%)
Peripheral swelling	1/18 (5.6%)		1/17 (5.9%)		2/35 (5.7%)
Pyrexia	4/18 (22.2%)		1/17 (5.9%)		5/35 (14.3%)
Ulcer	1/18 (5.6%)		0/17 (0%)		1/35 (2.9%)
Hepatobiliary disorders
Hyperbilirubinaemia	1/18 (5.6%)		0/17 (0%)		1/35 (2.9%)
Immune system disorders
Hypersensitivity	0/18 (0%)		1/17 (5.9%)		1/35 (2.9%)
Seasonal allergy	1/18 (5.6%)		2/17 (11.8%)		3/35 (8.6%)
Infections and infestations
Abscess limb	1/18 (5.6%)		0/17 (0%)		1/35 (2.9%)
Breast cellulitis	0/18 (0%)		1/17 (5.9%)		1/35 (2.9%)
Bronchitis	1/18 (5.6%)		1/17 (5.9%)		2/35 (5.7%)
Cellulitis	0/18 (0%)		3/17 (17.6%)		3/35 (8.6%)
Clostridium difficile infection	1/18 (5.6%)		0/17 (0%)		1/35 (2.9%)
Ear infection	1/18 (5.6%)		1/17 (5.9%)		2/35 (5.7%)
Herpes zoster	2/18 (11.1%)		0/17 (0%)		2/35 (5.7%)
Infection	1/18 (5.6%)		0/17 (0%)		1/35 (2.9%)
Influenza	1/18 (5.6%)		0/17 (0%)		1/35 (2.9%)
Laryngitis	1/18 (5.6%)		0/17 (0%)		1/35 (2.9%)
Localised infection	3/18 (16.7%)		0/17 (0%)		3/35 (8.6%)
Nasopharyngitis	1/18 (5.6%)		3/17 (17.6%)		4/35 (11.4%)
Perineal abscess	1/18 (5.6%)		0/17 (0%)		1/35 (2.9%)
Pharyngitis	1/18 (5.6%)		0/17 (0%)		1/35 (2.9%)
Pharyngitis streptococcal	1/18 (5.6%)		0/17 (0%)		1/35 (2.9%)
Postoperative wound infection	1/18 (5.6%)		0/17 (0%)		1/35 (2.9%)
Rhinitis	2/18 (11.1%)		0/17 (0%)		2/35 (5.7%)
Sepsis	1/18 (5.6%)		0/17 (0%)		1/35 (2.9%)
Sinusitis	2/18 (11.1%)		2/17 (11.8%)		4/35 (11.4%)
Skin infection	0/18 (0%)		1/17 (5.9%)		1/35 (2.9%)
Upper respiratory tract infection	3/18 (16.7%)		3/17 (17.6%)		6/35 (17.1%)
Urinary tract infection	1/18 (5.6%)		2/17 (11.8%)		3/35 (8.6%)
Injury, poisoning and procedural complications
Contusion	0/18 (0%)		1/17 (5.9%)		1/35 (2.9%)
Hand fracture	0/18 (0%)		1/17 (5.9%)		1/35 (2.9%)
Humerus fracture	0/18 (0%)		1/17 (5.9%)		1/35 (2.9%)
Incision site swelling	1/18 (5.6%)		0/17 (0%)		1/35 (2.9%)
Laceration	1/18 (5.6%)		0/17 (0%)		1/35 (2.9%)
Muscle strain	1/18 (5.6%)		0/17 (0%)		1/35 (2.9%)
Postoperative wound complication	0/18 (0%)		1/17 (5.9%)		1/35 (2.9%)
Procedural pain	2/18 (11.1%)		1/17 (5.9%)		3/35 (8.6%)
Radiation skin injury	0/18 (0%)		1/17 (5.9%)		1/35 (2.9%)
Thermal burn	0/18 (0%)		1/17 (5.9%)		1/35 (2.9%)
Tibia fracture	0/18 (0%)		1/17 (5.9%)		1/35 (2.9%)
Tooth fracture	0/18 (0%)		1/17 (5.9%)		1/35 (2.9%)
Investigations
Alanine aminotransferase increased	2/18 (11.1%)		1/17 (5.9%)		3/35 (8.6%)
Aspartate aminotransferase increased	1/18 (5.6%)		1/17 (5.9%)		2/35 (5.7%)
Blood alkaline phosphatase increased	1/18 (5.6%)		0/17 (0%)		1/35 (2.9%)
Blood glucose increased	1/18 (5.6%)		0/17 (0%)		1/35 (2.9%)
Blood urea increased	1/18 (5.6%)		0/17 (0%)		1/35 (2.9%)
Ejection fraction decreased	1/18 (5.6%)		0/17 (0%)		1/35 (2.9%)
Haemoglobin decreased	1/18 (5.6%)		0/17 (0%)		1/35 (2.9%)
