Neoplasms, Breast
Conditions
Keywords
Adjuvant, ErbB2-overexpressing, Early stage breast cancer, HER2/neu gene amplified
Brief summary
This was a four-arm (parallel group) randomized, open-label, multicenter Phase 3 study to investigate the use of a combination of Lapatinib and Trastuzumab, a sequence of Trastuzumab followed by Lapatinib, and Lapatinib alone, compared to Trastuzumab alone in the adjuvant treatment of Human Epidermal Growth Factor Receptor 2 (HER2) positive early breast cancer.
Detailed description
Treatment allocation was stratified by blocked randomization, with three stratification factors: * Hormone receptor status: Estrogen Receptor (ER) and/or Progesterone Receptor (PgR) positive versus both negative. * Axillary lymph node involvement: not assessed because of neoadjuvant chemotherapy versus node negative versus 1-3 positive nodes versus 4 or more positive nodes. * Timing of adjuvant chemotherapy: concurrently with taxanes and targeted therapy (Design 2) and concurrently with non-anthracycline-based platinum chemotherapy and targeted therapy (Design 2B) versus all other chemotherapy completed before randomization (Design 1). Treatments delivered differed according to the timing and type of adjuvant chemotherapy. 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. The 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.
Interventions
DRUGLapatinib
Small molecule inhibitor
BIOLOGICALTrastuzumab
Antibody
Sponsors
North Central Cancer Treatment Group
National Cancer Institute (NCI)
Breast International Group
Canadian Cancer Trials Group
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Patients \>= 18 years of age with histologically confirmed, non-metastatic, operable and over expression/amplification of HER2 (3+ by IHC and/or FISH positive) primary breast cancer, treated with definitive surgery, with baseline LVEF \>= 50%, known hormone receptor status (ER/PgR or ER alone) and ECOG performance status =\< 1, were included. * For Designs 1 and 2: Patients must have had received at least four cycles of an approved anthracycline-based (neo-) adjuvant chemotherapy regimen or a protocol specified exception. * Approved, signed written informed consent obtained prior to any study specific screening procedures. Key
Exclusion criteria
* History of any prior (ipsi- and/or contralateral) invasive breast carcinoma, past (less than 10 years) or current history of malignant neoplasms, any clinically staged T4 tumor, or bilateral tumors. * Concurrent anti-cancer treatment, except hormonal therapy or radiotherapy for the present breast cancer; * Patients with positive or suspicious internal mammary nodes identified by sentinel node technique, which had not been irradiated or would not be irradiated, or patients with supraclavicular lymph node involvement. * Any prior anti-HER therapy, which includes agents that target other members of the HER family of receptors, e.g. gefitinib (Iressa) * (Neo-) or adjuvant chemotherapy using peripheral stem cell or bone marrow stem cell support; * Serious cardiac illness or medical conditions. * Any of the following abnormal laboratory tests immediately prior to randomization: 1. Serum total bilirubin \>1.5 x upper limit of normal (ULN). In the case of known Gilbert's syndrome, a higher serum total bilirubin (\<2 x ULN) was allowed; 2. Alanine amino transferase (ALT) or aspartate amino transferase (AST) \>2.5 x ULN; 3. Alkaline phosphatase (ALP) \>2.5 x ULN; 4. Serum creatinine \>2.0 x ULN; 5. Total white blood cell count (WBC) \<2.5 x 10\^9/L; 6. Absolute neutrophil count \<1.5 x 10\^9/L; 7. Platelets \<100 x 10\^9/L. * Women of childbearing potential and male patients with partners of childbearing potential, who are unable or unwilling to use adequate contraceptive measures during study treatment, and pregnant or lactating women. * Concomitant use of CYP3A4 inhibitors or inducers.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Disease-Free Survival (DFS) at the Primary Analysis | 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 (median follow-up of 4.5 years) | 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. Only 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. DFS was estimated using the Kaplan Meier method. The 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) at the Primary Analysis | From randomization until death due to any cause (median follow-up of 4.5 years) | Overall Survival (OS) was defined as the time from randomization until death due to any cause. Participants who had not died were censored at the last date they were known to be alive, or date of withdrawal of consent. OS was calculated in years as (date of death minus the date of randomization +1) divided by 365.25. The percentile data values presented here indicate the percentage (99, 98, 97, 96, 95 and 90 percent) of participants who survived for the indicated years. |
