Treatment allocation was stratified by blocked randomization, with three stratification factors:
The primary objective of this study was to compare disease-free survival (DFS) in subjects with HER2 overexpressing and/or amplified breast cancer randomized to trastuzumab for one year versus lapatinib for one year versus trastuzumab (12 or 18 weeks, according to assigned design) followed by a six week treatment-free interval followed by lapatinib (28 or 34 weeks, according to assigned design) versus trastuzumab in combination with lapatinib for one year (52 weeks).
Secondary objectives included treatment comparisons with respect to overall survival, time to recurrence, time to distant recurrence, safety and tolerability, and incidence of brain metastasis.
Based on the recommendation of the Independent Data Monitoring Committee (IDMC) at the first interim analysis (18-Aug-2011), the Lapatinib alone arm was discontinued prior to primary analysis due to futility.\nThe IDMC also stated that the other three arms (trastuzumab alone, sequential trastuzumab/lapatinib arm and the combination arm) could continued as planned with no changes.
"},{"op":"add","path":"/protocolSection/designModule/designInfo/interventionModel","value":"PARALLEL"},{"op":"replace","path":"/protocolSection/designModule/enrollmentInfo/count","value":8381},{"op":"replace","path":"/protocolSection/armsInterventionsModule/armGroups/0/label","value":"Lapatinib plus Trastuzumab"},{"op":"replace","path":"/protocolSection/armsInterventionsModule/armGroups/0/type","value":"EXPERIMENTAL"},{"op":"replace","path":"/protocolSection/armsInterventionsModule/armGroups/0/description","value":"Design 1: Oral lapatinib 1000 mg daily concurrent with trastuzumab 8 mg/kg IV loading dose followed by 6mg/kg IV every 3 weeks (52 weeks total).
Design 2: Trastuzumab (4mg/kg loading dose followed by 2mg/kg IV weekly) concurrent with oral lapatinib 750 mg daily and either paclitaxel 80mg/m2 IV weekly for 12 weeks OR docetaxel 75mg/m2 every 21 days for 4 cycles (12 weeks).\nAfter completion of chemotherapy, the dose of lapatinib will be increased to 1000mg daily concurrently with trastuzumab every 3 weeks (6mg/kg without loading dose) for an additional 40 weeks (52 weeks total).
Design 2B: Docetaxel 75mg/m2 and carboplatin AUC 6 every 3 weeks for 6 cycles (18 weeks) administered concurrently with oral lapatinib 750mg plus weekly trastuzumab (4mg/kg IV loading dose followed by 2mg/kg IV.\nAfter the completion of chemotherapy, trastuzumab will be administered every 3 weeks (6mg/kg without loading dose) concurrent with lapatinib 1000mg daily for an additional 40 weeks (52 weeks total).
"},{"op":"add","path":"/protocolSection/armsInterventionsModule/armGroups/0/interventionNames/0","value":"Drug: Lapatinib"},{"op":"replace","path":"/protocolSection/armsInterventionsModule/armGroups/1/label","value":"Trastuzumab followed by Lapatinib"},{"op":"replace","path":"/protocolSection/armsInterventionsModule/armGroups/1/description","value":"Design 1: Trastuzumab (4mg/kg IV loading dose followed by 2mg/kg IV weekly) for 12 weeks followed by a 6 week treatment-free interval followed by oral lapatinib 1500mg daily for 34 weeks (52 weeks total).
Design 2: Trastuzumab (4mg/kg IV loading dose followed by 2mg/kg IV weekly) for 12 weeks administered concomitantly and either paclitaxel 80mg/m2 IV weekly for 12 weeks OR docetaxel 75mg/m2 every 21 days for 4 cycles; followed by a 6 week treatment-free interval followed by oral lapatinib 1500mg daily for 34 weeks (52 weeks total).
Design 2B: Docetaxel 75mg/m2 and carboplatin AUC 6 every 3 weeks for 6 cycles (18 weeks) administered concomitantly with trastuzumab (4mg/kg IV loading dose followed by 2mg/kg IV weekly) followed by a 6 week treatment-free interval followed by oral lapatinib 1500 mg daily for 28 weeks (52 weeks total).
