Estrogen Receptor Positive, HER2/Neu Negative, HER2 Positive Breast Carcinoma, Progesterone Receptor Positive, Recurrent Breast Carcinoma, Stage IIIB Breast Cancer AJCC v7, Stage IIIC Breast Cancer AJCC v7, Stage IV Breast Cancer AJCC v6 and v7
Conditions
Brief summary
This randomized phase III trial studies fulvestrant and lapatinib to see how well they work compared to fulvestrant and a placebo in treating postmenopausal women with stage III or stage IV breast cancer that is hormone receptor-positive. Estrogen can cause the growth of breast cancer cells. Hormone therapy using fulvestrant may fight breast cancer by lowering the amount of estrogen the body makes. Lapatinib may stop the growth of breast cancer cells by blocking some of the enzymes needed for cell growth. It is not yet known whether fulvestrant is more effective with or without lapatinib in treating breast cancer.
Detailed description
PRIMARY OBJECTIVES: I. To compare the effect, in terms of progression free survival, of the antiestrogen fulvestrant alone with fulvestrant administered in combination with the dual-kinase inhibitor lapatinib for postmenopausal women with estrogen receptor (ER) and/or progesterone receptor (PgR) positive advanced breast cancer. SECONDARY OBJECTIVES: I. To compare the effects of fulvestrant alone with fulvestrant and lapatinib on other clinical endpoints, including response rate, response and stable disease rate (complete response \[CR\] + partial response \[PR\] + stable disease \>= 6 months), duration of response, overall survival, symptom checklist scores, and toxicity. II. To define predictive markers of clinical activity among women receiving fulvestrant with or without lapatinib. III. To determine if the clinical benefits for combination of hormonal and growth factor inhibitor therapy are most pronounced in women whose tumors express higher levels of ER, epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), phosphorylated protein kinase B (pAkt), and/or phosphorylated mitogen-activated protein kinase 1/2 (pERK1/2). IV. To serologically determine if HER2 extracellular domain (ECD) and EGFR ECD levels can identify patients with a greater likelihood of response and clinical benefit to fulvestrant with or without lapatinib. OUTLINE: Patients are randomized to 1 of 2 treatment arms. ARM I: Patients receive lapatinib ditosylate orally (PO) once daily (QD) on days 1-28 and fulvestrant intramuscularly (IM) on days 1 and 15 of course 1 and on day 1 of each subsequent course. ARM II: Patients receive placebo PO QD on days 1-28 and fulvestrant as in Arm I. In both arms, treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 6 months for 2 years and then annually for 3 years.
Interventions
DRUGFulvestrant
Given IM
OTHERLaboratory Biomarker Analysis
Correlative studies
DRUGLapatinib Ditosylate
Given PO
OTHERPlacebo Administration
Given PO
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologic, pathologic or cytologic diagnosis of cancer of the female breast in either primary or metastatic setting; histological documentation of metastatic/recurrent disease is not required if there is unequivocal clinical evidence for recurrence * Stage IV breast cancer (using American Joint Committee on Cancer \[AJCC\] criteria, 6th edition), or locally advanced (stage III) breast cancer not considered amenable to curative therapy * Patients with symptomatic brain metastases or other symptomatic central nervous system (CNS) metastases are not eligible for the study; no screening studies are required among asymptomatic patients; patients with previously treated brain metastases, who are free of symptoms referable to CNS disease and who are \> 3 months from treatment for brain metastases are eligible * Tumors (as determined on pathology from either primary or metastatic sites) must be potentially sensitive to endocrine therapy, defined as expressing estrogen receptor (ER) and/or progesterone receptor (PgR) as determined immunohistochemical methods according to the local institution's standard protocol, \>= 1% cells will be considered to be positive * The protocol has been amended to permit tumors with any HER2 status, though a determination of HER2 status must have been made; patients will be considered to be eligible if HER2 expression is documented by one of the following methods: * Immunohistochemistry (IHC) 0 (i.e., negative), 1+, 2+, or 3+ levels of expression, or * Gene amplification (fluorescent in situ hybridization \[FISH\]) positive or negative * Patients must have at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as \>= 2.0 cm with conventional techniques or as \>= 1.0 cm with spiral computed tomography (CT) scan * Exception: Patients with lytic or blastic bone metastases as their only site of disease will be eligible for the study even though these patients are not considered to have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) criteria; these patients will be evaluable for time to progression, but not response * Patients with all other lesions, including small lesions (longest diameter \< 2.0 cm with conventional techniques or \< 1.0 cm with spiral CT scan) and truly non-measurable lesions including those listed below are not eligible * Lesions that are considered non-measurable include the following: * Bone lesions (women with