| Overall Survival (OS) at the 10-Year Follow-Up | From randomization until death due to any cause, assessed up to approximately 10 years | Overall Survival (OS) was defined as the time from randomization until death due to any cause. Participants who had not died were censored at the last date they were known to be alive, or date of withdrawal of consent. OS was calculated in years as (date of death minus the date of randomization +1) divided by 365.25. The percentile data values presented here indicate the percentage (99, 98, 95 and 90 percent) of participants who survived for the indicated years. |
| Analysis of Time to Recurrence (TTR) | From randomization until the date of the first occurrence of a disease recurrence, assessed up to approximately 10 years | 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. |
| Disease-Free Survival (DFS) at the 10-Year Follow-Up | 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 | 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. Only 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. DFS was estimated using the Kaplan Meier method. The 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. |
| Analysis of Time to Central Nervous System (CNS) Recurrence | From randomization until the first central nervous system recurrence, assessed up to approximately 10 years | Time to Central Nervous System (CNS) recurrence was defined as the time from randomization to first CNS recurrence. Both brain metastasis and meningitis carcinomatosa were considered. |
| Cumulative Incidence of Brain Metastases | From randomization until the date of the first occurrence of a disease recurrence, assessed up to approximately 10 years | 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. Because 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. |
| Analysis of Time to Distant Recurrence (TTDR) | From randomization until the date of the first occurrence of distant recurrence, assessed up to approximately 10 years | 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. |
Countries
Argentina, Australia, Austria, Belgium, Brazil, Bulgaria, Canada, Chile, China, Czechia, Denmark, Estonia, France, Germany, Greece, Hong Kong, Hungary, India, Ireland, Israel, Italy, Japan, Mexico, Netherlands, New Zealand, Norway, Pakistan, Peru, Philippines, Poland, Romania, Russia, Singapore, Slovakia, Slovenia, South Africa, South Korea, Spain, Switzerland, Taiwan, Thailand, Ukraine, United Kingdom, United States
Participant flow
Recruitment details
This study was conducted in 969 centers in 44 countries worldwide.
Pre-assignment details
Based on the IDMC results from 18 August 2011, any patient enrolled onto Lapatinib arm were considered for a new treatment strategy based on discussion with their physician.
Participants by arm
| Arm | Count |
|---|---|
| Lapatinib Plus Trastuzumab Participants received treatment per one of three designs and adjuvant radiotherapy / adjuvant anti-estrogen therapy when clinically indicated.
* Design 1: oral lapatinib (OL) 1000 milligrams (mg) daily with trastuzumab (tras) (8 milligrams per kilogram \[mg/kg\] intravenous \[IV\] loading dose \[LD\], followed by 6 mg/kg IV every 3 weeks \[E3W\]) for 52 weeks (wks).
* Design 2: OL 750 mg daily plus wkly tras (4 mg/kg LD, followed by 2 mg/kg IV) concomitantly (conc.) with wkly paclitaxel (pac) 80 mg per squared meter (mg/m\^2) IV or docetaxel (doc) 75 mg/m\^2 IV E3W for 12 wks. After completion of pac or doc, par. received OL at an increased dose of 1000 mg daily in combination with tras (6 mg/kg without a LD) E3W for 40 wks.
* Design 2B: OL 750 mg plus wkly tras (4 mg/kg IV LD, followed by 2 mg/kg IV wkly) conc. with doc 75 mg/m\^2 E3W and carboplatin (carb) AUC6 IV for 18 wks. After completion of doc and carb, par. received tras E3W (6 mg/kg without a LD) plus OL 1000 mg daily for 34 wks. | 2,093 |
| Trastuzumab Followed by Lapatinib Participants received treatment per one of three designs and adjuvant radiotherapy / adjuvant anti-estrogen therapy when clinically indicated.
* Design 1: weekly tras for 12 weeks (4 mg/kg IV loading dose, followed by 2 mg/kg IV weekly), followed by a 6-week washout period, followed by oral lap 1500 mg daily for 34 weeks.