Immunoglobulins decreased	0/18 (0%)		1/17 (5.9%)		1/35 (2.9%)
Neutrophil count decreased	1/18 (5.6%)		0/17 (0%)		1/35 (2.9%)
Neutrophil count increased	1/18 (5.6%)		0/17 (0%)		1/35 (2.9%)
Weight decreased	1/18 (5.6%)		1/17 (5.9%)		2/35 (5.7%)
White blood cell count decreased	0/18 (0%)		1/17 (5.9%)		1/35 (2.9%)
White blood cell count increased	1/18 (5.6%)		0/17 (0%)		1/35 (2.9%)
Metabolism and nutrition disorders
Dehydration	3/18 (16.7%)		0/17 (0%)		3/35 (8.6%)
Diabetes mellitus	1/18 (5.6%)		0/17 (0%)		1/35 (2.9%)
Hyperkalaemia	1/18 (5.6%)		1/17 (5.9%)		2/35 (5.7%)
Hypochloraemia	1/18 (5.6%)		0/17 (0%)		1/35 (2.9%)
Hypokalaemia	4/18 (22.2%)		0/17 (0%)		4/35 (11.4%)
Hypomagnesaemia	0/18 (0%)		1/17 (5.9%)		1/35 (2.9%)
Hyponatraemia	3/18 (16.7%)		0/17 (0%)		3/35 (8.6%)
Musculoskeletal and connective tissue disorders
Arthralgia	2/18 (11.1%)		3/17 (17.6%)		5/35 (14.3%)
Back pain	2/18 (11.1%)		0/17 (0%)		2/35 (5.7%)
Bone pain	1/18 (5.6%)		0/17 (0%)		1/35 (2.9%)
Flank pain	1/18 (5.6%)		0/17 (0%)		1/35 (2.9%)
Joint swelling	0/18 (0%)		1/17 (5.9%)		1/35 (2.9%)
Limb discomfort	0/18 (0%)		1/17 (5.9%)		1/35 (2.9%)
Muscle spasms	2/18 (11.1%)		4/17 (23.5%)		6/35 (17.1%)
Muscular weakness	0/18 (0%)		1/17 (5.9%)		1/35 (2.9%)
Musculoskeletal chest pain	2/18 (11.1%)		2/17 (11.8%)		4/35 (11.4%)
Musculoskeletal pain	4/18 (22.2%)		1/17 (5.9%)		5/35 (14.3%)
Musculoskeletal stiffness	1/18 (5.6%)		0/17 (0%)		1/35 (2.9%)
Myalgia	3/18 (16.7%)		0/17 (0%)		3/35 (8.6%)
Neck mass	0/18 (0%)		1/17 (5.9%)		1/35 (2.9%)
Neck pain	0/18 (0%)		1/17 (5.9%)		1/35 (2.9%)
Pain in extremity	4/18 (22.2%)		2/17 (11.8%)		6/35 (17.1%)
Rheumatoid arthritis	0/18 (0%)		1/17 (5.9%)		1/35 (2.9%)
Tendonitis	1/18 (5.6%)		0/17 (0%)		1/35 (2.9%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neuroma	0/18 (0%)		1/17 (5.9%)		1/35 (2.9%)
Nervous system disorders
Burning sensation	0/18 (0%)		1/17 (5.9%)		1/35 (2.9%)
Dizziness	3/18 (16.7%)		0/17 (0%)		3/35 (8.6%)
Dysgeusia	1/18 (5.6%)		0/17 (0%)		1/35 (2.9%)
Headache	4/18 (22.2%)		0/17 (0%)		4/35 (11.4%)
Hypoaesthesia	1/18 (5.6%)		1/17 (5.9%)		2/35 (5.7%)
Hypokinesia	0/18 (0%)		1/17 (5.9%)		1/35 (2.9%)
Loss of consciousness	1/18 (5.6%)		0/17 (0%)		1/35 (2.9%)
Memory impairment	1/18 (5.6%)		0/17 (0%)		1/35 (2.9%)
Paraesthesia	3/18 (16.7%)		0/17 (0%)		3/35 (8.6%)
Peripheral sensory neuropathy	0/18 (0%)		1/17 (5.9%)		1/35 (2.9%)
Psychiatric disorders
Anxiety	1/18 (5.6%)		0/17 (0%)		1/35 (2.9%)
Confusional state	1/18 (5.6%)		0/17 (0%)		1/35 (2.9%)
Depression	1/18 (5.6%)		1/17 (5.9%)		2/35 (5.7%)
Insomnia	3/18 (16.7%)		2/17 (11.8%)		5/35 (14.3%)
Libido decreased	0/18 (0%)		1/17 (5.9%)		1/35 (2.9%)
Renal and urinary disorders
Dysuria	1/18 (5.6%)		0/17 (0%)		1/35 (2.9%)
Pollakiuria	1/18 (5.6%)		1/17 (5.9%)		2/35 (5.7%)