bone lesions will be eligible as described above) * Leptomeningeal disease * Ascites * Pleural/pericardial effusion * Inflammatory breast cancer * Lymphangitis cutis/pulmonitis * Abdominal masses that are not confirmed and followed by imaging techniques * Cystic lesions * Patients must have had one or two prior endocrine treatments for breast cancer in either the adjuvant or metastatic setting, exclusive of treatment-related amenorrhea or ovarian suppression; sequential use of two different third-generation aromatase inhibitors is considered one treatment; it is not required that tumors be resistant to such treatments; for example: * A patient with de novo metastatic breast cancer who had never received endocrine therapy is not eligible; * A patient who received adjuvant tamoxifen and subsequent therapy with an aromatase inhibitor (adjuvant or metastatic) is eligible; * A patient who received an aromatase inhibitor in either the adjuvant or metastatic setting, and who discontinued therapy after several months because of side effects, is eligible; * A patient who received an aromatase inhibitor in the adjuvant setting is eligible, regardless of whether they did or did not receive tamoxifen at some point; * A patient who received adjuvant tamoxifen, and subsequently a nonsteroidal aromatase inhibitor and a steroidal aromatase inhibitor for advanced breast cancer in the adjuvant or metastatic setting is eligible; * A patient who received adjuvant tamoxifen, and then a nonsteroidal aromatase inhibitor and subsequently megesterol acetate for advanced breast cancer is not eligible * Tumors potentially sensitive to endocrine therapy, defined as \>= 3 months of prior endocrine therapy without disease progression in the adjuvant or metastatic setting * Patients must have had prior treatment in either the adjuvant or metastatic setting with a commercially available third-generation aromatase inhibitor (i.e. anastrozole, exemestane, or letrozole); it is not required that tumors be resistant to such therapies * Patients may have received up to one prior chemotherapy regimen for stage IV breast cancer; prior chemotherapy in the adjuvant and/or neoadjuvant setting is permitted; patients must have finished chemotherapy at least 1 week prior to starting protocol based treatment * Patients may have received prior trastuzumab therapy for stage IV breast cancer, in combination with up to one chemotherapy and/or endocrine therapy regimen, but that must have concluded at least 3 weeks prior to starting protocol-based therapy; prior trastuzumab therapy in the adjuvant and/or neoadjuvant setting is permitted, but must have concluded at least 3 weeks prior to starting protocol-based therapy * Prior therapy with commercially available inhibitor of EGFR (including but not limited to gefitinib, erlotinib, lapatinib or cetuximab) or experimental inhibitors of EGFR is prohibited * Patients may have initiated bisphosphonate therapy prior to study entry; such patients will have bone lesions considered evaluable for progression but not for response * Prior fulvestrant therapy is prohibited * Patients receiving a gonadotropin-releasing hormone (GnRH) agonist for ovarian suppression must remain on such therapy throughout the course of protocol treatment; patients must discontinue other endocrine treatments, including systemic hormone-replacement therapy and intravaginal estrogens prior to study entry; patients must have concluded radiation therapy prior to study entry; patients must be at least 1 week from prior chemotherapy or 3 weeks from prior trastuzumab therapy, with adequate recovery of bone marrow function and performance status * Patients must be postmenopausal women, defined as a woman fulfilling any of the following criteria: * Age \>= 60 years; or * Age \>= 45 years with an intact uterus and amenorrhea for 12 months or more; or * History of bilateral oophorectomy; or * Follicle stimulating hormone (FSH) levels within postmenopausal range according to the ranges established by the testing facility; or * Treatment with a GnRH agonist for ovarian suppression for at least 3 consecutive months prior to study registration, and remaining on such therapy throughout the course of protocol treatment * Women who are pregnant or nursing are not eligible for the study; clinicians should advise patients that there are no data for the safety of lapatinib or fulvestrant among pregnant patients, nor data on the impact of these agents on fertility or pregnancy * Eastern Cooperative Oncology Group (ECOG) (Zubrod) performance status 0-2 * Absence of pending visceral crisis, in the opinion of the treating physician * Absence of acquired or inherited bleeding disorder * Absence of need for therapeutic systemic anticoagulation (defined as maintaining international normalized ratio \[INR\] \> 1.6); patients may take low-dose warfarin or aspirin (or equivalent) for maintenance of central venous catheter patency * Granulocytes \>= 1,000/μl * Platelet count \>= 100,000/μl * Creatinine =\< 2 mg/dl * Total bilirubin =\< 1.5 x upper limits of normal (ULN) unless due to Gilbert's syndrome * Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =\< 2.5 x ULN without liver metastases; =\< 5 x ULN with liver metastases * INR =\< 1.6 * Left ventricular ejection fraction (LVEF) within institutional limits of normal