"},{"op":"add","path":"/protocolSection/armsInterventionsModule/armGroups/1/interventionNames/1","value":"Biological: Trastuzumab"},{"op":"replace","path":"/protocolSection/armsInterventionsModule/armGroups/2/label","value":"Lapatinib"},{"op":"replace","path":"/protocolSection/armsInterventionsModule/armGroups/2/description","value":"Design 1: Lapatinib 1500mg oral daily for a total of 52 weeks.
Design 2: Either paclitaxel 80mg/m2 IV weekly for 12 weeks OR docetaxel 75mg/m2 IV every 3 weeks for 4 cycles administered concomitantly with oral lapatinib at 750mg daily.\nAfter completion of chemotherapy, oral lapatinib administered at 1500mg daily for an additional 40 weeks (52 weeks total).
Design 2B: Docetaxel 75mg/m2 and carboplatin AUC 6 every 3 weeks for 6 cycles (18 weeks) administered concomitantly with oral lapatinib at 750mg daily.\nAfter completion of chemotherapy, the dose of lapatinib will be increased to 1500mg oral daily for an additional 40 weeks (52 weeks total).
"},{"op":"remove","path":"/protocolSection/armsInterventionsModule/armGroups/2/interventionNames/1"},{"op":"replace","path":"/protocolSection/armsInterventionsModule/armGroups/3/label","value":"Trastuzumab"},{"op":"replace","path":"/protocolSection/armsInterventionsModule/armGroups/3/type","value":"ACTIVE_COMPARATOR"},{"op":"replace","path":"/protocolSection/armsInterventionsModule/armGroups/3/description","value":"Design 1: Trastuzumab 8mg/kg IV loading dose followed by 6mg/kg IV every 3 weeks for a total of 52 weeks.
Design 2: Either paclitaxel 80mg/m2 IV weekly for 12 weeks OR docetaxel 75mg/m2 IV every 3 weeks for 4 cycles administered concomitantly with trastuzumab 4mg/kg IV loading dose followed by 2mg/kg IV weekly.\nAfter completion of chemotherapy, trastuzumab administered every 3 weeks (6mg/kg IV without loading dose) for an additional 40 weeks (52 weeks total).
Design 2B: Docetaxel 75mg/m2 and carboplatin AUC 6 every 3 weeks for 6 cycles (18 weeks) administered concomitantly with trastuzumab 4mg/kg IV loading dose followed by 2mg/kg IV weekly.\nAfter completion of chemotherapy, trastuzumab (6mg/kg without loading dose) every 3 weeks for an additional 40 weeks (52 weeks total).
"},{"op":"remove","path":"/protocolSection/armsInterventionsModule/armGroups/3/interventionNames/0"},{"op":"replace","path":"/protocolSection/armsInterventionsModule/interventions/0/armGroupLabels/0","value":"Lapatinib"},{"op":"replace","path":"/protocolSection/armsInterventionsModule/interventions/0/armGroupLabels/1","value":"Lapatinib plus Trastuzumab"},{"op":"replace","path":"/protocolSection/armsInterventionsModule/interventions/0/armGroupLabels/2","value":"Trastuzumab followed by Lapatinib"},{"op":"add","path":"/protocolSection/armsInterventionsModule/interventions/0/otherNames","value":["GW572016"]},{"op":"replace","path":"/protocolSection/armsInterventionsModule/interventions/1/armGroupLabels/0","value":"Lapatinib plus Trastuzumab"},{"op":"replace","path":"/protocolSection/armsInterventionsModule/interventions/1/armGroupLabels/1","value":"Trastuzumab"},{"op":"replace","path":"/protocolSection/armsInterventionsModule/interventions/1/armGroupLabels/2","value":"Trastuzumab followed by Lapatinib"},{"op":"replace","path":"/protocolSection/outcomesModule/primaryOutcomes/0/measure","value":"Disease-Free Survival (DFS) at the Primary Analysis"},{"op":"replace","path":"/protocolSection/outcomesModule/primaryOutcomes/0/description","value":"Disease-Free Survival (DFS) was defined as the interval between randomization and the date of first occurrence of disease recurrence (local, regional or distant), a contralateral invasive breast cancer, a second primary cancer or death without recurrence.\nOnly deaths occurring in participants whose clinical follow-up was ongoing at the time of death and who had no recurrence, contralateral breast cancer (CBC) or second primary malignancy (SPM) reported prior to death were considered as death without recurrence.\nDFS was estimated using the Kaplan Meier method.\nThe percentile data values presented here indicate the percentage (95, 90, 85, 80 and 75 percent) of participants who had disease free survival for the indicated years."},{"op":"replace","path":"/protocolSection/outcomesModule/secondaryOutcomes/0/measure","value":"Disease-Free Survival (DFS) at the 10-Year Follow-Up"},{"op":"replace","path":"/protocolSection/outcomesModule/secondaryOutcomes/0/description","value":"Disease-Free Survival (DFS) was defined as the interval between randomization and the date of first occurrence of disease recurrence (local, regional or distant), a contralateral invasive breast cancer, a second primary cancer or death without recurrence.