Reproductive system and breast disorders
Breast pain	0/18 (0%)		2/17 (11.8%)		2/35 (5.7%)
Genital rash	1/18 (5.6%)		0/17 (0%)		1/35 (2.9%)
Respiratory, thoracic and mediastinal disorders
Cough	1/18 (5.6%)		3/17 (17.6%)		4/35 (11.4%)
Dyspnoea	7/18 (38.9%)		0/17 (0%)		7/35 (20%)
Dyspnoea exertional	1/18 (5.6%)		0/17 (0%)		1/35 (2.9%)
Epistaxis	1/18 (5.6%)		0/17 (0%)		1/35 (2.9%)
Haemoptysis	0/18 (0%)		1/17 (5.9%)		1/35 (2.9%)
Nasal congestion	2/18 (11.1%)		2/17 (11.8%)		4/35 (11.4%)
Nasal cyst	1/18 (5.6%)		0/17 (0%)		1/35 (2.9%)
Nasal dryness	1/18 (5.6%)		0/17 (0%)		1/35 (2.9%)
Oropharyngeal pain	3/18 (16.7%)		0/17 (0%)		3/35 (8.6%)
Pleural effusion	2/18 (11.1%)		0/17 (0%)		2/35 (5.7%)
Pleurisy	1/18 (5.6%)		0/17 (0%)		1/35 (2.9%)
Pleuritic pain	1/18 (5.6%)		0/17 (0%)		1/35 (2.9%)
Pneumonia aspiration	1/18 (5.6%)		0/17 (0%)		1/35 (2.9%)
Productive cough	1/18 (5.6%)		0/17 (0%)		1/35 (2.9%)
Pulmonary oedema	1/18 (5.6%)		0/17 (0%)		1/35 (2.9%)
Rhinorrhoea	1/18 (5.6%)		0/17 (0%)		1/35 (2.9%)
Sinus disorder	1/18 (5.6%)		0/17 (0%)		1/35 (2.9%)
Wheezing	1/18 (5.6%)		0/17 (0%)		1/35 (2.9%)
Skin and subcutaneous tissue disorders
Drug eruption	1/18 (5.6%)		1/17 (5.9%)		2/35 (5.7%)
Dry skin	3/18 (16.7%)		0/17 (0%)		3/35 (8.6%)
Eczema nummular	1/18 (5.6%)		0/17 (0%)		1/35 (2.9%)
Hair growth abnormal	1/18 (5.6%)		0/17 (0%)		1/35 (2.9%)
Hyperhidrosis	1/18 (5.6%)		0/17 (0%)		1/35 (2.9%)
Ingrowing nail	1/18 (5.6%)		0/17 (0%)		1/35 (2.9%)
Miliaria	0/18 (0%)		1/17 (5.9%)		1/35 (2.9%)
Nail disorder	4/18 (22.2%)		0/17 (0%)		4/35 (11.4%)
Night sweats	1/18 (5.6%)		0/17 (0%)		1/35 (2.9%)
Onycholysis	1/18 (5.6%)		0/17 (0%)		1/35 (2.9%)
Onychomadesis	1/18 (5.6%)		0/17 (0%)		1/35 (2.9%)
Pain of skin	1/18 (5.6%)		0/17 (0%)		1/35 (2.9%)
Palmar-plantar erythrodysaesthesia syndrome	2/18 (11.1%)		0/17 (0%)		2/35 (5.7%)
Papule	0/18 (0%)		1/17 (5.9%)		1/35 (2.9%)
Pruritus	3/18 (16.7%)		3/17 (17.6%)		6/35 (17.1%)
Rash	10/18 (55.6%)		4/17 (23.5%)		14/35 (40%)
Scab	1/18 (5.6%)		0/17 (0%)		1/35 (2.9%)
Skin discolouration	1/18 (5.6%)		0/17 (0%)		1/35 (2.9%)
Skin fissures	1/18 (5.6%)		0/17 (0%)		1/35 (2.9%)
Skin irritation	1/18 (5.6%)		0/17 (0%)		1/35 (2.9%)
Skin lesion	1/18 (5.6%)		0/17 (0%)		1/35 (2.9%)
Vascular disorders
Aortic arteriosclerosis	1/18 (5.6%)		0/17 (0%)		1/35 (2.9%)
Hot flush	3/18 (16.7%)		1/17 (5.9%)		4/35 (11.4%)
Hypertension	1/18 (5.6%)		0/17 (0%)		1/35 (2.9%)
Hypotension	1/18 (5.6%)		0/17 (0%)		1/35 (2.9%)

Limitations/Caveats

This study was closed to further enrollment since the enrollment rate would not allow the study to complete enrollment within an acceptable timeframe.

More Information

Certain Agreements

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

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