* Design 2: weekly tras (4 mg/kg IV loading dose, followed by 2 mg/kg IV) concomitantly with weekly paclitaxel 80 mg/m\^2 IV or docetaxel 75 mg/m\^2 IV every 3 weeks for 12 weeks, followed by a 6-week washout period, followed by oral lap 1500 mg daily for 34 weeks.
* Design 2B: weekly tras (4 mg/kg IV loading dose, followed by 2 mg/kg IV weekly) concomitantly with docetaxel 75 mg/m\^2 every 3 weeks and carboplatin AUC6 IV for 18 weeks, followed by a 6-week washout period, followed by oral lap 1500 mg daily for 28 weeks. | 2,091 |
| Lapatinib Participants received treatment per one of three designs and adjuvant radiotherapy / adjuvant anti-estrogen therapy when clinically indicated.
* Design 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. After completion of paclitaxel or docetaxel, participants received oral lap at an increased dose of 1500 mg daily for 40 weeks.
* Design 2B: oral lap 750 mg daily concomitantly with docetaxel 75 mg/m\^2 every 3 weeks and carboplatin AUC6 IV, for 18 weeks. After completion of docetaxel and carboplatin, oral lap was given at an increased dose of 1500 mg for 34 weeks. | 2,100 |
| Trastuzumab Participants received treatment per one of three designs and adjuvant radiotherapy / adjuvant anti-estrogen therapy when clinically indicated.
* Design 1: tras 8 mg/kg IV LD, followed by 6 mg/kg IV every 3 weeks for 52 weeks.
* Design 2: weekly tras (4 mg/kg IV LD, followed by 2 mg/kg IV weekly) concomitantly with weekly paclitaxel 80 mg/m\^2 IV or docetaxel 75 mg/m\^2 IV every 3 weeks, for 12 weeks. After completion of paclitaxel or docetaxel, participants received tras (6 mg/kg without a LD every 3 weeks for 40 weeks.
* Design 2B: weekly tras (4 mg/kg IV LD, followed by 2 mg/kg IV weekly) concomitantly with docetaxel 75 mg/m\^2 every 3 weeks and carboplatin AUC6 IV, for 18 weeks. After completion of docetaxel and carboplatin, participants received tras every 3 weeks (6 mg/kg without a LD) for 34 weeks. | 2,097 |
| Total | 8,381 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Data unavailable due to lapsed ethical consent | 14 | 13 | 14 | 14 |
| Overall Study | Data unavailable due to regulatory issues | 98 | 96 | 85 | 95 |
| Overall Study | Lost to Follow-up | 249 | 216 | 205 | 229 |
| Overall Study | Other reasons as defined per protocol | 98 | 84 | 82 | 105 |
| Overall Study | Patient did not sign ICF 12 | 169 | 176 | 139 | 167 |
| Overall Study | Withdrawal by Subject | 333 | 322 | 396 | 295 |
Baseline characteristics
| Characteristic | Trastuzumab Followed by Lapatinib | Total | Trastuzumab | Lapatinib | Lapatinib Plus Trastuzumab |
|---|---|---|---|---|---|
| Age, Continuous | 50.8 years STANDARD_DEVIATION 10.32 | 51.0 years STANDARD_DEVIATION 10.24 | 51.0 years STANDARD_DEVIATION 10.25 | 51.2 years STANDARD_DEVIATION 10.18 | 50.9 years STANDARD_DEVIATION 10.23 |
| Axillary Lymph Node Status 1-3 positive nodes (no neoadjuvant chemotherapy) | 617 Participants | 2457 Participants | 603 Participants | 620 Participants | 617 Participants |
| Axillary Lymph Node Status >= 4 positive nodes (no neoadjuvant chemotherapy) | 462 Participants | 1866 Participants | 469 Participants | 472 Participants | 463 Participants |
| Axillary Lymph Node Status Node negative (no neoadjuvant chemotherapy) | 842 Participants | 3372 Participants | 844 Participants | 841 Participants | 845 Participants |
| Axillary Lymph Node Status Not applicable (neoadjuvant chemotherapy) | 170 Participants | 686 Participants | 181 Participants | 167 Participants | 168 Participants |
| Hormone Receptor (HR) Status Negative | 886 Participants | 3576 Participants | 897 Participants | 903 Participants | 890 Participants |