\nOnly deaths occurring in participants whose clinical follow-up was ongoing at the time of death and who had no recurrence, contralateral breast cancer (CBC) or second primary malignancy (SPM) reported prior to death were considered as death without recurrence.\nDFS was estimated using the Kaplan Meier method.\nThe percentile data values presented here indicate the percentage (95, 90, 85 and 80 percent) of participants who had disease free survival for the indicated years."},{"op":"replace","path":"/protocolSection/outcomesModule/secondaryOutcomes/0/timeFrame","value":"From randomization until the date of the first occurrence of disease recurrence, a contralateral invasive breast cancer, a second primary cancer, or death from any cause, assessed up to approximately 10 years"},{"op":"replace","path":"/protocolSection/outcomesModule/secondaryOutcomes/1/measure","value":"Overall Survival (OS) at the Primary Analysis"},{"op":"replace","path":"/protocolSection/outcomesModule/secondaryOutcomes/1/description","value":"Overall Survival (OS) was defined as the time from randomization until death due to any cause.\nParticipants who had not died were censored at the last date they were known to be alive, or date of withdrawal of consent.\nOS was calculated in years as (date of death minus the date of randomization +1) divided by 365.25.\nThe percentile data values presented here indicate the percentage (99, 98, 97, 96, 95 and 90 percent) of participants who survived for the indicated years."},{"op":"replace","path":"/protocolSection/outcomesModule/secondaryOutcomes/1/timeFrame","value":"From randomization until death due to any cause (median follow-up of 4.5 years)"},{"op":"replace","path":"/protocolSection/outcomesModule/secondaryOutcomes/2/measure","value":"Overall Survival (OS) at the 10-Year Follow-Up"},{"op":"replace","path":"/protocolSection/outcomesModule/secondaryOutcomes/2/description","value":"Overall Survival (OS) was defined as the time from randomization until death due to any cause.\nParticipants who had not died were censored at the last date they were known to be alive, or date of withdrawal of consent.\nOS was calculated in years as (date of death minus the date of randomization +1) divided by 365.25.\nThe percentile data values presented here indicate the percentage (99, 98, 95 and 90 percent) of participants who survived for the indicated years."},{"op":"replace","path":"/protocolSection/outcomesModule/secondaryOutcomes/2/timeFrame","value":"From randomization until death due to any cause, assessed up to approximately 10 years"},{"op":"replace","path":"/protocolSection/outcomesModule/secondaryOutcomes/3/measure","value":"Analysis of Time to Recurrence (TTR)"},{"op":"replace","path":"/protocolSection/outcomesModule/secondaryOutcomes/3/description","value":"Time to Recurrence (TTR) was defined as the the time from randomization to breast cancer recurrence, ignoring second primary cancers (including contralateral breast cancers and non-breast second malignancies) and counting deaths without recurrence as a competing risk."},{"op":"replace","path":"/protocolSection/outcomesModule/secondaryOutcomes/3/timeFrame","value":"From randomization until the date of the first occurrence of a disease recurrence, assessed up to approximately 10 years"},{"op":"replace","path":"/protocolSection/outcomesModule/secondaryOutcomes/4/measure","value":"Analysis of Time to Distant Recurrence (TTDR)"},{"op":"replace","path":"/protocolSection/outcomesModule/secondaryOutcomes/4/description","value":"Time to Distant Recurrence (TTDR) was defined as the the time from randomization to first distant breast cancer recurrence, ignoring locoregional recurrences and second primary cancers, (including contralateral breast cancers and non-breast second malignancies ) and counting deaths without recurrence as a competing risk."},{"op":"replace","path":"/protocolSection/outcomesModule/secondaryOutcomes/4/timeFrame","value":"From randomization until the date of the first occurrence of distant recurrence, assessed up to approximately 10 years"},{"op":"add","path":"/protocolSection/outcomesModule/secondaryOutcomes/5","value":{"description":"Time to Central Nervous System (CNS) recurrence was defined as the time from randomization to first CNS recurrence.