Breast Cancer
Conditions
Keywords
HER-2/erbB-2 positive breast cancer, breast cancer, adjuvant therapy, neratinib, HKI-272, Nerlynx, PB-272
Brief summary
The purpose of this study is to investigate whether neratinib can further reduce the risk of recurrence from previously diagnosed HER-2 positive breast cancer after adjuvant treatment with trastuzumab.
Interventions
DRUGneratinib
OTHERplacebo
Sponsors
Puma Biotechnology, Inc.
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
* Stage II through IIIC HER-2/erbB-2 positive breast cancer with node positive disease. * Been treated for early breast cancer with standard of care duration of trastuzumab. * Could have been treated neoadjuvantly but have not reached pathologic complete response.
Exclusion criteria
* Positive clinical and radiologic assessments for local or regional recurrence of disease at the time of study entry. * History of heart disease. * Corrected QT (QTc) interval \>0.45 seconds * History of gastrointestinal disease with diarrhea as the major symptom.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Invasive Disease-free Survival (iDFS) in Neratinib Arm Compared to Placebo Arm at Year 2 | From randomization until time of event up to 2 years | Invasive disease-free survival time is defined as the time from date of randomization until the first disease recurrence of the following events: invasive ipsilateral breast tumor recurrence, invasive contralateral breast cancer, local/regional invasive recurrence, distant recurrence and death from any cause. |
| Kaplan-Meier Estimates of Invasive Disease-free Survival (iDFS) at Year 2 by Treatment Arms | From randomization until time of event up to 2 years | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Kaplan-Meier Estimates of Disease-free Survival Including Ductal Carcinoma in Situ (DFS-DCIS) at Year 2 by Treatment Arms | From randomization until time of event up to 2 years | — |
| Distant Disease-free Survival (DDFS) in Neratinib Arm Compared to Placebo Arm at Year 2 | From randomization until time of event up to 2 years | Distant disease-free survival time is defined as the time from date of randomization until the first occurrence of distant recurrence or death from any cause. |
| Kaplan-Meier Estimates of Distant Disease-free Survival (DDFS) at Year 2 by Treatment Arms | From randomization until time of event up to 2 years | — |
| Percentage of Participants With Time to Distant Recurrence (TTDR) Event in Neratinib Arm Compared to Placebo Arm at Year 2 | From randomization until time of event up to 2 years | Percentage of Participants with TTDR events is reported. TTDR is defined as the time from date of randomization until the first occurrence of distant recurrence or death from breast cancer. |
| Kaplan-Meier Estimates of Time to Distant Recurrence (TTDR) Survival at Year 2 by Treatment Arms | From randomization until time of event up to 2 years | — |
| Central Nervous System Recurrence in Neratinib Arm Compared to Placebo Arm at Year 2 | From randomization until time of event up to 2 years | CNS recurrence is defined as the time from randomization to CNS as the first distant recurrence. Competing events include distant recurrence at other sites as the first distant recurrence and death from any cause prior to distant recurrence. |
| Cumulative Incidence of Central Nervous System Recurrence (CNS) at Year 2 | From randomization until time of event up to 2 years | Cumulative incidence of Central Nervous System Recurrence (CNS) is estimated by Gray's method (Gray,1988). |
| Overall Survival (OS) | Randomization until death due to any cause (up to 119 Months) | OS was defined as the time from randomization to death due to any cause, censored at the last date known alive. |
| Disease-free Survival Including Ductal Carcinoma in Situ (DFS-DCIS) in Neratinib Arm Compared to Placebo Arm at Year 2 | From randomization until time of event up to 2 years | Disease-free survival including DCIS time is defined as the time from date of randomization until the first occurrence of DCIS or an iDFS event (an iDFS event including invasive ipsilateral breast tumor recurrence, invasive contralateral breast cancer, local/regional invasive recurrence, or distant recurrence and death from any. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Distant Disease-free Survival (DDFS) in Neratinib Arm Compared to Placebo Arm at Year 5 | From randomization until time of event up to 5 years | Distant disease-free survival time is defined as the time from date of randomization until the first occurrence of distant recurrence or death from any cause. |
