Cancer
Conditions
Keywords
carcinoma, breast lump, Pagets disease, breast cancer positive for human epidermal growth factor receptor 2, breast cancer progression, estrogen-receptor
Brief summary
This was a randomized, open-label, multi-center Phase III study evaluating the efficacy and safety of lapatinib in combination with trastuzumab versus trastuzumab alone as continued HER2 suppression therapy in women with HER2-positive metastatic breast cancer (MBC). Eligible subjects should have completed 12 to 24 weeks of first- or second-line treatment with trastuzumab plus chemotherapy, experienced either complete disappearance of all metastatic lesions, or persistence of metastatic disease (stable disease) without unequivocal progression or the occurrence of new lesions, and been indicated to continue to receive trastuzumab alone as maintenance therapy. Eligible subjects who entered the LPT112515 study on first-line treatment should not have known history of central nervous system (CNS) metastases; subjects who entered the study on second-line treatment should not have known history of CNS metastases or have stable (asymptomatic and off steroids ≥3 months) CNS metastases. The primary objective of this study was to compare progression-free survival (PFS) in subjects with HER2-positive MBC randomized to receive treatment with lapatinib plus trastuzumab versus those randomized to receive trastuzumab alone. The secondary objectives included overall survival, clinical benefit response rate (CR, PR or SD ≥24 weeks) and the qualitative and quantitative adverse event profile of the 2 treatment arms. It was estimated that 280 subjects (140 per group) would be required to observe 193 PFS events.
Interventions
DRUGLapatinib
Oral Lapatinib 1000 mg once daily. Lapatinib was a small molecule, reversible inhibitor targeting HER2 tyrosine kinase receptor.
BIOLOGICALTrastuzumab
IV Trastuzumab 6 mg/kg every three weeks. Trastuzumab was a humanized, monoclonal antibody directed against the extracellular domain of the HER2 tyrosine kinase receptor.
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Signed the informed consent form (ICF) * Female, ≥18 years of age * Histologically verified breast cancer with distant metastases (metastatic breast cancer) * Documentation of HER2 overexpression or gene amplification in the invasive component of either the primary tumor or metastatic disease site defined as: * 3+ by IHC and/or * HER2/neu gene amplification by fluorescence, chromogenic or silver in situ hybridization \[FISH, CISH or SISH; \>6 HER2/neu gene copies per nucleus or a FISH, CISH or SISH HER2 gene copies to chromosome 17 signal ratio of ≥2.0\] * Completed 12 to 24 weeks of first- or second-line treatment with trastuzumab in combination with chemotherapy * Either complete disappearance of all lesions, or persistence of metastatic disease (stable disease) without unequivocal progression or the occurrence of new lesions * Documentation of lesion response during the course of therapy received prior to randomization (i.e., improvement or no worsening of tumor burden; the absence of new lesions) * Measurable disease is not required for study participation * No known or suspected (associated neurological signs and symptoms) brain metastases (including leptomeningeal involvement) * Stable brain metastasis (defined as asymptomatic and off steroids ≥3 months) are permitted in subjects on second-line treatment (completed 12-24 weeks of second-line treatment with trastuzumab plus chemotherapy) * Baseline of Left Ventricular Ejection Fraction (LVEF) ≥50% measured by echocardiography (ECHO) or multi-gated acquisition scan (MUGA) * Completion of screening assessments * Have adequate marrow and organ function
Exclusion criteria
* History of other malignancy. Subjects who have been disease-free for 5 years or subjects with a history of completely resected non-melanoma skin cancer (basal or squamous) are eligible * Eastern Cooperative Oncology Group (ECOG) Performance Status \>2 * Concurrent anti-cancer treatment, except anti-hormonal therapy for subjects with hormone receptor positive breast cancer * Concurrent treatment with an investigational agent * Prior treatment with anti-HER2 therapy, except trastuzumab or lapatinib * Concurrent treatment with protocol-defined prohibited medications (refer to protocol for details) * Serious cardiac illness or medical condition including but not confined to: * Uncontrolled arrhythmias * Uncontrolled or symptomatic angina * History of congestive heart failure (CHF) * Myocardial infarction \<6 months from study entry * Acute or current active (requiring anti-viral therapy) hepatic or biliary disease (with the exception of subjects with Gilbert's syndrome, asymptomatic gallstones, liver metastases or stable chronic liver disease per investigator assessment) * Concurrent disease or condition that may interfere with study participation, or any serious medical disorder that would interfere with the subject's safety (for example, active or uncontrolled infection or any psychiatric condition prohibiting understanding or rendering of informed consent) * Women of childbearing potential, including women whose last menstrual period was \<12 months ago (unless surgically sterile) who are unable or unwilling to use adequate contraceptive measures during the study treatment period. Adequate contraception includes intra-uterine device, barrier methods with spermicide, or oral contraceptives (unless clinically contraindicated for the subject population or per local practice, refer to protocol for further details) * Pregnant or lactating females * Any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels. * Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to any of the study agents or their excipients that, in the opinion of the Investigator or GSK medical monitor , contra-indicates participation
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival | Time from randomization until disease progression or death, approximately 4 years | Progression-free survival (PFS) with lapatinib plus trastuzumab versus trastuzumab alone. Progression-free survival (PFS) is defined as the time from randomization to the earliest date of disease progression (with radiological evidence) or death from any cause, or to last contact date up to 21Feb2014. Disease Progression was defined using Response Evaluation Criteria In Solid Tumors (RECIST v1.1), a 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum diameters recorded since the treatment started (the sum must have an absolute increase from nadir of 5mm), or an unequivocal progression of existing non-target lesions, or the appearance of new lesions. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | Time from randomization until death, approximately 4 years | Overall Survival is defined as the interval of time (in months) between the date of randomization and the date of death due to any cause. |
| Best Overall Response | approximately 4 years | The best overall response was the best response from the start of the treatment until disease progression/recurrence and was determined programmatically using investigators assessment of responses of target lesion, non-target lesion and new lesions based on RECIST v1.1. Complete Response (CR) = disappearance of all target lesion and non-target lesions if applicable, and no new lesion; Partial Response (PR) = ≥30% decrease in the sum of the longest diameter of target lesions and non-target lesion was neither complete response nor progressive disease (Non-CR/Non-PD) or not evaluable (NE); SD = Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD; PD = ≥ 20% increase from nadir of the target lesions or appearance of new lesion. CR and PR were confirmed responses. Confirmed CR - at least two determinations of CR at least 4 weeks apart before PD; Confirmed PR - at least two determinations of PR or better at least 4 weeks apart before PD. |
| Clinical Benefit Response Rate (CR, PR or SD ≥24 Weeks) | approximately 4 years | Clinical Benefit Rate (CBR) was defined as the percentage of patients achieving either a confirmed CR or PR at any time or maintaining SD for at least 24 weeks while on study, according to the investigator assessment of response per RECIST 1.1 criteria. Confirmed CR - at least two determinations of CR at least 4 weeks apart before PD; Confirmed PR - at least two determinations of PR or better at least 4 weeks apart before PD. |
| Adverse Event Profile of the Two Treatment Arms | From first dose of study treatment until 30 days after the last dose of study treatment, approximately 8 years. | — |
Countries
Canada, United States
Participant flow
Recruitment details
A total of 37 subjects with HER2-positive metastatic breast cancer were enrolled.
Pre-assignment details
Subjects enrolled in the study were randomized 1:1 to either of the arms.