\nBoth brain metastasis and meningitis carcinomatosa were considered.","measure":"Analysis of Time to Central Nervous System (CNS) Recurrence","timeFrame":"From randomization until the first central nervous system recurrence, assessed up to approximately 10 years"}},{"op":"add","path":"/protocolSection/outcomesModule/secondaryOutcomes/6","value":{"description":"The cumulative incidence of brain metastases as the first site of breast cancer recurrence among treatment arms was assessed using a hierarchy of primary type and location of first DFS event in cases where more than one event was identified simultaneously.\nBecause diagnostic procedures for different types of recurrence could not be performed on exactly the same day, any diagnoses noted within a two month (60 day) period of the first reported event was considered as identified simultaneously for purposes of defining the type of the first event and the date of event was be regarded as the earliest of the relevant events.","measure":"Cumulative Incidence of Brain Metastases","timeFrame":"From randomization until the date of the first occurrence of a disease recurrence, assessed up to approximately 10 years"}},{"op":"replace","path":"/protocolSection/eligibilityModule/eligibilityCriteria","value":"Key Inclusion Criteria:
Key Exclusion Criteria:
Any of the following abnormal laboratory tests immediately prior to randomization:
Participants received treatment per one of three designs and adjuvant radiotherapy / adjuvant anti-estrogen therapy when clinically indicated.
Participants received treatment per one of three designs and adjuvant radiotherapy / adjuvant anti-estrogen therapy when clinically indicated.
Participants received treatment per one of three designs and adjuvant radiotherapy / adjuvant anti-estrogen therapy when clinically indicated.
Participants received treatment per one of three designs and adjuvant radiotherapy / adjuvant anti-estrogen therapy when clinically indicated.
Participants received treatment per one of three designs and adjuvant radiotherapy / adjuvant anti-estrogen therapy when clinically indicated.
Participants received treatment per one of three designs and adjuvant radiotherapy / adjuvant anti-estrogen therapy when clinically indicated.
Participants received treatment per one of three designs and adjuvant radiotherapy / adjuvant anti-estrogen therapy when clinically indicated.
Participants received treatment per one of three designs and adjuvant radiotherapy / adjuvant anti-estrogen therapy when clinically indicated.
Participants received treatment per one of three designs and adjuvant radiotherapy / adjuvant anti-estrogen therapy when clinically indicated.
Participants received treatment per one of three designs and adjuvant radiotherapy / adjuvant anti-estrogen therapy when clinically indicated.
Participants received treatment per one of three designs and adjuvant radiotherapy / adjuvant anti-estrogen therapy when clinically indicated.
Participants received treatment per one of three designs and adjuvant radiotherapy / adjuvant anti-estrogen therapy when clinically indicated.
Participants received treatment per one of three designs and adjuvant radiotherapy / adjuvant anti-estrogen therapy when clinically indicated.
Participants received treatment per one of three designs and adjuvant radiotherapy / adjuvant anti-estrogen therapy when clinically indicated.
Participants received treatment per one of three designs and adjuvant radiotherapy / adjuvant anti-estrogen therapy when clinically indicated.
Participants received treatment per one of three designs and adjuvant radiotherapy / adjuvant anti-estrogen therapy when clinically indicated.
Participants received treatment per one of the following three designs.\nDesign 1: oral lap 1500 mg daily for 52 weeks.
Design 2: oral lap 750 mg daily concomitantly with weekly paclitaxel 80 mg/m^2 IV or docetaxel 75 mg/m^2 IV every 3 weeks, for 12 weeks.\nAfter completion of paclitaxel or docetaxel, participants received oral lap at an increased dose of 1500 mg daily for 40 weeks.\nDesign 2B: oral lap 750 mg daily concomitantly with docetaxel 75 mg/m^2 every 3 weeks and carboplatin AUC6 IV, for 18 weeks.\nAfter completion of docetaxel and carboplatin, oral lap was given at an increased dose of 1500 mg for 34 weeks.\nParticipants also received adjuvant radiotherapy and adjuvant antiestrogen therapy when clinically indicated.