| Percentage of Participants With Time to Distant Recurrence (TTDR) Event in Neratinib Arm Compared to Placebo Arm at Year 5 | From randomization until time of event up to 5 years | Percentage of Participants with TTDR events is reported. TTDR is defined as the time from date of randomization until the first occurrence of distant recurrence or death from breast cancer. |
| Cumulative Incidence of Central Nervous System Recurrence (CNS) at Year 5 | From randomization until time of event up to 5 years | Cumulative incidence of Central Nervous System Recurrence (CNS) is estimated by Gray's method (Gray,1988). |
| Disease-free Survival Including Ductal Carcinoma in Situ (DFS-DCIS) in Neratinib Arm Compared to Placebo Arm at Year 5 | From randomization until time of event up to 5 years | Disease-free survival including DCIS time is defined as the time from date of randomization until the first occurrence of DCIS or an iDFS event (an iDFS event including invasive ipsilateral breast tumor recurrence, invasive contralateral breast cancer, local/regional invasive recurrence, or distant recurrence and death from any. |
| Kaplan-Meier Estimates of Invasive Disease-free Survival (iDFS) at Year 5 by Treatment Arms | From randomization until time of event up to 5 years | — |
| Invasive Disease-free Survival (iDFS) in Neratinib Arm Compared to Placebo Arm at Year 5 | From randomization until time of event up to 5 years | Invasive disease-free survival time is defined as the time from date of randomization until the first disease recurrence of the following events: invasive ipsilateral breast tumor recurrence, invasive contralateral breast cancer, local/regional invasive recurrence, distant recurrence and death from any cause. |
Countries
Australia, Belgium, Brazil, Bulgaria, Canada, China, Colombia, Croatia, Czechia, Denmark, France, Germany, Greece, Hong Kong, Hungary, Israel, Italy, Japan, Lithuania, Malaysia, Malta, Mexico, Netherlands, New Zealand, North Macedonia, Peru, Poland, Romania, Serbia, Singapore, Slovakia, South Korea, Spain, Sweden, Switzerland, Taiwan, The Bahamas, Turkey (Türkiye), United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Neratinib Patients who completed prior adjuvant trastuzumab received six 40 mg neratinib tablets (240 mg) taken orally once daily with food, preferably in the morning, continuously for one year. Therapy continued until unacceptable toxicity, recurrent disease, death, or withdrawal of consent occurred. | 1,420 |
| Placebo Patients who completed prior adjuvant trastuzumab received six 40 mg placebo tablets (240 mg) taken orally once daily with food, preferably in the morning, continuously for one year. Therapy continued until unacceptable toxicity, recurrent disease, death, or withdrawal of consent occurred. | 1,420 |
| Total | 2,840 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 35 | 33 |
| Overall Study | Other Reasons | 93 | 84 |
| Overall Study | Withdrawal by Subject | 197 | 120 |
Baseline characteristics
| Characteristic | Neratinib | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 52.3 years STANDARD_DEVIATION 10.08 | 52.3 years STANDARD_DEVIATION 10.28 | 52.3 years STANDARD_DEVIATION 10.18 |
| Race/Ethnicity, Customized Asian | 188 Participants | 197 Participants | 385 Participants |
| Race/Ethnicity, Customized Black or African American | 27 Participants | 47 Participants | 74 Participants |
| Race/Ethnicity, Customized Other | 40 Participants | 41 Participants | 81 Participants |
| Race/Ethnicity, Customized White | 1165 Participants | 1135 Participants | 2300 Participants |
| Sex: Female, Male Female | 1420 Participants | 1420 Participants | 2840 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 | 1,386 / 1,408 | 1,234 / 1,408 |
| serious Total, serious adverse events | 103 / 1,408 | 85 / 1,408 |
Outcome results
Primary
Invasive Disease-free Survival (iDFS) in Neratinib Arm Compared to Placebo Arm at Year 2
Invasive disease-free survival time is defined as the time from date of randomization until the first disease recurrence of the following events: invasive ipsilateral breast tumor recurrence, invasive contralateral breast cancer, local/regional invasive recurrence, distant recurrence and death from any cause.
