Neoplasms, Breast
Conditions
Keywords
ErbB2 Overexpressing, ErbB2 Positive, Lapatinib, Invasive Breast Cancer
Brief summary
This study will examine safety and efficacy of Lapatinib in combination with a standard neoadjuvant chemotherapy including 5FU, Epirubicin, Cyclophosphamide and Paclitaxel. Tumor tissue will be obtained at 3 timepoints (optional 4th) to evaluate tumor response to treatment.
Interventions
DRUGTrastuzumab
4mg/kg IV loading dose followed by 2mg/kg IV weekly
DRUGPaclitaxel
80mg/m2 IV weekly for 4 (21 day) cycles
DRUGFEC75
5FU 500mg/m2 + Epirubicin 75 mg/m2 + cyclophosphamide 500 mg/m2 IV on day 1 of 4 (21 day) cycles
DRUGLapatinib
1250 mg oral daily dose in arm 2, 750 mg oral daily dose for FEC cycles and then 1000 mg oral daily dose during the Paclitaxel cycles in arm 3
Sponsors
GlaxoSmithKline
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Have signed an informed consent form (ICF) and a Patient Authorization Form (HIPAA). * Have histologically or cytologically confirmed ErbB2- (HER2/neu-) overexpressing invasive breast cancer (T2-4, N0-2). * ErbB2 overexpressing breast cancer, defined as one of the following definitions: * 3+ staining by immunohistochemistry (IHC), * a fluorescent in situ hybridization (FISH) result of more than six HER2 gene copies per nucleus * a FISH ratio of more than 2.2. * Have either measurable or evaluable disease. * Have an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-1 (Refer to Section 11.4). * Have LVEF within the institutional range of normal as measured by either echocardiogram (ECHO) or MUGA scans. The same modality must be used consistently throughout the study. * Be deemed able to tolerate 8 cycles of preoperative chemotherapy, including 4 cycles with an anthracycline (epirubicin). * Must be willing to undergo 2 mandatory core biopsies (4 passes each) after diagnosis to obtain tissue for biologic expression profiling. Any subject with clinically palpable residual disease may undergo an optional third biopsy to allow identification of presumed pathways of resistance to therapy. This information might be useful in providing the subject with options for other targeted therapies if definitive surgery confirms residual disease. Definitive local therapy with surgery and radiation therapy as indicated will be performed after completion of 12 weeks of paclitaxel-based chemotherapy. * Are able to swallow and retain oral medication (intact pill). * Are able to complete all screening assessments as outlined in the protocol. * Have adequate organ function as defined in Table 4: Table 1 Baseline Laboratory Values Hematologic: ANC (absolute neutrophil count) \>1.5 x 109/L hemoglobin \>9 g/dL platelets \>75 x 109/L Hepatic: albumin \>2.5 g/dL serum bilirubin \<1.25 x ULN AST / ALT \<3 x ULN if no documented liver metastases AST / ALT \<3 x ULN with documented liver metastases Renal: serum creatinine \<2.0 mg/dL * OR - calculated creatinine clearance \>40 mL/min * Are subjects aged \>18 years with any menopausal status: Non-child-bearing potential (i.e., women with functioning ovaries who have a current documented tubal ligation or hysterectomy, or women who are postmenopausal) Child-bearing potential (i.e., women with functioning ovaries and no documented impairment of oviductal or uterine function that would cause sterility.) This category includes women with oligomenorrhea (severe), women who are perimenopausal, and young women who have begun to menstruate. These subjects must have a negative serum pregnancy test at screening and agree to one of the following: Complete abstinence from intercourse from 2 weeks prior to administration of the first dose of study medication until 28 days after the final dose of study medication; or Consistent and correct use of one of the following acceptable methods of birth control: male partner who is sterile prior to the female subject's entry into the study and is the sole sexual partner for that female subject; any intrauterine device (IUD) with a documented failure rate of less than 1% per year; oral contraceptives (either combined or progestogen only) where not contraindicated for this subject population or per local practice.; or barrier methods, including diaphragm or condom with a spermicide. Please note that breast cancer subjects on this trial cannot receive injectable levonorgestrel or injectable progestogen due to the potential for an adverse effect of anti-hormonal therapies on chemotherapy administered for breast cancer \[Albain, 2002\]. Progestogen may also affect the proliferative rate of endocrine-responsive tumors.
