HER2 Positive Breast Cancer
Conditions
Keywords
Tucatinib, Capecitabine, Trastuzumab, Xeloda, Herceptin, Breast Cancer, ARRY-380, ONT-380, HER2 Positive Breast Carcinoma, HER2 Positive Locally Advanced Breast Cancer, HER-2 Positive Breast Cancer, HER-2 Positive Breast Carcinoma, HER-2 Positive Locally Advanced Breast Cancer, Recurrent Breast Carcinoma, Stage IV Breast Cancer, Metastatic Breast Cancer, Breast Carcinoma, Metastatic Malignant Neoplasm in the Brain, Brain Metastases in Breast Cancer, Asymptomatic Brain Metastases in Breast Cancer, Low Symptomatic Brain Metastases in Breast Cancer, Seattle Genetics
Brief summary
This study is being done to see if tucatinib works better than placebo to help patients who have a specific type of breast cancer called HER2 positive breast carcinoma. The breast cancer in this study is either metastatic (spread into other parts of the body) or cannot be removed completely with surgery. All patients in the study will get capecitabine and trastuzumab, two drugs that are often used to treat this cancer. There are two parts to this study. The first part of the study is already complete. Patients were randomly assigned to get either tucatinib or placebo (a pill with no medicine). Since this part was blinded, neither patients nor their doctors knew whether a patient got tucatinib or placebo. The second part of the study is called the Unblinded Phase. In this part of the study, participants and their doctors know which drugs are being given. Participants who used to get or are currently getting placebo may be able to start taking tucatinib instead. Each treatment cycle lasts 21 days. Patients will swallow tucatinib pills two times every day. They will swallow capecitabine pills two times a day during the first two weeks of each cycle. Patients will get trastuzumab injections from the study site staff on the first day of every cycle.
Detailed description
This is a randomized, international, multi-center study in patients with progressive unresectable locally advanced or metastatic HER2+ breast cancer who have had prior treatment with trastuzumab, pertuzumab and T-DM1. There are two phases to this trial: the Double-blind Phase and the Unblinded Phase. In the Double-blind phase, participants were randomized in a 2:1 ratio to receive tucatinib or placebo in combination with capecitabine and trastuzumab. In the Unblinded Phase, patients on placebo may be offered tucatinib. Stratification factors include presence or history of treated or untreated brain metastases or brain lesions of equivocal significance (yes/no), Eastern Cooperative Oncology Group (ECOG) Performance Status (0 vs. 1), and region of world (US vs. Canada vs. Rest of World). Safety assessments will be performed at a minimum of once every three weeks throughout study treatment and 30 days after the last dose of study drugs. Laboratory assessments will be performed locally at sites. Left ventricular ejection fraction will be assessed by MUGA or ECHO at screening and once every 12 weeks thereafter. For the blinded phase, contrast brain MRI was performed at baseline. Efficacy assessments (CT of chest, abdomen and pelvis at a minimum) utilized RECIST 1.1 and included patients with evaluable tumors defined as measurable target lesions and non-measurable non-target lesions. RECIST assessment was performed at baseline, every 6 weeks for the first 24 weeks, and then every 9 weeks thereafter. Repeat MRI of the brain was required on this same schedule only in those patients with brain metastases identified at baseline. All treatment decisions were made based upon investigator assessment. All patients underwent a repeat MRI of the brain within 30 days of the end of treatment unless previously performed at time of disease progression. For the unblinded phase, RECIST assessments will be performed per standard clinical practice as determined by investigator with a maximum interval of 12 weeks.
Interventions
DRUGtucatinib
300 mg orally twice daily
DRUGcapecitabine
1000 mg/m2 orally twice daily on Days 1-14 of each 21-day cycle
DRUGtrastuzumab
8 mg/kg intravenously (IV) on Day 1 of Cycle 1, followed by 6 mg/kg on Day1 of each 21-day cycle. In regions where approved, trastuzumab may be given at 600mg subcutaneously once every 3-weeks at either study initiation or crossing over from previous IV trastuzumab.