| Hormone Receptor (HR) Status Positive | 1205 Participants | 4805 Participants | 1200 Participants | 1197 Participants | 1203 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 45 Participants | 187 Participants | 47 Participants | 47 Participants | 48 Participants |
| Race/Ethnicity, Customized Asian: Central/South | 103 Participants | 429 Participants | 109 Participants | 110 Participants | 107 Participants |
| Race/Ethnicity, Customized Asian: East | 312 Participants | 1236 Participants | 314 Participants | 299 Participants | 311 Participants |
| Race/Ethnicity, Customized Asian: Japanese | 36 Participants | 145 Participants | 43 Participants | 33 Participants | 33 Participants |
| Race/Ethnicity, Customized Asian: South East | 92 Participants | 383 Participants | 89 Participants | 107 Participants | 95 Participants |
| Race/Ethnicity, Customized Black or African American | 30 Participants | 136 Participants | 25 Participants | 43 Participants | 38 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific | 4 Participants | 15 Participants | 5 Participants | 4 Participants | 2 Participants |
| Race/Ethnicity, Customized Other Race | 14 Participants | 65 Participants | 14 Participants | 23 Participants | 14 Participants |
| Race/Ethnicity, Customized Unknown/Missing | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized White: Arabic | 52 Participants | 236 Participants | 69 Participants | 62 Participants | 53 Participants |
| Race/Ethnicity, Customized White: Caucasian | 1402 Participants | 5548 Participants | 1382 Participants | 1372 Participants | 1392 Participants |
| Sex: Female, Male Female | 2086 Participants | 8372 Participants | 2097 Participants | 2098 Participants | 2091 Participants |
| Sex: Female, Male Male | 5 Participants | 9 Participants | 0 Participants | 2 Participants | 2 Participants |
| Timing of Chemotherapy Concurrent | 948 Participants | 3768 Participants | 950 Participants | 932 Participants | 938 Participants |
| Timing of Chemotherapy Sequential | 1143 Participants | 4613 Participants | 1147 Participants | 1168 Participants | 1155 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk |
|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 7 / 2,093 | 7 / 2,091 | 13 / 2,100 | 5 / 2,097 | 189 / 2,055 | 190 / 2,071 | 250 / 2,044 | 228 / 2,073 |
| other Total, other adverse events | 1,930 / 2,061 | 1,862 / 2,076 | 1,887 / 2,056 | 1,649 / 2,076 | 0 / 0 | 0 / 0 | 0 / 0 | 0 / 0 |
| serious Total, serious adverse events | 379 / 2,061 | 299 / 2,076 | 394 / 2,056 | 251 / 2,076 | 0 / 0 | 0 / 0 | 0 / 0 | 0 / 0 |
Outcome results
Primary
Disease-Free Survival (DFS) at the Primary Analysis
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. Only 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. DFS was estimated using the Kaplan Meier method. The 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.
Time frame: 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 (median follow-up of 4.5 years)
Population: Intent-to-Treat (ITT) Population. DFS data for the Lapatinib alone arm include date collected up to the first interim analysis (data cut-off 11th July 2011), as the Lapatinib arm was discontinued prior to the primary analysis due to futility. All the other arms include data up to median follow-up of 4.5 years.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Lapatinib Plus Trastuzumab | Disease-Free Survival (DFS) at the Primary Analysis | 80th Percentile | 6.1 Years |
| Lapatinib Plus Trastuzumab | Disease-Free Survival (DFS) at the Primary Analysis | 90th Percentile | 3.2 Years |
| Lapatinib Plus Trastuzumab | Disease-Free Survival (DFS) at the Primary Analysis | 75th Percentile | 6.1 Years |