Exclusion criteria
* Have received any prior chemotherapy. * Had prior therapy with an ErbB1 and/or ErbB2 inhibitor. * Are receiving concurrent anti-cancer therapy (chemotherapy, immunotherapy, and biologic therapy) while taking study medication. * Have malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel. Women with ulcerative colitis are also excluded. * Have a concurrent disease or condition that would make the woman inappropriate for study participation, or any serious medical disorder that would interfere with the woman's safety. * Have an active or uncontrolled infection. * Have dementia, altered mental status, or any psychiatric condition that would prohibit the understanding or rendering of informed consent. * Have active cardiac disease, defined as one or more of the following: History of uncontrolled or symptomatic angina History of arrhythmias requiring medications, or clinically significant Myocardial infarction \<6 months from study entry Uncontrolled or symptomatic congestive heart failure Ejection fraction below the institutional normal limit Any other cardiac condition, which in the opinion of the treating physician, would make this protocol unreasonably hazardous for the patient * Are pregnant or breastfeeding. * Have received concurrent treatment with an investigational agent or participate in another clinical trial. * Have received concurrent treatment with prohibited medications (refer to Section 5.8.2 for details on prohibited medications). * Have used an investigational drug within 30 days or 5 half-lives, whichever is longer, preceding the first dose of study medication. * Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to any of the agents used in this study or their excipients. * Are receiving therapeutic anti-coagulation therapy (i.e. warfarin, heparin).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Overall Pathological Complete Response (pCR) After 26 Weeks of Therapy | Week 26 | A pCR in the breast was defined as no pathologic evidence of invasive disease (residual ductal carcinoma in situ \[DCIS\] or lobular carcinoma in situ \[LCIS\] was allowed). A pCR in the axillary lymph node(s) was defined as no evidence of breast cancer cells in the lymph node (including subcapsular sinus). Overall pCR was defined as the sum of pCR in the breast and pCR in the lymph nodes. 26 weeks of therapy comprised the 2-week run-in phase, 12 weeks of treatment with FEC, and 12 weeks of treatment with Paclitaxel. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants (Par.) With Disease-free Survival (DFS) at the End of 5 Years From Randomization | From first dose date until disease progression, assessed up to a maximum of 5 years | Percentage is the Kaplan Meier estimate of DFS. DFS is time from randomization until disease recurrence (contralateral breast cancer; second primary cancer; progression during neo-adjuvant treatment; or death from any cause). Par. who experienced progression during treatment and were withdrawn were considered to have a DFS event at withdrawal. |
| Percentage of Participants With Clinical Complete Response (cCR) at 26 Weeks or at End of Treatment (EOT) or Early Withdrawal | Week 26 or EOT or Early withdrawal | cCR was defined as the percentage of participants achieving either a Complete Response (CR) or a Partial Response (PR) using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. CR was defined as the disappearance of all target lesions, and PR was defined as at least a 30% decrease in the sum of the longest diameter (LD) of target lesions taking as reference the baseline sum LD. |
| Number of Participants With the Indicated Electrocardiogram (ECG) Status at Baseline and at EOT or Early Withdrawal | Baseline and EOT (up to Week 26) or Early withdrawal | 12-lead ECGs were performed, and participants were classified as having normal ECG, abnormal- not clinically significant (NCS) ECG, and abnormal-clinically significant (CS) ECG per investigator opinion and reported result. |
| Cumulative Number of Participants With at Least One Decrease of More Than or Equal to 20% in Left Ventricular Ejection Fraction (LVEF) at the Indicated Time Points Compared to LVEF at Baseline | Weeks 3, 9, and 15; EOT or early withdrawal; and 3- and 6-month survival follow-up after last chemotherapy course | LVEF is the measurement of how much blood is being pumped out of the left ventricle of the heart (the main pumping chamber) with each contraction and is used to determine cardiac function. LVEF was measured by performing echocardiogram (ECHO). If ECHO could not be performed or if the investigator believed that it was not conclusive to evaluate LVEF, then a multigated acquisition (MUGA) scan was performed. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Transcriptional Profiling of Total RNA and the Correlation to Response/Non-response to Treatment | Tumor core biopsy taken at Baseline and Treatment Day 14 | Transcriptional data were of poor quality and thus could not be analyzed. Gene pathways that correlate with response/non-response to treatment were to have been evaluated. The unit of measure is unit less; however, the processed values would be considered normalized relative expression level. |
| Cancer Stem Cells and the Correlation to Response/Non-response to Treatment | Tumor core biopsy taken at Baseline and Treatment Day 14 | Stem cell data were of poor quality and thus could not be analyzed. Increases or decreases in cancer stem cells and how the changes correlated with response/non-response to treatment were to have been assessed. |