Time frame: From randomization until time of event up to 2 years
Population: Intent to treat (ITT) population included all participants who were randomized regardless of whether they received any study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Neratinib | Invasive Disease-free Survival (iDFS) in Neratinib Arm Compared to Placebo Arm at Year 2 | 4.7 percentage of participants with events |
| Placebo | Invasive Disease-free Survival (iDFS) in Neratinib Arm Compared to Placebo Arm at Year 2 | 7.5 percentage of participants with events |
Comparison: Invasive disease-free survival (iDFS) in neratinib arm compared to placebo arm.p-value: 0.00895% CI: [0.49, 0.9]Log Rank
Primary
Kaplan-Meier Estimates of Invasive Disease-free Survival (iDFS) at Year 2 by Treatment Arms
Time frame: From randomization until time of event up to 2 years
Population: Intent to treat (ITT) population included all participants who were randomized regardless of whether they received any study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Neratinib | Kaplan-Meier Estimates of Invasive Disease-free Survival (iDFS) at Year 2 by Treatment Arms | 94.2 percentage of participants |
| Placebo | Kaplan-Meier Estimates of Invasive Disease-free Survival (iDFS) at Year 2 by Treatment Arms | 91.9 percentage of participants |
Secondary
Central Nervous System Recurrence in Neratinib Arm Compared to Placebo Arm at Year 2
CNS recurrence is defined as the time from randomization to CNS as the first distant recurrence. Competing events include distant recurrence at other sites as the first distant recurrence and death from any cause prior to distant recurrence.
Time frame: From randomization until time of event up to 2 years
Population: Intent to treat (ITT) population included all participants who were randomized regardless of whether they received any study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Neratinib | Central Nervous System Recurrence in Neratinib Arm Compared to Placebo Arm at Year 2 | 0.8 percentage of participants with events |
| Placebo | Central Nervous System Recurrence in Neratinib Arm Compared to Placebo Arm at Year 2 | 1.1 percentage of participants with events |
Secondary
Cumulative Incidence of Central Nervous System Recurrence (CNS) at Year 2
Cumulative incidence of Central Nervous System Recurrence (CNS) is estimated by Gray's method (Gray,1988).
Time frame: From randomization until time of event up to 2 years
Population: Intent to treat (ITT) population included all participants who were randomized regardless of whether they received any study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Neratinib | Cumulative Incidence of Central Nervous System Recurrence (CNS) at Year 2 | 0.92 percentage of participants |
| Placebo | Cumulative Incidence of Central Nervous System Recurrence (CNS) at Year 2 | 1.16 percentage of participants |
Secondary
Disease-free Survival Including Ductal Carcinoma in Situ (DFS-DCIS) in Neratinib Arm Compared to Placebo Arm at Year 2
Disease-free survival including DCIS time is defined as the time from date of randomization until the first occurrence of DCIS or an iDFS event (an iDFS event including invasive ipsilateral breast tumor recurrence, invasive contralateral breast cancer, local/regional invasive recurrence, or distant recurrence and death from any.
Time frame: From randomization until time of event up to 2 years
Population: Intent to treat (ITT) population included all participants who were randomized regardless of whether they received any study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Neratinib | Disease-free Survival Including Ductal Carcinoma in Situ (DFS-DCIS) in Neratinib Arm Compared to Placebo Arm at Year 2 | 4.7 percentage of participants with events |
| Placebo | Disease-free Survival Including Ductal Carcinoma in Situ (DFS-DCIS) in Neratinib Arm Compared to Placebo Arm at Year 2 | 8.0 percentage of participants with events |
Comparison: Disease-free survival including ductal carcinoma in situ (DFS-DCIS) in neratinib arm compared to placebo arm.95% CI: [0.45, 0.83]
Secondary
Distant Disease-free Survival (DDFS) in Neratinib Arm Compared to Placebo Arm at Year 2
Distant disease-free survival time is defined as the time from date of randomization until the first occurrence of distant recurrence or death from any cause.