Participants by arm
| Arm | Count |
|---|---|
| Lapatinib + Trastuzumab Lapatinib 1000 mg oral once daily plus intravenous (iv) trastuzumab 6 mg/kg once every 3 weeks. | 20 |
| Trastuzumab Trastuzumab iv 6 mg/kg once every 3 weeks | 17 |
| Total | 37 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Physician Decision | 1 | 2 |
| Overall Study | Protocol defined stopping criteria | 3 | 1 |
| Overall Study | Study closed/terminated | 10 | 10 |
| Overall Study | Withdrawal by Subject | 2 | 0 |
Baseline characteristics
| Characteristic | Trastuzumab | Total | Lapatinib + Trastuzumab |
|---|---|---|---|
| Age, Continuous | 59.1 years STANDARD_DEVIATION 9.44 | 56.5 years STANDARD_DEVIATION 11.43 | 54.3 years STANDARD_DEVIATION 12.7 |
| Race/Ethnicity, Customized Hispanic or Latino | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 17 Participants | 36 Participants | 19 Participants |
| Sex: Female, Male Female | 17 Participants | 37 Participants | 20 Participants |
| Sex: Female, Male Male | 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 | 0 / 18 | 0 / 17 | 0 / 35 |
| other Total, other adverse events | 18 / 18 | 16 / 17 | 34 / 35 |
| serious Total, serious adverse events | 7 / 18 | 4 / 17 | 11 / 35 |
Outcome results
Primary
Progression-free Survival
Progression-free survival (PFS) with lapatinib plus trastuzumab versus trastuzumab alone. Progression-free survival (PFS) is defined as the time from randomization to the earliest date of disease progression (with radiological evidence) or death from any cause, or to last contact date up to 21Feb2014. Disease Progression was defined using Response Evaluation Criteria In Solid Tumors (RECIST v1.1), a 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum diameters recorded since the treatment started (the sum must have an absolute increase from nadir of 5mm), or an unequivocal progression of existing non-target lesions, or the appearance of new lesions.
Time frame: Time from randomization until disease progression or death, approximately 4 years
Population: Intent-to-treat population: All randomized subjects and based on the treatment to which the subject was randomized.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lapatinib + Trastuzumab | Progression-free Survival | 25 months |
| Trastuzumab | Progression-free Survival | 2 months |
Secondary
Adverse Event Profile of the Two Treatment Arms
Time frame: From first dose of study treatment until 30 days after the last dose of study treatment, approximately 8 years.
Population: Safety population: All subjects who received any dose of lapatinib + trastuzumab or trastuzumab.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Lapatinib + Trastuzumab | Adverse Event Profile of the Two Treatment Arms | Any AEs | 18 Participants |
| Lapatinib + Trastuzumab | Adverse Event Profile of the Two Treatment Arms | Any SAE | 7 Participants |
| Lapatinib + Trastuzumab | Adverse Event Profile of the Two Treatment Arms | AE leading to dose reduction | 0 Participants |
| Lapatinib + Trastuzumab | Adverse Event Profile of the Two Treatment Arms | SAEs related to study treatment | 3 Participants |
| Lapatinib + Trastuzumab | Adverse Event Profile of the Two Treatment Arms | AEs leading to discont. of study treatment | 3 Participants |
| Lapatinib + Trastuzumab | Adverse Event Profile of the Two Treatment Arms | Fatal SAEs | 0 Participants |
| Lapatinib + Trastuzumab | Adverse Event Profile of the Two Treatment Arms | AE leading to dose interruption/delay | 11 Participants |
| Lapatinib + Trastuzumab | Adverse Event Profile of the Two Treatment Arms | Fatal SAEs related to study treatment | 0 Participants |
| Lapatinib + Trastuzumab | Adverse Event Profile of the Two Treatment Arms | AEs related to study treatment | 16 Participants |
| Trastuzumab | Adverse Event Profile of the Two Treatment Arms | Fatal SAEs related to study treatment | 0 Participants |
| Trastuzumab | Adverse Event Profile of the Two Treatment Arms | Any AEs | 16 Participants |
| Trastuzumab | Adverse Event Profile of the Two Treatment Arms | AEs related to study treatment | 7 Participants |
| Trastuzumab | Adverse Event Profile of the Two Treatment Arms | AEs leading to discont. of study treatment | 0 Participants |