| Mean Intra-tumoral Expression of the Indicated Proteins at Baseline and Day 14 | Tumor core biopsy taken at Baseline and Treatment Day 14 | Expression (exp) of biomarker proteins (prot) were analyzed to determine if individual prot levels either in the Baseline or Day 14 breast tumor biopsy specimen correlated with breast pCR. A biomarker indicates a change in exp or state of a prot that correlates with the risk or disease progression, or with the susceptibility of the disease to a given treatment. Biomarkers are characteristic biological properties that can be detected and measured in parts of the body like blood or tissue. pCR=yes: participants (par.) had breast pCR. pCR=no: par. did not have breast pCR. Prot exp values are represented as normalized, scaled values; the unit of measurement is unit-less. Raw exp values were processed as follows: background subtraction of the raw exp value, then that value divided by beta-acting exp to normalize the exp value. A Standard Z score was calculated to scale the exp value. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Trastuzumab Participants received trastuzumab alone (a loading dose of 4 milligrams \[mg\]/kilogram \[kg\] on Day 1, followed by a dose of 2 mg/kg on Day 1 of Week 2 and weekly thereafter). Participants were treated with trastuzumab in a 2-week run-in period. On Day 14, a second core needle biopsy was performed, followed by initiation of chemotherapy with 2 combination regimens of 4 cycles each (1 cycle=3 weeks): FEC75 (5-fluorouracil \[5-FU\] 500 mg/meters squared \[m\^2\], epirubicin 75 mg/m\^2, cyclophosphamide 500 mg/m\^2 x 4 cycles on Day 1), then paclitaxel (80 mg/m\^2 x 4 cycles on Day 1, Day 8, and Day 15) in combination with trastuzumab. | 33 |
| Lapatinib Participants received lapatinib alone (1250 mg orally \[PO\] once daily \[QD\]). Participants were treated with lapatinib in a 2-week run-in period. On Day 14, a second core needle biopsy was performed, followed by initiation of chemotherapy with 2 combination regimens of 4 cycles each (1 cycle=3 weeks): FEC75 (5-FU 500 mg/m\^2, epirubicin 75 mg/m\^2, cyclophosphamide 500 mg/m\^2 x 4 cycles on Day 1), then paclitaxel (80 mg/m\^2 x 4 cycles on Day 1, Day 8, and Day 15) in combination with lapatinib. | 34 |
| Trastuzumab+Lapatinib Participants received trastuzumab (given as in Arm 1) and lapatinib (750/1000 mg PO QD). Participants were treated with these medications in a 2-week run-in period. On Day 14, a second core needle biopsy was performed, followed by initiation of chemotherapy with 2 combination regimens of 4 cycles each (1 cycle=3 weeks): FEC75 (5-FU 500 mg/m\^2, epirubicin 75 mg/m\^2, cyclophosphamide 500 mg/m\^2 x 4 cycles on Day 1), then paclitaxel (80 mg/m\^2 x 4 cycles on Day 1, Day 8, and Day 15) in combination with trastuzumab+lapatinib. | 33 |
| Total | 100 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 2 | 3 |
| Overall Study | Completed 5 years | 0 | 0 | 1 |
| Overall Study | Death | 0 | 2 | 3 |
| Overall Study | Did not Complete Study Dosing | 1 | 0 | 0 |
| Overall Study | Disease Progression | 0 | 4 | 1 |
| Overall Study | Disease Recurrence | 0 | 1 | 0 |
| Overall Study | Lost to Follow-up | 6 | 0 | 3 |
| Overall Study | Physician Decision | 0 | 0 | 1 |
| Overall Study | Protocol Violation | 0 | 1 | 1 |
| Overall Study | Sponsor Request | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 3 | 0 | 4 |
| Overall Study | Worsening Peripheral Neuropathy | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Trastuzumab | Lapatinib | Trastuzumab+Lapatinib | Total |
|---|---|---|---|---|
| Age, Continuous | 51.1 Years STANDARD_DEVIATION 10.9 | 50.8 Years STANDARD_DEVIATION 8.76 | 49.2 Years STANDARD_DEVIATION 10.47 | 50.4 Years STANDARD_DEVIATION 10.01 |
| Race/Ethnicity, Customized African American/African heritage | 8 participants | 1 participants | 2 participants | 11 participants |
| Race/Ethnicity, Customized American Indian or Alaska native | 0 participants | 0 participants | 1 participants | 1 participants |
| Race/Ethnicity, Customized Asian - Central/South Asian heritage | 0 participants | 1 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized Asian - East Asian heritage | 0 participants | 1 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized Asian - South East Asian heritage | 0 participants | 2 participants | 1 participants | 3 participants |
| Race/Ethnicity, Customized Mixed race | 0 participants | 1 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized White - Arabic/North African heritage | 0 participants | 1 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized White - White/Caucasian/European heritage | 25 participants | 27 participants | 29 participants | 81 participants |
| Sex: Female, Male Female | 33 Participants | 34 Participants | 33 Participants | 100 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 31 / 32 | 34 / 34 | 31 / 31 |
| serious Total, serious adverse events | 7 / 32 | 7 / 34 | 8 / 31 |
Outcome results
Primary
Percentage of Participants With Overall Pathological Complete Response (pCR) After 26 Weeks of Therapy
A pCR in the breast was defined as no pathologic evidence of invasive disease (residual ductal carcinoma in situ \[DCIS\] or lobular carcinoma in situ \[LCIS\] was allowed). A pCR in the axillary lymph node(s) was defined as no evidence of breast cancer cells in the lymph node (including subcapsular sinus). Overall pCR was defined as the sum of pCR in the breast and pCR in the lymph nodes. 26 weeks of therapy comprised the 2-week run-in phase, 12 weeks of treatment with FEC, and 12 weeks of treatment with Paclitaxel.