Time frame: From randomization until time of event up to 2 years
Population: Intent to treat (ITT) population included all participants who were randomized regardless of whether they received any study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Neratinib | Distant Disease-free Survival (DDFS) in Neratinib Arm Compared to Placebo Arm at Year 2 | 3.8 percentage of participants with events |
| Placebo | Distant Disease-free Survival (DDFS) in Neratinib Arm Compared to Placebo Arm at Year 2 | 5.4 percentage of participants with events |
Comparison: Distant disease free survival (DDFS) in neratinib arm compared to placebo arm.95% CI: [0.52, 1.05]
Secondary
Kaplan-Meier Estimates of Disease-free Survival Including Ductal Carcinoma in Situ (DFS-DCIS) at Year 2 by Treatment Arms
Time frame: From randomization until time of event up to 2 years
Population: Intent to treat (ITT) population included all participants who were randomized regardless of whether they received any study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Neratinib | Kaplan-Meier Estimates of Disease-free Survival Including Ductal Carcinoma in Situ (DFS-DCIS) at Year 2 by Treatment Arms | 94.2 percentage of participants |
| Placebo | Kaplan-Meier Estimates of Disease-free Survival Including Ductal Carcinoma in Situ (DFS-DCIS) at Year 2 by Treatment Arms | 91.3 percentage of participants |
Secondary
Kaplan-Meier Estimates of Distant Disease-free Survival (DDFS) at Year 2 by Treatment Arms
Time frame: From randomization until time of event up to 2 years
Population: Intent to treat (ITT) population included all participants who were randomized regardless of whether they received any study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Neratinib | Kaplan-Meier Estimates of Distant Disease-free Survival (DDFS) at Year 2 by Treatment Arms | 95.3 percentage of participants |
| Placebo | Kaplan-Meier Estimates of Distant Disease-free Survival (DDFS) at Year 2 by Treatment Arms | 94.0 percentage of participants |
Secondary
Kaplan-Meier Estimates of Time to Distant Recurrence (TTDR) Survival at Year 2 by Treatment Arms
Time frame: From randomization until time of event up to 2 years
Population: Intent to treat (ITT) population included all participants who were randomized regardless of whether they received any study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Neratinib | Kaplan-Meier Estimates of Time to Distant Recurrence (TTDR) Survival at Year 2 by Treatment Arms | 95.5 percentage of participants |
| Placebo | Kaplan-Meier Estimates of Time to Distant Recurrence (TTDR) Survival at Year 2 by Treatment Arms | 94.2 percentage of participants |
Secondary
Overall Survival (OS)
OS was defined as the time from randomization to death due to any cause, censored at the last date known alive.
Time frame: Randomization until death due to any cause (up to 119 Months)
Population: Intent to treat (ITT) population included all participants who were randomized regardless of whether they received any study treatment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Neratinib | Overall Survival (OS) | 3 Year Kaplan-Meier Estimate | 96.74 percentage of participants |
| Neratinib | Overall Survival (OS) | 7 Year Kaplan-Meier Estimate | 91.36 percentage of participants |
| Neratinib | Overall Survival (OS) | 5 Year Kaplan-Meier Estimate | 94.09 percentage of participants |
| Neratinib | Overall Survival (OS) | 9 Year Kaplan-Meier Estimate | 89.06 percentage of participants |
| Neratinib | Overall Survival (OS) | 1 Year Kaplan-Meier Estimate | 99.64 percentage of participants |
| Placebo | Overall Survival (OS) | 9 Year Kaplan-Meier Estimate | 88.65 percentage of participants |
| Placebo | Overall Survival (OS) | 1 Year Kaplan-Meier Estimate | 99.43 percentage of participants |
| Placebo | Overall Survival (OS) | 3 Year Kaplan-Meier Estimate | 96.44 percentage of participants |
| Placebo | Overall Survival (OS) | 5 Year Kaplan-Meier Estimate | 93.26 percentage of participants |
| Placebo | Overall Survival (OS) | 7 Year Kaplan-Meier Estimate | 91.29 percentage of participants |
Comparison: The 2-sided P-value was based on stratified log-rank test (stratification factors: prior Trastuzumab (concurrent or sequential), nodal status (\<=3 or \>=4) and ER/PgR status (positive or negative). The hazard ratio and corresponding 95% CI from the stratified cox proportional hazard model were also presented.p-value: 0.691495% CI: [0.747, 1.212]Log Rank
Secondary
Percentage of Participants With Time to Distant Recurrence (TTDR) Event in Neratinib Arm Compared to Placebo Arm at Year 2
Percentage of Participants with TTDR events is reported. TTDR is defined as the time from date of randomization until the first occurrence of distant recurrence or death from breast cancer.
Time frame: From randomization until time of event up to 2 years
Population: Intent to treat (ITT) population included all participants who were randomized regardless of whether they received any study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Neratinib | Percentage of Participants With Time to Distant Recurrence (TTDR) Event in Neratinib Arm Compared to Placebo Arm at Year 2 | 3.7 percentage of participants with events |
| Placebo | Percentage of Participants With Time to Distant Recurrence (TTDR) Event in Neratinib Arm Compared to Placebo Arm at Year 2 | 5.3 percentage of participants with events |
Comparison: Time to distant recurrence (TTDR) in neratinib arm compared to placebo arm.95% CI: [0.51, 1.04]
Other Pre-specified
Cumulative Incidence of Central Nervous System Recurrence (CNS) at Year 5
Cumulative incidence of Central Nervous System Recurrence (CNS) is estimated by Gray's method (Gray,1988).