DRUGplacebo
Oral dose twice daily
Sponsors
Seagen Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Masking applied only during the Double-blind phase of the trial. The Unblinded Phase is open-label.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Double-blind Phase Inclusion Criteria * Histologically confirmed HER2+ breast carcinoma, with HER2+ defined by in situ hybridization (ISH), immunohistochemistry (IHC), or fluorescence in situ hybridization (FISH) methodology * Received previous treatment with trastuzumab, pertuzumab, and T-DM1 * Progression of unresectable locally advanced or metastatic breast cancer after last systemic therapy (as confirmed by investigator), or be intolerant of last systemic therapy * Have measurable or non-measurable disease assessable by RECIST 1.1 * Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 * Adequate hepatic and renal function and hematologic parameters * Left ventricular ejection fraction (LVEF) ≥ 50% * CNS Inclusion - Based on screening brain magnetic resonance imaging (MRI), patients must have one of the following: 1. No evidence of brain metastases 2. Untreated brain metastases not needing immediate local therapy 3. Previously treated brain metastases not needing immediate local therapy 1. Brain metastases previously treated with local therapy may either be stable since treatment or may have progressed since prior local CNS therapy 2. Patients treated with CNS local therapy for newly identified lesions found on contrast brain MRI performed during screening for this study may be eligible to enroll if the following criteria are met: i. Time since whole brain radiation therapy (WBRT) is ≥ 21 days prior to first dose of study treatment, time since stereotactic radiosurgery (SRS) is ≥ 7 days prior to first dose of study treatment, or time since surgical resection is ≥ 28 days. ii. Other sites of disease assessable by RECIST 1.1 are present 4. Relevant records of any CNS treatment must be available to allow for classification of target and non-target lesions Double-blind Phase
Exclusion criteria
* Previously been treated with: 1. lapatinib within 12 months of starting study treatment (except in cases where lapatinib was given for ≤ 21 days and was discontinued for reasons other than disease progression or toxicity) 2. neratinib, afatinib, or other investigational HER2/epidermal growth factor receptor (EGFR) or HER2 tyrosine kinase inhibitor (TKI) at any time previously 3. capecitabine (or other fluoropyrimidine) for metastatic disease except in cases where capecitabine was given for \< 21 days and was discontinued for reasons other than disease progression or toxicity. Patients who have received capecitabine for adjuvant or neoadjuvant treatment at least 12 months prior to starting study treatment are eligible. * Clinically significant cardiopulmonary disease * Carriers of Hepatitis B or Hepatitis C or have other known chronic liver disease * Positive for human immunodeficiency virus (HIV) * Unable for any reason to undergo MRI of the brain * Have used a strong CYP3A4 or CYP2C8 inhibitor within 5 half-lives of the inhibitor, or a strong CYP3A4 or CYP2C8 inducer within 5 days prior to first dose of study treatment * Have known dihydropyrimidine dehydrogenase deficiency (DPD) * CNS Exclusion - Based on screening brain MRI, patients must not have any of the following: 1. Any untreated brain lesions \> 2.0 cm in size, unless approved by medical monitor 2. Ongoing use of systemic corticosteroids for control of symptoms of brain metastases at a total daily dose of \> 2 mg of dexamethasone (or equivalent) 3. Any brain lesion thought to require immediate local therapy. Patients who undergo local treatment for such lesions identified by screening contrast brain MRI may still be eligible for the study based on criteria described under CNS inclusion criteria 4. Known or suspected leptomeningeal disease (LMD) 5. Poorly controlled seizures Unblinded Phase Crossover Inclusion Criteria - Participants who were randomized to the control arm (placebo + trastuzumab + capecitabine) must meet the following criteria to be eligible to crossover to the experimental arm. * Have measurable or non-measurable disease assessable by RECIST 1.1 * For patients who were randomized to the control arm and on the long-term follow-up period at the time of crossover screening: have progression of unresectable locally advanced or metastatic breast cancer after last systemic therapy (as confirmed by investigator), or be intolerant of last systemic therapy. * Have an ECOG Performance Status of 0 or 1 * Have a life expectancy of at least 6 months * Have adequate hepatic and renal function and hematologic parameters * Left ventricular ejection fraction (LVEF) ≥ 50% * CNS Inclusion - Based on screening brain magnetic resonance imaging (MRI), patients must have one of the following: i. No evidence of brain metastases ii. Untreated brain metastases not needing immediate local therapy iii. Previously treated brain metastases not needing immediate local therapy * Brain metastases previously treated with local therapy may either be stable since treatment or may have progressed since prior local CNS therapy * Patients treated with CNS local therapy for newly identified lesions found on contrast brain MRI performed during screening for this study may be eligible to enroll if the following criteria are met: 1. Time since whole brain radiation therapy (WBRT) is ≥ 21 days prior to first dose of study treatment, time since stereotactic radiosurgery (SRS) is ≥ 7 days prior to first dose of study treatment, or time since surgical resection is ≥ 28 days. 2. Other sites of disease assessable by RECIST 1.1 are present Unblinded Phase Crossover