Time frame: Week 26
Population: Intent-to-Treat-Evaluable (ITT-E) Population: ITT participants with evaluable tumor responses who had been \>=75% compliant to 5-fluorouracil (5-FU) 500 mg/m\^2, epirubicin 75 mg/m\^2, cyclophosphamide 500 mg/m\^2 (FEC75) and paclitaxel 80 mg/m\^2 and had undergone surgery.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Trastuzumab | Percentage of Participants With Overall Pathological Complete Response (pCR) After 26 Weeks of Therapy | 54.0 percentage of participants |
| Lapatinib | Percentage of Participants With Overall Pathological Complete Response (pCR) After 26 Weeks of Therapy | 45.0 percentage of participants |
| Trastuzumab+Lapatinib | Percentage of Participants With Overall Pathological Complete Response (pCR) After 26 Weeks of Therapy | 74.0 percentage of participants |
95% CI: [-38.1, 17.9]
95% CI: [-8, 49.4]
Secondary
Cumulative Number of Participants With at Least One Decrease of More Than or Equal to 20% in Left Ventricular Ejection Fraction (LVEF) at the Indicated Time Points Compared to LVEF at Baseline
LVEF is the measurement of how much blood is being pumped out of the left ventricle of the heart (the main pumping chamber) with each contraction and is used to determine cardiac function. LVEF was measured by performing echocardiogram (ECHO). If ECHO could not be performed or if the investigator believed that it was not conclusive to evaluate LVEF, then a multigated acquisition (MUGA) scan was performed.
Time frame: Weeks 3, 9, and 15; EOT or early withdrawal; and 3- and 6-month survival follow-up after last chemotherapy course
Population: Safety Population. Not all participants in the Safety Population were analyzed: some participants were randomized to an arm they did not want or participants were randomized in error (eligibility criteria weren't met).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Trastuzumab | Cumulative Number of Participants With at Least One Decrease of More Than or Equal to 20% in Left Ventricular Ejection Fraction (LVEF) at the Indicated Time Points Compared to LVEF at Baseline | Week 3, n= 30, 31, 26 | 1 participants |
| Trastuzumab | Cumulative Number of Participants With at Least One Decrease of More Than or Equal to 20% in Left Ventricular Ejection Fraction (LVEF) at the Indicated Time Points Compared to LVEF at Baseline | Week 9, n= 30, 32, 27 | 1 participants |
| Trastuzumab | Cumulative Number of Participants With at Least One Decrease of More Than or Equal to 20% in Left Ventricular Ejection Fraction (LVEF) at the Indicated Time Points Compared to LVEF at Baseline | Week 15, n= 31, 34, 28 | 1 participants |
| Trastuzumab | Cumulative Number of Participants With at Least One Decrease of More Than or Equal to 20% in Left Ventricular Ejection Fraction (LVEF) at the Indicated Time Points Compared to LVEF at Baseline | Early withdrawal/EOT, n= 31, 34, 28 | 1 participants |
| Trastuzumab | Cumulative Number of Participants With at Least One Decrease of More Than or Equal to 20% in Left Ventricular Ejection Fraction (LVEF) at the Indicated Time Points Compared to LVEF at Baseline | 3-month survival follow-up, n= 31, 34, 28 | 2 participants |
| Trastuzumab | Cumulative Number of Participants With at Least One Decrease of More Than or Equal to 20% in Left Ventricular Ejection Fraction (LVEF) at the Indicated Time Points Compared to LVEF at Baseline | 6-month survival follow-up, n= 31, 34, 28 | 4 participants |