| Trastuzumab | Adverse Event Profile of the Two Treatment Arms | AE leading to dose reduction | 0 Participants |
| Trastuzumab | Adverse Event Profile of the Two Treatment Arms | AE leading to dose interruption/delay | 2 Participants |
| Trastuzumab | Adverse Event Profile of the Two Treatment Arms | Any SAE | 4 Participants |
| Trastuzumab | Adverse Event Profile of the Two Treatment Arms | SAEs related to study treatment | 1 Participants |
| Trastuzumab | Adverse Event Profile of the Two Treatment Arms | Fatal SAEs | 0 Participants |
Secondary
Best Overall Response
The best overall response was the best response from the start of the treatment until disease progression/recurrence and was determined programmatically using investigators assessment of responses of target lesion, non-target lesion and new lesions based on RECIST v1.1. Complete Response (CR) = disappearance of all target lesion and non-target lesions if applicable, and no new lesion; Partial Response (PR) = ≥30% decrease in the sum of the longest diameter of target lesions and non-target lesion was neither complete response nor progressive disease (Non-CR/Non-PD) or not evaluable (NE); SD = Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD; PD = ≥ 20% increase from nadir of the target lesions or appearance of new lesion. CR and PR were confirmed responses. Confirmed CR - at least two determinations of CR at least 4 weeks apart before PD; Confirmed PR - at least two determinations of PR or better at least 4 weeks apart before PD.
Time frame: approximately 4 years
Population: Intent-to-treat population: All randomized subjects and based on the treatment to which the subject was randomized
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Lapatinib + Trastuzumab | Best Overall Response | Stable disease (SD) | 1 Participants |
| Lapatinib + Trastuzumab | Best Overall Response | Complete response (CR) | 0 Participants |
| Lapatinib + Trastuzumab | Best Overall Response | Partial response (PR) | 2 Participants |
| Lapatinib + Trastuzumab | Best Overall Response | Non - CR/Non - PD | 4 Participants |
| Lapatinib + Trastuzumab | Best Overall Response | Progressive disease (PD) | 1 Participants |
| Lapatinib + Trastuzumab | Best Overall Response | Not evaluable (NE) | 12 Participants |
| Trastuzumab | Best Overall Response | Progressive disease (PD) | 7 Participants |
| Trastuzumab | Best Overall Response | Non - CR/Non - PD | 3 Participants |
| Trastuzumab | Best Overall Response | Complete response (CR) | 0 Participants |
| Trastuzumab | Best Overall Response | Not evaluable (NE) | 5 Participants |
| Trastuzumab | Best Overall Response | Partial response (PR) | 0 Participants |
| Trastuzumab | Best Overall Response | Stable disease (SD) | 2 Participants |
Secondary
Clinical Benefit Response Rate (CR, PR or SD ≥24 Weeks)
Clinical Benefit Rate (CBR) was defined as the percentage of patients achieving either a confirmed CR or PR at any time or maintaining SD for at least 24 weeks while on study, according to the investigator assessment of response per RECIST 1.1 criteria. Confirmed CR - at least two determinations of CR at least 4 weeks apart before PD; Confirmed PR - at least two determinations of PR or better at least 4 weeks apart before PD.
Time frame: approximately 4 years
Population: Intent-to-treat population: All randomized subjects and based on the treatment to which the subject was randomized
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lapatinib + Trastuzumab | Clinical Benefit Response Rate (CR, PR or SD ≥24 Weeks) | 10 Percentages of participants |
| Trastuzumab | Clinical Benefit Response Rate (CR, PR or SD ≥24 Weeks) | 0 Percentages of participants |
Secondary
Overall Survival
Overall Survival is defined as the interval of time (in months) between the date of randomization and the date of death due to any cause.
Time frame: Time from randomization until death, approximately 4 years
Population: Intent-to-treat population: All randomized subjects and based on the treatment to which the subject was randomized.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lapatinib + Trastuzumab | Overall Survival | NA Months |
| Trastuzumab | Overall Survival | NA Months |