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) Per RECIST 1.1 as Determined by Blinded Independent Central Review (BICR) | 34.6 months | Defined as the time from the date of randomization to the date of documented disease progression. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| PFS in Patients With Brain Metastases at Baseline Using RECIST 1.1 as Determined by BICR | 34.6 months | Defined as the time from the date of randomization to the date of documented disease progression. |
| Overall Survival (OS) at Time of Primary Analysis | 35.9 months | Defined as time from randomization to death from any cause |
| Confirmed Objective Response Rate (ORR) Per RECIST 1.1 as Determined by BICR | 34.6 months | Defined as achieving a best overall response of confirmed complete response (CR) or confirmed partial response (PR). |
| PFS Per RECIST 1.1 as Determined by Investigator Assessment at Time of Primary Analysis | 34.6 months | Defined as the time from the date of randomization to the date of documented disease progression |
| Duration of Response (DOR) Per RECIST 1.1 as Determined by BICR | 24.6 months | Defined as the time from the first objective response to documented disease progression or death from any cause, whichever occurred first. |
| DOR Per RECIST 1.1 as Determined by Investigator Assessment | 33.2 months | Defined as the time from the first objective response to documented disease progression or death from any cause, whichever occurred first. |
| Clinical Benefit Rate (CBR) as Determined by BICR Per RECIST 1.1 | 34.6 months | Clinical benefit was defined as achieving stable disease (SD) or non-complete response (CR)/non-progressive disease (PD) for at least 6 months or a best overall response of confirmed CR or confirmed partial response (PR). |
| CBR Per RECIST 1.1 as Determined by Investigator Assessment | 34.6 months | Clinical benefit was defined as achieving stable disease (SD) or non-CR/non-PD for at least 6 months or a best overall response of confirmed CR or confirmed PR. |
| ORR Per RECIST 1.1 as Determined by Investigator Assessment | 34.6 months | Defined as achieving a best overall response of confirmed CR or confirmed PR. |
| Frequency of Dose Modifications | 35.1 months | — |
| Incidence of Health Resources Utilization | 36.1 months | Cumulative incidence of health resource utilization, including length of stay, hospitalizations, and ER visits using the EQ-5D-5L questionnaire. |
| Pharmacokinetic Measure: Ctrough of Tucatinib | 3.5 months | Individual plasma tucatinib concentrations at each sampling time |
| Pharmacokinetic Measure: ONT-993 | 3.5 months | Individual plasma primary metabolite concentrations at each sampling time |
| Overall Survival (OS) at Time of Final Analysis | Up to 60.1 months | Defined as time from randomization to death from any cause |
| PFS Per RECIST 1.1 as Determined by Investigator Assessment at Time of Final Analysis | Up to 58.0 months | Defined as the time from the date of randomization to the date of documented disease progression |
| Incidence of Adverse Events (AEs) at Time of Final Analysis | Up to 60.1 months | As determined by assessment of AEs, clinical laboratory tests, and vital signs measurements. AEs were classified by system organ class (SOC) and preferred term using the Medical Dictionary for Regulatory Activities (MedDRA) Version 22.0 or higher; AE severities were classified using Version 4.03 of the (Common Terminology Criteria for Adverse Events) CTCAE criteria. |
| Frequency of Dose Modifications at Time of Final Analysis | Up to 60.1 months | — |
| Incidence of Adverse Events (AEs) at Time of Primary Analysis | 36.1 months | As determined by assessment of AEs, clinical laboratory tests, and vital signs measurements. AEs were classified by system organ class (SOC) and preferred term using the Medical Dictionary for Regulatory Activities (MedDRA) Version 22.0 or higher; AE severities were classified using Version 4.03 of the (Common Terminology Criteria for Adverse Events) CTCAE criteria. |
Countries
Australia, Austria, Belgium, Canada, Czechia, Denmark, France, Germany, Israel, Italy, Portugal, Spain, Switzerland, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Tuc+Cap+Tra Tucatinib in combination with capecitabine & trastuzumab | 410 |
| Pbo+Cap+Tra Placebo in combination with capecitabine & trastuzumab | 202 |
| Total | 612 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 258 | 151 |