| Lapatinib | Cumulative Number of Participants With at Least One Decrease of More Than or Equal to 20% in Left Ventricular Ejection Fraction (LVEF) at the Indicated Time Points Compared to LVEF at Baseline | 6-month survival follow-up, n= 31, 34, 28 | 4 participants |
| Lapatinib | Cumulative Number of Participants With at Least One Decrease of More Than or Equal to 20% in Left Ventricular Ejection Fraction (LVEF) at the Indicated Time Points Compared to LVEF at Baseline | Week 3, n= 30, 31, 26 | 0 participants |
| Lapatinib | Cumulative Number of Participants With at Least One Decrease of More Than or Equal to 20% in Left Ventricular Ejection Fraction (LVEF) at the Indicated Time Points Compared to LVEF at Baseline | Early withdrawal/EOT, n= 31, 34, 28 | 4 participants |
| Lapatinib | Cumulative Number of Participants With at Least One Decrease of More Than or Equal to 20% in Left Ventricular Ejection Fraction (LVEF) at the Indicated Time Points Compared to LVEF at Baseline | 3-month survival follow-up, n= 31, 34, 28 | 4 participants |
| Lapatinib | Cumulative Number of Participants With at Least One Decrease of More Than or Equal to 20% in Left Ventricular Ejection Fraction (LVEF) at the Indicated Time Points Compared to LVEF at Baseline | Week 9, n= 30, 32, 27 | 0 participants |
| Lapatinib | Cumulative Number of Participants With at Least One Decrease of More Than or Equal to 20% in Left Ventricular Ejection Fraction (LVEF) at the Indicated Time Points Compared to LVEF at Baseline | Week 15, n= 31, 34, 28 | 2 participants |
| Trastuzumab+Lapatinib | Cumulative Number of Participants With at Least One Decrease of More Than or Equal to 20% in Left Ventricular Ejection Fraction (LVEF) at the Indicated Time Points Compared to LVEF at Baseline | Week 9, n= 30, 32, 27 | 1 participants |
| Trastuzumab+Lapatinib | Cumulative Number of Participants With at Least One Decrease of More Than or Equal to 20% in Left Ventricular Ejection Fraction (LVEF) at the Indicated Time Points Compared to LVEF at Baseline | Week 15, n= 31, 34, 28 | 2 participants |
| Trastuzumab+Lapatinib | Cumulative Number of Participants With at Least One Decrease of More Than or Equal to 20% in Left Ventricular Ejection Fraction (LVEF) at the Indicated Time Points Compared to LVEF at Baseline | 6-month survival follow-up, n= 31, 34, 28 | 4 participants |
| Trastuzumab+Lapatinib | Cumulative Number of Participants With at Least One Decrease of More Than or Equal to 20% in Left Ventricular Ejection Fraction (LVEF) at the Indicated Time Points Compared to LVEF at Baseline | Early withdrawal/EOT, n= 31, 34, 28 | 2 participants |
| Trastuzumab+Lapatinib | Cumulative Number of Participants With at Least One Decrease of More Than or Equal to 20% in Left Ventricular Ejection Fraction (LVEF) at the Indicated Time Points Compared to LVEF at Baseline | Week 3, n= 30, 31, 26 | 1 participants |
| Trastuzumab+Lapatinib | Cumulative Number of Participants With at Least One Decrease of More Than or Equal to 20% in Left Ventricular Ejection Fraction (LVEF) at the Indicated Time Points Compared to LVEF at Baseline | 3-month survival follow-up, n= 31, 34, 28 | 3 participants |
Secondary
Number of Participants With the Indicated Electrocardiogram (ECG) Status at Baseline and at EOT or Early Withdrawal
12-lead ECGs were performed, and participants were classified as having normal ECG, abnormal- not clinically significant (NCS) ECG, and abnormal-clinically significant (CS) ECG per investigator opinion and reported result.