Time frame: From randomization until time of event up to 5 years
Population: Intent to treat (ITT) population included all participants who were randomized regardless of whether they received any study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Neratinib | Cumulative Incidence of Central Nervous System Recurrence (CNS) at Year 5 | 1.3 percentage of participants |
| Placebo | Cumulative Incidence of Central Nervous System Recurrence (CNS) at Year 5 | 1.82 percentage of participants |
Other Pre-specified
Disease-free Survival Including Ductal Carcinoma in Situ (DFS-DCIS) in Neratinib Arm Compared to Placebo Arm at Year 5
Disease-free survival including DCIS time is defined as the time from date of randomization until the first occurrence of DCIS or an iDFS event (an iDFS event including invasive ipsilateral breast tumor recurrence, invasive contralateral breast cancer, local/regional invasive recurrence, or distant recurrence and death from any.
Time frame: From randomization until time of event up to 5 years
Population: Intent to treat (ITT) population included all participants who were randomized regardless of whether they received any study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Neratinib | Disease-free Survival Including Ductal Carcinoma in Situ (DFS-DCIS) in Neratinib Arm Compared to Placebo Arm at Year 5 | 8.5 percentage of participants with events |
| Placebo | Disease-free Survival Including Ductal Carcinoma in Situ (DFS-DCIS) in Neratinib Arm Compared to Placebo Arm at Year 5 | 12.3 percentage of participants with events |
95% CI: [0.56, 0.89]
Other Pre-specified
Distant Disease-free Survival (DDFS) in Neratinib Arm Compared to Placebo Arm at Year 5
Distant disease-free survival time is defined as the time from date of randomization until the first occurrence of distant recurrence or death from any cause.
Time frame: From randomization until time of event up to 5 years
Population: Intent to treat (ITT) population included all participants who were randomized regardless of whether they received any study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Neratinib | Distant Disease-free Survival (DDFS) in Neratinib Arm Compared to Placebo Arm at Year 5 | 7.0 percentage of participants with events |
| Placebo | Distant Disease-free Survival (DDFS) in Neratinib Arm Compared to Placebo Arm at Year 5 | 9.2 percentage of participants with events |
95% CI: [0.6, 1.01]
Other Pre-specified
Invasive Disease-free Survival (iDFS) in Neratinib Arm Compared to Placebo Arm at Year 5
Invasive disease-free survival time is defined as the time from date of randomization until the first disease recurrence of the following events: invasive ipsilateral breast tumor recurrence, invasive contralateral breast cancer, local/regional invasive recurrence, distant recurrence and death from any cause.
Time frame: From randomization until time of event up to 5 years
Population: Intent to treat (ITT) population included all participants who were randomized regardless of whether they received any study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Neratinib | Invasive Disease-free Survival (iDFS) in Neratinib Arm Compared to Placebo Arm at Year 5 | 8.2 percentage of participants with events |
| Placebo | Invasive Disease-free Survival (iDFS) in Neratinib Arm Compared to Placebo Arm at Year 5 | 11.5 percentage of participants with events |
Comparison: Invasive disease-free survival (iDFS) in neratinib arm compared to placebo arm.p-value: 0.00895% CI: [0.57, 0.92]Log Rank
Other Pre-specified
Kaplan-Meier Estimates of Invasive Disease-free Survival (iDFS) at Year 5 by Treatment Arms
Time frame: From randomization until time of event up to 5 years
Population: Intent to treat (ITT) population included all participants who were randomized regardless of whether they received any study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Neratinib | Kaplan-Meier Estimates of Invasive Disease-free Survival (iDFS) at Year 5 by Treatment Arms | 90.2 percentage of participants |
| Placebo | Kaplan-Meier Estimates of Invasive Disease-free Survival (iDFS) at Year 5 by Treatment Arms | 87.7 percentage of participants |
Other Pre-specified
Percentage of Participants With Time to Distant Recurrence (TTDR) Event in Neratinib Arm Compared to Placebo Arm at Year 5
Percentage of Participants with TTDR events is reported. TTDR is defined as the time from date of randomization until the first occurrence of distant recurrence or death from breast cancer.
Time frame: From randomization until time of event up to 5 years
Population: Intent to treat (ITT) population included all participants who were randomized regardless of whether they received any study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Neratinib | Percentage of Participants With Time to Distant Recurrence (TTDR) Event in Neratinib Arm Compared to Placebo Arm at Year 5 | 6.8 percentage of participants with events |
| Placebo | Percentage of Participants With Time to Distant Recurrence (TTDR) Event in Neratinib Arm Compared to Placebo Arm at Year 5 | 8.9 percentage of participants with events |
95% CI: [0.6, 1.03]