"},{"op":"replace","path":"/resultsSection/outcomeMeasuresModule/outcomeMeasures/2/groups/3/title","value":"Trastuzumab"},{"op":"replace","path":"/resultsSection/outcomeMeasuresModule/outcomeMeasures/2/groups/3/description","value":"Participants received treatment per one of three designs and adjuvant radiotherapy / adjuvant anti-estrogen therapy when clinically indicated.
Participants received treatment per one of three designs and adjuvant radiotherapy / adjuvant anti-estrogen therapy when clinically indicated.
Participants received treatment per one of three designs and adjuvant radiotherapy / adjuvant anti-estrogen therapy when clinically indicated.
Participants received treatment per one of the following three designs.\nDesign 1: oral lap 1500 mg daily for 52 weeks.
Design 2: oral lap 750 mg daily concomitantly with weekly paclitaxel 80 mg/m^2 IV or docetaxel 75 mg/m^2 IV every 3 weeks, for 12 weeks.\nAfter completion of paclitaxel or docetaxel, participants received oral lap at an increased dose of 1500 mg daily for 40 weeks.\nDesign 2B: oral lap 750 mg daily concomitantly with docetaxel 75 mg/m^2 every 3 weeks and carboplatin AUC6 IV, for 18 weeks.\nAfter completion of docetaxel and carboplatin, oral lap was given at an increased dose of 1500 mg for 34 weeks.\nParticipants also received adjuvant radiotherapy and adjuvant antiestrogen therapy when clinically indicated.
"},{"op":"replace","path":"/resultsSection/outcomeMeasuresModule/outcomeMeasures/3/groups/3/title","value":"Trastuzumab"},{"op":"replace","path":"/resultsSection/outcomeMeasuresModule/outcomeMeasures/3/groups/3/description","value":"Participants received treatment per one of three designs and adjuvant radiotherapy / adjuvant anti-estrogen therapy when clinically indicated.
Participants received treatment per one of three designs and adjuvant radiotherapy / adjuvant anti-estrogen therapy when clinically indicated.
Participants received treatment per one of three designs and adjuvant radiotherapy / adjuvant anti-estrogen therapy when clinically indicated.
Participants received treatment per one of three designs and adjuvant radiotherapy / adjuvant anti-estrogen therapy when clinically indicated.
Participants received treatment per one of three designs and adjuvant radiotherapy / adjuvant anti-estrogen therapy when clinically indicated.
Participants received treatment per one of three designs and adjuvant radiotherapy / adjuvant anti-estrogen therapy when clinically indicated.
Participants received treatment per one of three designs and adjuvant radiotherapy / adjuvant anti-estrogen therapy when clinically indicated.
Participants received treatment per one of three designs and adjuvant radiotherapy / adjuvant anti-estrogen therapy when clinically indicated.
Participants received treatment per one of three designs and adjuvant radiotherapy / adjuvant anti-estrogen therapy when clinically indicated.
Participants received treatment per one of three designs and adjuvant radiotherapy / adjuvant anti-estrogen therapy when clinically indicated.
Participants received treatment per one of three designs and adjuvant radiotherapy / adjuvant anti-estrogen therapy when clinically indicated.
Participants received treatment per one of three designs and adjuvant radiotherapy / adjuvant anti-estrogen therapy when clinically indicated.
Participants received treatment per one of three designs and adjuvant radiotherapy / adjuvant anti-estrogen therapy when clinically indicated.
Pre-treatment deaths were collected from day of participant's informed consent to the day before first dose of study medication.
On-treatment deaths were collected from first dose of study medication to 30 days after last dose of study medication (on-treatment), up to approximately 56 weeks.
Deaths were collected in the post treatment survival follow up from 31 days after last dose of study medication until the end of the study, up to approximately 10 years.
","groups":[{"description":"Participants received treatment per one of three designs and adjuvant radiotherapy / adjuvant anti-estrogen therapy when clinically indicated.
Participants received treatment per one of three designs and adjuvant radiotherapy / adjuvant anti-estrogen therapy when clinically indicated.
Participants received treatment per one of three designs and adjuvant radiotherapy / adjuvant anti-estrogen therapy when clinically indicated.