Time frame: Baseline and EOT (up to Week 26) or Early withdrawal
Population: Safety Population: all randomized participants (par) who received at least one dose of investigational product, based on actual treatment received if this differed from that to which par was randomized. Not all par were analyzed: some par were randomized to an arm they did not want or par were randomized in error (eligibility criteria weren't met).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Trastuzumab | Number of Participants With the Indicated Electrocardiogram (ECG) Status at Baseline and at EOT or Early Withdrawal | Baseline, Normal, n= 28, 32, 30 | 18 participants |
| Trastuzumab | Number of Participants With the Indicated Electrocardiogram (ECG) Status at Baseline and at EOT or Early Withdrawal | Baseline, Abnormal-NCS, n= 28, 32, 30 | 10 participants |
| Trastuzumab | Number of Participants With the Indicated Electrocardiogram (ECG) Status at Baseline and at EOT or Early Withdrawal | Baseline, Abnormal-CS, n= 28, 32, 30 | 0 participants |
| Trastuzumab | Number of Participants With the Indicated Electrocardiogram (ECG) Status at Baseline and at EOT or Early Withdrawal | EOT/early withdrawal, Normal, n= 16, 21, 16 | 10 participants |
| Trastuzumab | Number of Participants With the Indicated Electrocardiogram (ECG) Status at Baseline and at EOT or Early Withdrawal | EOT/early withdrawal, Abnormal-NCS, n= 16, 21, 16 | 6 participants |
| Trastuzumab | Number of Participants With the Indicated Electrocardiogram (ECG) Status at Baseline and at EOT or Early Withdrawal | EOT/early withdrawal, Abnormal-CS, n= 16, 21, 16 | 0 participants |
| Lapatinib | Number of Participants With the Indicated Electrocardiogram (ECG) Status at Baseline and at EOT or Early Withdrawal | EOT/early withdrawal, Abnormal-CS, n= 16, 21, 16 | 1 participants |
| Lapatinib | Number of Participants With the Indicated Electrocardiogram (ECG) Status at Baseline and at EOT or Early Withdrawal | Baseline, Normal, n= 28, 32, 30 | 23 participants |
| Lapatinib | Number of Participants With the Indicated Electrocardiogram (ECG) Status at Baseline and at EOT or Early Withdrawal | EOT/early withdrawal, Normal, n= 16, 21, 16 | 12 participants |
| Lapatinib | Number of Participants With the Indicated Electrocardiogram (ECG) Status at Baseline and at EOT or Early Withdrawal | EOT/early withdrawal, Abnormal-NCS, n= 16, 21, 16 | 8 participants |
| Lapatinib | Number of Participants With the Indicated Electrocardiogram (ECG) Status at Baseline and at EOT or Early Withdrawal | Baseline, Abnormal-NCS, n= 28, 32, 30 | 8 participants |
| Lapatinib | Number of Participants With the Indicated Electrocardiogram (ECG) Status at Baseline and at EOT or Early Withdrawal | Baseline, Abnormal-CS, n= 28, 32, 30 | 1 participants |
| Trastuzumab+Lapatinib | Number of Participants With the Indicated Electrocardiogram (ECG) Status at Baseline and at EOT or Early Withdrawal | Baseline, Abnormal-NCS, n= 28, 32, 30 | 7 participants |
| Trastuzumab+Lapatinib | Number of Participants With the Indicated Electrocardiogram (ECG) Status at Baseline and at EOT or Early Withdrawal | Baseline, Abnormal-CS, n= 28, 32, 30 | 0 participants |
| Trastuzumab+Lapatinib | Number of Participants With the Indicated Electrocardiogram (ECG) Status at Baseline and at EOT or Early Withdrawal | EOT/early withdrawal, Abnormal-CS, n= 16, 21, 16 | 0 participants |
| Trastuzumab+Lapatinib | Number of Participants With the Indicated Electrocardiogram (ECG) Status at Baseline and at EOT or Early Withdrawal | EOT/early withdrawal, Normal, n= 16, 21, 16 | 12 participants |
| Trastuzumab+Lapatinib | Number of Participants With the Indicated Electrocardiogram (ECG) Status at Baseline and at EOT or Early Withdrawal | Baseline, Normal, n= 28, 32, 30 | 23 participants |
| Trastuzumab+Lapatinib | Number of Participants With the Indicated Electrocardiogram (ECG) Status at Baseline and at EOT or Early Withdrawal | EOT/early withdrawal, Abnormal-NCS, n= 16, 21, 16 | 4 participants |
Secondary
Percentage of Participants (Par.) With Disease-free Survival (DFS) at the End of 5 Years From Randomization
Percentage is the Kaplan Meier estimate of DFS. DFS is time from randomization until disease recurrence (contralateral breast cancer; second primary cancer; progression during neo-adjuvant treatment; or death from any cause). Par. who experienced progression during treatment and were withdrawn were considered to have a DFS event at withdrawal.
Time frame: From first dose date until disease progression, assessed up to a maximum of 5 years
Population: ITT Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Trastuzumab | Percentage of Participants (Par.) With Disease-free Survival (DFS) at the End of 5 Years From Randomization | 90 Percentage |
| Lapatinib | Percentage of Participants (Par.) With Disease-free Survival (DFS) at the End of 5 Years From Randomization | 67 Percentage |
| Trastuzumab+Lapatinib | Percentage of Participants (Par.) With Disease-free Survival (DFS) at the End of 5 Years From Randomization | 66 Percentage |
Secondary
Percentage of Participants With Clinical Complete Response (cCR) at 26 Weeks or at End of Treatment (EOT) or Early Withdrawal
cCR was defined as the percentage of participants achieving either a Complete Response (CR) or a Partial Response (PR) using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. CR was defined as the disappearance of all target lesions, and PR was defined as at least a 30% decrease in the sum of the longest diameter (LD) of target lesions taking as reference the baseline sum LD.