| Lapatinib Plus Trastuzumab | Disease-Free Survival (DFS) at the Primary Analysis | 85th Percentile | 5.1 Years |
| Lapatinib Plus Trastuzumab | Disease-Free Survival (DFS) at the Primary Analysis | 95th Percentile | 1.9 Years |
| Trastuzumab Followed by Lapatinib | Disease-Free Survival (DFS) at the Primary Analysis | 85th Percentile | 4.8 Years |
| Trastuzumab Followed by Lapatinib | Disease-Free Survival (DFS) at the Primary Analysis | 80th Percentile | NA Years |
| Trastuzumab Followed by Lapatinib | Disease-Free Survival (DFS) at the Primary Analysis | 75th Percentile | NA Years |
| Trastuzumab Followed by Lapatinib | Disease-Free Survival (DFS) at the Primary Analysis | 90th Percentile | 2.8 Years |
| Trastuzumab Followed by Lapatinib | Disease-Free Survival (DFS) at the Primary Analysis | 95th Percentile | 1.3 Years |
| Lapatinib | Disease-Free Survival (DFS) at the Primary Analysis | 85th Percentile | 2.8 Years |
| Lapatinib | Disease-Free Survival (DFS) at the Primary Analysis | 95th Percentile | 1.0 Years |
| Lapatinib | Disease-Free Survival (DFS) at the Primary Analysis | 90th Percentile | 1.8 Years |
| Lapatinib | Disease-Free Survival (DFS) at the Primary Analysis | 80th Percentile | NA Years |
| Lapatinib | Disease-Free Survival (DFS) at the Primary Analysis | 75th Percentile | NA Years |
| Trastuzumab | Disease-Free Survival (DFS) at the Primary Analysis | 80th Percentile | 5.6 Years |
| Trastuzumab | Disease-Free Survival (DFS) at the Primary Analysis | 90th Percentile | 2.6 Years |
| Trastuzumab | Disease-Free Survival (DFS) at the Primary Analysis | 95th Percentile | 1.5 Years |
| Trastuzumab | Disease-Free Survival (DFS) at the Primary Analysis | 85th Percentile | 4.2 Years |
| Trastuzumab | Disease-Free Survival (DFS) at the Primary Analysis | 75th Percentile | NA Years |
p-value: 0.04895% CI: [0.71, 1]Log Rank
p-value: 0.6195% CI: [0.81, 1.13]Log Rank
Secondary
Analysis of Time to Central Nervous System (CNS) Recurrence
Time to Central Nervous System (CNS) recurrence was defined as the time from randomization to first CNS recurrence. Both brain metastasis and meningitis carcinomatosa were considered.
Time frame: From randomization until the first central nervous system recurrence, assessed up to approximately 10 years
Population: Intent-to-Treat (ITT) Population. The Lapatinib alone arm was discontinued prior to primary analysis due to futility.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Lapatinib Plus Trastuzumab | Analysis of Time to Central Nervous System (CNS) Recurrence | Death as a competing risk | 114 Participants |
| Lapatinib Plus Trastuzumab | Analysis of Time to Central Nervous System (CNS) Recurrence | CNS recurrence | 91 Participants |
| Lapatinib Plus Trastuzumab | Analysis of Time to Central Nervous System (CNS) Recurrence | Censored | 1888 Participants |
| Trastuzumab Followed by Lapatinib | Analysis of Time to Central Nervous System (CNS) Recurrence | Death as a competing risk | 117 Participants |
| Trastuzumab Followed by Lapatinib | Analysis of Time to Central Nervous System (CNS) Recurrence | CNS recurrence | 91 Participants |
| Trastuzumab Followed by Lapatinib | Analysis of Time to Central Nervous System (CNS) Recurrence | Censored | 1883 Participants |
| Trastuzumab | Analysis of Time to Central Nervous System (CNS) Recurrence | CNS recurrence | 95 Participants |
| Trastuzumab | Analysis of Time to Central Nervous System (CNS) Recurrence | Censored | 1860 Participants |
| Trastuzumab | Analysis of Time to Central Nervous System (CNS) Recurrence | Death as a competing risk | 142 Participants |
95% CI: [0.74, 1.31]
95% CI: [0.74, 1.31]
Secondary
Analysis of Time to Distant Recurrence (TTDR)
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.