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) | Interval from randomization until disease progression or death, whichever occurs first, assessed up to 5 years | PFS was defined as the interval from study entry until disease progression or death resulting from any cause, which ever occurred first. Progression is defined as a 20% increase in the sum of longest diameter of target lesions (per RECIST criteria). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective Tumor Response Rate | Up to 5 years | Response was defined by the Response Evaluation Criteria in Solid Tumors (RECIST). A responding participant had either a Complete Response (disappearance of all target lesions) or Partial Response (30% decrease in sum of longest diameter of target lesions). The response rate of measurable tumors will be estimated with its 95% confidence interval according to treatment arm. |
| Overall Survival (OS) | Study entry to death or last follow-up, up to 5 years | Overall survival was measured as the interval from study entry until death, from any cause, or last contact. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival for Participants With HER2-negative Tumors | Up to 5 years | PFS was defined as the interval from study entry until disease progression or death resulting from any cause, which ever occurred first. |
| Objective Tumor Response Rate for Participants With HER2-positive Tumors | Up to 5 years | Response was defined by the RECIST. A responding participant had either a Complete Response (disappearance of all target lesions) or Partial Response (30% decrease in sum of longest diameter of target lesions). The response rate of measurable tumors will be estimated with its 95% confidence interval according to treatment arm. |
| Progression-free Survival for Participants With HER2-positive Tumors | Up to 5 years | PFS was defined as the interval from study entry until disease progression or death resulting from any cause, whichever occurred first. |
| Objective Tumor Response Rate for Participants With HER2-negative Tumors | Up to 5 years | Response was defined by the RECIST. A responding participant had either a Complete Response (disappearance of all target lesions) or Partial Response (30% decrease in sum of longest diameter of target lesions). The response rate of measurable tumors will be estimated with its 95% confidence interval according to treatment arm. |
Countries
United States
Participant flow
Recruitment details
Between September 2006 and July 2010, 295 participants were recruited.
Participants by arm
| Arm | Count |
|---|---|
| Arm I (Lapatinib) Patients receive 1500 mg lapatinib ditosylate PO QD on days 1-28 and fulvestrant IM on days 1 (500 mg) and 15 (250 mg) of course 1 and on day 1 (250 mg)of each subsequent course. | 146 |
| Arm II (Placebo) Patients receive placebo PO QD on days 1-28 and fulvestrant IM on days 1 (500 mg) and 15 (250 mg) of course 1 and on day 1 (250 mg) of each subsequent course. | 145 |
| Total | 291 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 17 | 3 |
| Overall Study | Alternate Treatment | 0 | 1 |
| Overall Study | Other Medical Reasons | 7 | 11 |
| Overall Study | Withdrawal by Subject | 8 | 8 |
Baseline characteristics
| Characteristic | Arm I (Lapatinib) | Arm II (Placebo) | Total |
|---|---|---|---|
| Age, Customized <40 | 8 participants | 7 participants | 15 participants |
| Age, Customized 40-49 | 21 participants | 17 participants | 38 participants |
| Age, Customized 50-59 | 49 participants | 54 participants | 103 participants |
| Age, Customized 60-69 | 41 participants | 47 participants | 88 participants |
| Age, Customized 70+ | 27 participants | 20 participants | 47 participants |
| Bond disease only No | 101 participants | 102 participants | 203 participants |
| Bond disease only Yes | 45 participants | 43 participants | 88 participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 7 Participants | 7 Participants | 14 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 130 Participants | 129 Participants | 259 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 9 Participants | 9 Participants | 18 Participants |
| Prior tamoxifen therapy No | 63 participants | 63 participants | 126 participants |
| Prior tamoxifen therapy Yes | 83 participants | 82 participants | 165 participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 4 Participants | 2 Participants | 6 Participants |
| Race (NIH/OMB) Black or African American | 11 Participants | 8 Participants | 19 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants | 1 Participants | 4 Participants |
| Race (NIH/OMB) White | 127 Participants | 132 Participants | 259 Participants |
| Region of Enrollment United States | 146 participants | 145 participants | 291 participants |
| Sex: Female, Male Female | 146 Participants | 145 Participants | 291 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 128 / 141 | 114 / 137 |
| serious Total, serious adverse events | 12 / 141 | 14 / 137 |
Outcome results
Primary
Progression-free Survival (PFS)
PFS was defined as the interval from study entry until disease progression or death resulting from any cause, which ever occurred first. Progression is defined as a 20% increase in the sum of longest diameter of target lesions (per RECIST criteria).