Time frame: Week 26 or EOT or Early withdrawal
Population: ITT Population: all randomized participants regardless of whether they had received any treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Trastuzumab | Percentage of Participants With Clinical Complete Response (cCR) at 26 Weeks or at End of Treatment (EOT) or Early Withdrawal | 61.0 percentage of participants |
| Lapatinib | Percentage of Participants With Clinical Complete Response (cCR) at 26 Weeks or at End of Treatment (EOT) or Early Withdrawal | 68.0 percentage of participants |
| Trastuzumab+Lapatinib | Percentage of Participants With Clinical Complete Response (cCR) at 26 Weeks or at End of Treatment (EOT) or Early Withdrawal | 61.0 percentage of participants |
p-value: 0.62795% CI: [-17.8, 32.5]Fisher Exact
p-value: 195% CI: [-25.1, 25.1]Fisher Exact
Other Pre-specified
Cancer Stem Cells and the Correlation to Response/Non-response to Treatment
Stem cell data were of poor quality and thus could not be analyzed. Increases or decreases in cancer stem cells and how the changes correlated with response/non-response to treatment were to have been assessed.
Time frame: Tumor core biopsy taken at Baseline and Treatment Day 14
Other Pre-specified
Mean Intra-tumoral Expression of the Indicated Proteins at Baseline and Day 14
Expression (exp) of biomarker proteins (prot) were analyzed to determine if individual prot levels either in the Baseline or Day 14 breast tumor biopsy specimen correlated with breast pCR. A biomarker indicates a change in exp or state of a prot that correlates with the risk or disease progression, or with the susceptibility of the disease to a given treatment. Biomarkers are characteristic biological properties that can be detected and measured in parts of the body like blood or tissue. pCR=yes: participants (par.) had breast pCR. pCR=no: par. did not have breast pCR. Prot exp values are represented as normalized, scaled values; the unit of measurement is unit-less. Raw exp values were processed as follows: background subtraction of the raw exp value, then that value divided by beta-acting exp to normalize the exp value. A Standard Z score was calculated to scale the exp value.
Time frame: Tumor core biopsy taken at Baseline and Treatment Day 14
Population: ITT-E Population. Only those participants with matched pairs of biopsy samples for analysis at Baseline and on Day 14 were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Trastuzumab | Mean Intra-tumoral Expression of the Indicated Proteins at Baseline and Day 14 | Baseline, EGFR_Tyr1068; pCR=yes, n=0, 4 | NA : normalized relative expression level | — |
| Trastuzumab | Mean Intra-tumoral Expression of the Indicated Proteins at Baseline and Day 14 | Baseline, Baseline, EGFR_Tyr1068; pCR=no, n=0, 11 | NA : normalized relative expression level | — |
| Trastuzumab | Mean Intra-tumoral Expression of the Indicated Proteins at Baseline and Day 14 | Post Baseline, EGFR_Tyr1068; pCR=yes, n=9, 0 | 0.65 : normalized relative expression level | Standard Deviation 1.02 |
| Trastuzumab | Mean Intra-tumoral Expression of the Indicated Proteins at Baseline and Day 14 | Post Baseline, EGFR_Tyr1068; pCR=no, n=6, 0 | -0.26 : normalized relative expression level | Standard Deviation 0.56 |
| Trastuzumab | Mean Intra-tumoral Expression of the Indicated Proteins at Baseline and Day 14 | Day 14, pSTAT5; pCR=yes, n=11, 6 | NA : normalized relative expression level | — |
| Trastuzumab | Mean Intra-tumoral Expression of the Indicated Proteins at Baseline and Day 14 | Day 14, pSTAT5; pCR=no, n=9, 11 | NA : normalized relative expression level | — |
| Trastuzumab | Mean Intra-tumoral Expression of the Indicated Proteins at Baseline and Day 14 | Post Baseline, PI3K; pCR=yes, n=0, 5 | NA : normalized relative expression level | — |
| Trastuzumab | Mean Intra-tumoral Expression of the Indicated Proteins at Baseline and Day 14 | Post Baseline, PI3K; pCR=no, n=0, 10 | NA : normalized relative expression level | — |
| Trastuzumab | Mean Intra-tumoral Expression of the Indicated Proteins at Baseline and Day 14 | Post Baseline, LC3B; pCR=yes, n=0, 5 | NA : normalized relative expression level | — |