Time frame: From randomization until the date of the first occurrence of distant recurrence, assessed up to approximately 10 years
Population: Intent-to-Treat (ITT) Population. The Lapatinib alone arm was discontinued prior to primary analysis due to futility.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Lapatinib Plus Trastuzumab | Analysis of Time to Distant Recurrence (TTDR) | Censored | 1835 Participants |
| Lapatinib Plus Trastuzumab | Analysis of Time to Distant Recurrence (TTDR) | Death as a competing risk | 45 Participants |
| Lapatinib Plus Trastuzumab | Analysis of Time to Distant Recurrence (TTDR) | Distant recurrence | 213 Participants |
| Trastuzumab Followed by Lapatinib | Analysis of Time to Distant Recurrence (TTDR) | Censored | 1812 Participants |
| Trastuzumab Followed by Lapatinib | Analysis of Time to Distant Recurrence (TTDR) | Distant recurrence | 238 Participants |
| Trastuzumab Followed by Lapatinib | Analysis of Time to Distant Recurrence (TTDR) | Death as a competing risk | 41 Participants |
| Trastuzumab | Analysis of Time to Distant Recurrence (TTDR) | Censored | 1793 Participants |
| Trastuzumab | Analysis of Time to Distant Recurrence (TTDR) | Death as a competing risk | 54 Participants |
| Trastuzumab | Analysis of Time to Distant Recurrence (TTDR) | Distant recurrence | 250 Participants |
95% CI: [0.71, 1.02]
95% CI: [0.81, 1.16]
Secondary
Analysis of Time to Recurrence (TTR)
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.
Time frame: From randomization until the date of the first occurrence of a disease recurrence, assessed up to approximately 10 years
Population: Intent-to-Treat (ITT) Population. The Lapatinib alone arm was discontinued prior to primary analysis due to futility.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Lapatinib Plus Trastuzumab | Analysis of Time to Recurrence (TTR) | Death as a competing risk | 43 Participants |
| Lapatinib Plus Trastuzumab | Analysis of Time to Recurrence (TTR) | Local, regional, or distant recurrence | 243 Participants |
| Lapatinib Plus Trastuzumab | Analysis of Time to Recurrence (TTR) | Censored | 1807 Participants |
| Trastuzumab Followed by Lapatinib | Analysis of Time to Recurrence (TTR) | Death as a competing risk | 38 Participants |
| Trastuzumab Followed by Lapatinib | Analysis of Time to Recurrence (TTR) | Local, regional, or distant recurrence | 275 Participants |
| Trastuzumab Followed by Lapatinib | Analysis of Time to Recurrence (TTR) | Censored | 1778 Participants |
| Trastuzumab | Analysis of Time to Recurrence (TTR) | Local, regional, or distant recurrence | 298 Participants |
| Trastuzumab | Analysis of Time to Recurrence (TTR) | Censored | 1753 Participants |
| Trastuzumab | Analysis of Time to Recurrence (TTR) | Death as a competing risk | 46 Participants |
95% CI: [0.68, 0.96]
95% CI: [0.79, 1.1]
Secondary
Cumulative Incidence of Brain Metastases
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. Because 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.
Time frame: From randomization until the date of the first occurrence of a disease recurrence, assessed up to approximately 10 years
Population: Intent-to-Treat (ITT) Population. The Lapatinib alone arm was discontinued prior to primary analysis due to futility.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Lapatinib Plus Trastuzumab | Cumulative Incidence of Brain Metastases | 50 Participants |
| Trastuzumab Followed by Lapatinib | Cumulative Incidence of Brain Metastases | 52 Participants |
| Trastuzumab | Cumulative Incidence of Brain Metastases | 48 Participants |
Secondary
Disease-Free Survival (DFS) at the 10-Year Follow-Up
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. Only 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. DFS was estimated using the Kaplan Meier method. The 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.