Time frame: Interval from randomization until disease progression or death, whichever occurs first, assessed up to 5 years
Population: 4 participants who never received protocol therapy were excluded.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm I (Lapatinib) | Progression-free Survival (PFS) | 4.7 months |
| Arm II (Placebo) | Progression-free Survival (PFS) | 3.8 months |
p-value: 0.3795% CI: [0.82, 1.33]Log Rank
Secondary
Objective Tumor Response Rate
Response was defined by the Response Evaluation Criteria in Solid Tumors (RECIST). A responding participant had either a Complete Response (disappearance of all target lesions) or Partial Response (30% decrease in sum of longest diameter of target lesions). The response rate of measurable tumors will be estimated with its 95% confidence interval according to treatment arm.
Time frame: Up to 5 years
Population: Participants who started protocol therapy and had measurable disease were evaluated.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm I (Lapatinib) | Objective Tumor Response Rate | 20 percentage of participants |
| Arm II (Placebo) | Objective Tumor Response Rate | 9 percentage of participants |
Secondary
Overall Survival (OS)
Overall survival was measured as the interval from study entry until death, from any cause, or last contact.
Time frame: Study entry to death or last follow-up, up to 5 years
Population: 4 participants who never started protocol therapy were excluded.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm I (Lapatinib) | Overall Survival (OS) | 29.9 months |
| Arm II (Placebo) | Overall Survival (OS) | 26.4 months |
Other Pre-specified
Objective Tumor Response Rate for Participants With HER2-negative Tumors
Response was defined by the RECIST. A responding participant had either a Complete Response (disappearance of all target lesions) or Partial Response (30% decrease in sum of longest diameter of target lesions). The response rate of measurable tumors will be estimated with its 95% confidence interval according to treatment arm.
Time frame: Up to 5 years
Population: Participants who started protocol therapy, had measurable disease and HER-2 negative disease were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm I (Lapatinib) | Objective Tumor Response Rate for Participants With HER2-negative Tumors | 13 percentage of participants |
| Arm II (Placebo) | Objective Tumor Response Rate for Participants With HER2-negative Tumors | 23 percentage of participants |
Other Pre-specified
Objective Tumor Response Rate for Participants With HER2-positive Tumors
Response was defined by the RECIST. A responding participant had either a Complete Response (disappearance of all target lesions) or Partial Response (30% decrease in sum of longest diameter of target lesions). The response rate of measurable tumors will be estimated with its 95% confidence interval according to treatment arm.
Time frame: Up to 5 years
Population: Participants who started protocol therapy, had measurable disease and HER-2 positive disease were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm I (Lapatinib) | Objective Tumor Response Rate for Participants With HER2-positive Tumors | 38 percentage of participants |
| Arm II (Placebo) | Objective Tumor Response Rate for Participants With HER2-positive Tumors | 17 percentage of participants |
Other Pre-specified
Progression-free Survival for Participants With HER2-negative Tumors
PFS was defined as the interval from study entry until disease progression or death resulting from any cause, which ever occurred first.
Time frame: Up to 5 years
Population: Participants who began protocol therapy with HER-2 negative tumors were analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm I (Lapatinib) | Progression-free Survival for Participants With HER2-negative Tumors | 4.1 months |
| Arm II (Placebo) | Progression-free Survival for Participants With HER2-negative Tumors | 3.8 months |
Other Pre-specified
Progression-free Survival for Participants With HER2-positive Tumors
PFS was defined as the interval from study entry until disease progression or death resulting from any cause, whichever occurred first.
Time frame: Up to 5 years
Population: Participants who started protocol therapy and had HER2-positive disease were analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm I (Lapatinib) | Progression-free Survival for Participants With HER2-positive Tumors | 5.9 months |
| Arm II (Placebo) | Progression-free Survival for Participants With HER2-positive Tumors | 3.3 months |