| Trastuzumab | Mean Intra-tumoral Expression of the Indicated Proteins at Baseline and Day 14 | Post Baseline, LC3B; pCR=no, n=0, 10 | NA : normalized relative expression level | — |
| Trastuzumab | Mean Intra-tumoral Expression of the Indicated Proteins at Baseline and Day 14 | Post Baseline, MMP9; pCR=yes, n=0, 5 | NA : normalized relative expression level | — |
| Trastuzumab | Mean Intra-tumoral Expression of the Indicated Proteins at Baseline and Day 14 | Post Baseline, MMP9; pCR=no, n=0, 5 | NA : normalized relative expression level | — |
| Trastuzumab | Mean Intra-tumoral Expression of the Indicated Proteins at Baseline and Day 14 | Post Baseline, GSK3_a_b_Tyr279_216; pCR=yes, n=8,0 | 0.26 : normalized relative expression level | Standard Deviation 0.82 |
| Trastuzumab | Mean Intra-tumoral Expression of the Indicated Proteins at Baseline and Day 14 | Post Baseline, GSK3_a_b_Tyr279_216; pCR=no, n=5,0 | -0.86 : normalized relative expression level | Standard Deviation 0.67 |
| Lapatinib | Mean Intra-tumoral Expression of the Indicated Proteins at Baseline and Day 14 | Post Baseline, MMP9; pCR=yes, n=0, 5 | 0.71 : normalized relative expression level | Standard Deviation 0.34 |
| Lapatinib | Mean Intra-tumoral Expression of the Indicated Proteins at Baseline and Day 14 | Baseline, EGFR_Tyr1068; pCR=yes, n=0, 4 | -0.70 : normalized relative expression level | Standard Deviation 0.47 |
| Lapatinib | Mean Intra-tumoral Expression of the Indicated Proteins at Baseline and Day 14 | Post Baseline, PI3K; pCR=no, n=0, 10 | -0.53 : normalized relative expression level | Standard Deviation 0.67 |
| Lapatinib | Mean Intra-tumoral Expression of the Indicated Proteins at Baseline and Day 14 | Baseline, Baseline, EGFR_Tyr1068; pCR=no, n=0, 11 | 0.05 : normalized relative expression level | Standard Deviation 0.55 |
| Lapatinib | Mean Intra-tumoral Expression of the Indicated Proteins at Baseline and Day 14 | Post Baseline, GSK3_a_b_Tyr279_216; pCR=yes, n=8,0 | NA : normalized relative expression level | — |
| Lapatinib | Mean Intra-tumoral Expression of the Indicated Proteins at Baseline and Day 14 | Post Baseline, EGFR_Tyr1068; pCR=yes, n=9, 0 | NA : normalized relative expression level | — |
| Lapatinib | Mean Intra-tumoral Expression of the Indicated Proteins at Baseline and Day 14 | Post Baseline, LC3B; pCR=yes, n=0, 5 | 0.68 : normalized relative expression level | Standard Deviation 0.81 |
| Lapatinib | Mean Intra-tumoral Expression of the Indicated Proteins at Baseline and Day 14 | Post Baseline, EGFR_Tyr1068; pCR=no, n=6, 0 | NA : normalized relative expression level | — |
| Lapatinib | Mean Intra-tumoral Expression of the Indicated Proteins at Baseline and Day 14 | Post Baseline, MMP9; pCR=no, n=0, 5 | -0.48 : normalized relative expression level | Standard Deviation 0.48 |
| Lapatinib | Mean Intra-tumoral Expression of the Indicated Proteins at Baseline and Day 14 | Day 14, pSTAT5; pCR=yes, n=11, 6 | NA : normalized relative expression level | — |
| Lapatinib | Mean Intra-tumoral Expression of the Indicated Proteins at Baseline and Day 14 | Post Baseline, LC3B; pCR=no, n=0, 10 | -0.43 : normalized relative expression level | Standard Deviation 0.75 |
| Lapatinib | Mean Intra-tumoral Expression of the Indicated Proteins at Baseline and Day 14 | Day 14, pSTAT5; pCR=no, n=9, 11 | NA : normalized relative expression level | — |
| Lapatinib | Mean Intra-tumoral Expression of the Indicated Proteins at Baseline and Day 14 | Post Baseline, GSK3_a_b_Tyr279_216; pCR=no, n=5,0 | NA : normalized relative expression level | — |
| Lapatinib | Mean Intra-tumoral Expression of the Indicated Proteins at Baseline and Day 14 | Post Baseline, PI3K; pCR=yes, n=0, 5 | 0.46 : normalized relative expression level | Standard Deviation 0.73 |
Other Pre-specified
Transcriptional Profiling of Total RNA and the Correlation to Response/Non-response to Treatment
Transcriptional data were of poor quality and thus could not be analyzed. Gene pathways that correlate with response/non-response to treatment were to have been evaluated. The unit of measure is unit less; however, the processed values would be considered normalized relative expression level.
Time frame: Tumor core biopsy taken at Baseline and Treatment Day 14