Time frame: 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
Population: Intent-to-Treat (ITT) Population. The Lapatinib alone arm was discontinued prior to primary analysis due to futility.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Lapatinib Plus Trastuzumab | Disease-Free Survival (DFS) at the 10-Year Follow-Up | 95th Percentile | 1.89 Years |
| Lapatinib Plus Trastuzumab | Disease-Free Survival (DFS) at the 10-Year Follow-Up | 90th Percentile | 3.21 Years |
| Lapatinib Plus Trastuzumab | Disease-Free Survival (DFS) at the 10-Year Follow-Up | 85th Percentile | 5.92 Years |
| Lapatinib Plus Trastuzumab | Disease-Free Survival (DFS) at the 10-Year Follow-Up | 80th Percentile | 8.99 Years |
| Trastuzumab Followed by Lapatinib | Disease-Free Survival (DFS) at the 10-Year Follow-Up | 80th Percentile | 9.18 Years |
| Trastuzumab Followed by Lapatinib | Disease-Free Survival (DFS) at the 10-Year Follow-Up | 95th Percentile | 1.27 Years |
| Trastuzumab Followed by Lapatinib | Disease-Free Survival (DFS) at the 10-Year Follow-Up | 85th Percentile | 4.85 Years |
| Trastuzumab Followed by Lapatinib | Disease-Free Survival (DFS) at the 10-Year Follow-Up | 90th Percentile | 2.80 Years |
| Trastuzumab | Disease-Free Survival (DFS) at the 10-Year Follow-Up | 80th Percentile | 7.42 Years |
| Trastuzumab | Disease-Free Survival (DFS) at the 10-Year Follow-Up | 90th Percentile | 2.63 Years |
| Trastuzumab | Disease-Free Survival (DFS) at the 10-Year Follow-Up | 85th Percentile | 4.43 Years |
| Trastuzumab | Disease-Free Survival (DFS) at the 10-Year Follow-Up | 95th Percentile | 1.49 Years |
95% CI: [0.77, 1.02]
95% CI: [0.8, 1.05]
Secondary
Overall Survival (OS) at the 10-Year Follow-Up
Overall Survival (OS) was defined as the time from randomization until death due to any cause. Participants who had not died were censored at the last date they were known to be alive, or date of withdrawal of consent. OS was calculated in years as (date of death minus the date of randomization +1) divided by 365.25. The percentile data values presented here indicate the percentage (99, 98, 95 and 90 percent) of participants who survived for the indicated years.
Time frame: From randomization until death due to any cause, assessed up to approximately 10 years
Population: Intent-to-Treat (ITT) Population. The Lapatinib alone arm was discontinued prior to primary analysis due to futility.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Lapatinib Plus Trastuzumab | Overall Survival (OS) at the 10-Year Follow-Up | 99th Percentile | 1.68 Years |
| Lapatinib Plus Trastuzumab | Overall Survival (OS) at the 10-Year Follow-Up | 98th Percentile | 2.19 Years |
| Lapatinib Plus Trastuzumab | Overall Survival (OS) at the 10-Year Follow-Up | 95th Percentile | 3.92 Years |
| Lapatinib Plus Trastuzumab | Overall Survival (OS) at the 10-Year Follow-Up | 90th Percentile | 8.31 Years |
| Trastuzumab Followed by Lapatinib | Overall Survival (OS) at the 10-Year Follow-Up | 90th Percentile | 8.49 Years |
| Trastuzumab Followed by Lapatinib | Overall Survival (OS) at the 10-Year Follow-Up | 99th Percentile | 1.17 Years |
| Trastuzumab Followed by Lapatinib | Overall Survival (OS) at the 10-Year Follow-Up | 95th Percentile | 3.52 Years |
| Trastuzumab Followed by Lapatinib | Overall Survival (OS) at the 10-Year Follow-Up | 98th Percentile | 1.60 Years |
| Trastuzumab | Overall Survival (OS) at the 10-Year Follow-Up | 90th Percentile | 6.72 Years |
| Trastuzumab | Overall Survival (OS) at the 10-Year Follow-Up | 98th Percentile | 2.07 Years |
| Trastuzumab | Overall Survival (OS) at the 10-Year Follow-Up | 95th Percentile | 3.65 Years |
| Trastuzumab | Overall Survival (OS) at the 10-Year Follow-Up | 99th Percentile | 1.75 Years |
95% CI: [0.7, 1.03]
95% CI: [0.71, 1.04]
Secondary
Overall Survival (OS) at the Primary Analysis
Overall Survival (OS) was defined as the time from randomization until death due to any cause. Participants who had not died were censored at the last date they were known to be alive, or date of withdrawal of consent. OS was calculated in years as (date of death minus the date of randomization +1) divided by 365.25. The percentile data values presented here indicate the percentage (99, 98, 97, 96, 95 and 90 percent) of participants who survived for the indicated years.
Time frame: From randomization until death due to any cause (median follow-up of 4.5 years)
Population: Intent-to-Treat (ITT) Population. Zero participants were analyzed in the lapatinib arm, as the Independent Data Monitoring Committee discontinued the lapatinib-alone arm due to futility at the time of the first interim analysis (lapatinib participants were then offered trastuzumab).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Lapatinib Plus Trastuzumab | Overall Survival (OS) at the Primary Analysis | 99th Percentile | 1.7 Years |
| Lapatinib Plus Trastuzumab | Overall Survival (OS) at the Primary Analysis | 98th Percentile | 2.2 Years |
| Lapatinib Plus Trastuzumab | Overall Survival (OS) at the Primary Analysis | 97th Percentile | 2.8 Years |
| Lapatinib Plus Trastuzumab | Overall Survival (OS) at the Primary Analysis | 96th Percentile | 3.4 Years |
| Lapatinib Plus Trastuzumab | Overall Survival (OS) at the Primary Analysis | 95th Percentile | 3.9 Years |
| Lapatinib Plus Trastuzumab | Overall Survival (OS) at the Primary Analysis | 90th Percentile | NA Years |
| Trastuzumab Followed by Lapatinib | Overall Survival (OS) at the Primary Analysis | 90th Percentile | NA Years |
| Trastuzumab Followed by Lapatinib | Overall Survival (OS) at the Primary Analysis | 99th Percentile | 1.2 Years |
| Trastuzumab Followed by Lapatinib | Overall Survival (OS) at the Primary Analysis | 96th Percentile | 2.9 Years |
| Trastuzumab Followed by Lapatinib | Overall Survival (OS) at the Primary Analysis | 95th Percentile | 3.7 Years |
| Trastuzumab Followed by Lapatinib | Overall Survival (OS) at the Primary Analysis | 98th Percentile | 1.6 Years |
| Trastuzumab Followed by Lapatinib | Overall Survival (OS) at the Primary Analysis | 97th Percentile | 2.2 Years |
| Trastuzumab | Overall Survival (OS) at the Primary Analysis | 98th Percentile | 2.1 Years |
| Trastuzumab | Overall Survival (OS) at the Primary Analysis | 97th Percentile | 2.6 Years |
| Trastuzumab | Overall Survival (OS) at the Primary Analysis | 90th Percentile | 5.9 Years |
| Trastuzumab | Overall Survival (OS) at the Primary Analysis | 96th Percentile | 3.0 Years |
| Trastuzumab | Overall Survival (OS) at the Primary Analysis | 99th Percentile | 1.7 Years |
| Trastuzumab | Overall Survival (OS) at the Primary Analysis | 95th Percentile | 3.6 Years |
p-value: 0.07895% CI: [0.62, 1.03]Log Rank
p-value: 0.43395% CI: [0.71, 1.16]Log Rank
Post Hoc
All Collected Deaths
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.
Time frame: Pre-treatment deaths: Up to 14 days prior to treatment. On-treatment deaths: Up to 56 weeks. Post-treatment deaths: up to 10 years.
Population: Intent-to-Treat (ITT) Population.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Lapatinib Plus Trastuzumab | All Collected Deaths | Pre-treatment deaths | 1 Participants |
| Lapatinib Plus Trastuzumab | All Collected Deaths | On-treatment deaths | 6 Participants |
| Lapatinib Plus Trastuzumab | All Collected Deaths | Post-treatment deaths | 189 Participants |
| Lapatinib Plus Trastuzumab | All Collected Deaths | All deaths | 196 Participants |
| Trastuzumab Followed by Lapatinib | All Collected Deaths | On-treatment deaths | 5 Participants |
| Trastuzumab Followed by Lapatinib | All Collected Deaths | Post-treatment deaths | 190 Participants |
| Trastuzumab Followed by Lapatinib | All Collected Deaths | All deaths | 197 Participants |
| Trastuzumab Followed by Lapatinib | All Collected Deaths | Pre-treatment deaths | 2 Participants |
| Lapatinib | All Collected Deaths | Post-treatment deaths | 250 Participants |
| Lapatinib | All Collected Deaths | On-treatment deaths | 12 Participants |
| Lapatinib | All Collected Deaths | All deaths | 263 Participants |
| Lapatinib | All Collected Deaths | Pre-treatment deaths | 1 Participants |
| Trastuzumab | All Collected Deaths | All deaths | 233 Participants |
| Trastuzumab | All Collected Deaths | On-treatment deaths | 3 Participants |
| Trastuzumab | All Collected Deaths | Pre-treatment deaths | 2 Participants |
| Trastuzumab | All Collected Deaths | Post-treatment deaths | 228 Participants |