| Overall Study | Hospital closure | 1 | 0 |
| Overall Study | Lost to Follow-up | 7 | 0 |
| Overall Study | Physician Decision | 1 | 1 |
| Overall Study | Study closure by Sponsor | 119 | 45 |
| Overall Study | Withdrawal by Subject | 24 | 5 |
Baseline characteristics
| Characteristic | Tuc+Cap+Tra | Total | Pbo+Cap+Tra |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 82 Participants | 116 Participants | 34 Participants |
| Age, Categorical Between 18 and 65 years | 328 Participants | 496 Participants | 168 Participants |
| Age, Continuous | 55 years | 54 years | 54 years |
| Eastern Cooperative Oncology Group (ECOG) Performance Status 0: Normal activity | 204 Participants | 298 Participants | 94 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status 1: Symptoms, but ambulatory | 206 Participants | 314 Participants | 108 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 37 Participants | 51 Participants | 14 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 362 Participants | 546 Participants | 184 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 11 Participants | 15 Participants | 4 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 18 Participants | 23 Participants | 5 Participants |
| Race (NIH/OMB) Black or African American | 41 Participants | 55 Participants | 14 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 64 Participants | 90 Participants | 26 Participants |
| Race (NIH/OMB) White | 287 Participants | 444 Participants | 157 Participants |
| Region of Enrollment Australia | 27 Participants | 39 Participants | 12 Participants |
| Region of Enrollment Austria | 6 Participants | 7 Participants | 1 Participants |
| Region of Enrollment Belgium | 4 Participants | 10 Participants | 6 Participants |
| Region of Enrollment Canada | 26 Participants | 38 Participants | 12 Participants |
| Region of Enrollment Czech Republic | 2 Participants | 3 Participants | 1 Participants |
| Region of Enrollment Denmark | 13 Participants | 20 Participants | 7 Participants |
| Region of Enrollment France | 29 Participants | 46 Participants | 17 Participants |
| Region of Enrollment Germany | 9 Participants | 17 Participants | 8 Participants |
| Region of Enrollment Israel | 13 Participants | 16 Participants | 3 Participants |
| Region of Enrollment Italy | 6 Participants | 9 Participants | 3 Participants |
| Region of Enrollment Portugal | 3 Participants | 4 Participants | 1 Participants |
| Region of Enrollment Spain | 19 Participants | 26 Participants | 7 Participants |
| Region of Enrollment Switzerland | 0 Participants | 1 Participants | 1 Participants |
| Region of Enrollment United Kingdom | 33 Participants | 45 Participants | 12 Participants |
| Region of Enrollment United States | 220 Participants | 331 Participants | 111 Participants |
| Sex: Female, Male Female | 407 Participants | 607 Participants | 200 Participants |
| Sex: Female, Male Male | 3 Participants | 5 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 262 / 410 | 152 / 202 |
| other Total, other adverse events | 399 / 404 | 188 / 197 |
| serious Total, serious adverse events | 124 / 404 | 62 / 197 |
Outcome results
Primary
Progression-free Survival (PFS) Per RECIST 1.1 as Determined by Blinded Independent Central Review (BICR)
Defined as the time from the date of randomization to the date of documented disease progression.
Time frame: 34.6 months
Population: Intent-to-treat Progression Free Survival (ITT-PFS) Population: Includes the first 480 randomized participants in the ITT analysis population (evaluated by their random treatment assignment).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Tuc+Cap+Tra | Progression-free Survival (PFS) Per RECIST 1.1 as Determined by Blinded Independent Central Review (BICR) | 7.8 months |
| Pbo+Cap+Tra | Progression-free Survival (PFS) Per RECIST 1.1 as Determined by Blinded Independent Central Review (BICR) | 5.6 months |
Secondary
CBR Per RECIST 1.1 as Determined by Investigator Assessment
Clinical benefit was defined as achieving stable disease (SD) or non-CR/non-PD for at least 6 months or a best overall response of confirmed CR or confirmed PR.
Time frame: 34.6 months
Population: ITT-OS Population: Includes all randomized participants evaluated by their randomized treatment assignment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tuc+Cap+Tra | CBR Per RECIST 1.1 as Determined by Investigator Assessment | 58.0 percentage of participants |
| Pbo+Cap+Tra | CBR Per RECIST 1.1 as Determined by Investigator Assessment | 37.6 percentage of participants |
Secondary
Clinical Benefit Rate (CBR) as Determined by BICR Per RECIST 1.1
Clinical benefit was defined as achieving stable disease (SD) or non-complete response (CR)/non-progressive disease (PD) for at least 6 months or a best overall response of confirmed CR or confirmed partial response (PR).
Time frame: 34.6 months
Population: ITT-OS Population: Includes all randomized participants evaluated by their randomized treatment assignment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tuc+Cap+Tra | Clinical Benefit Rate (CBR) as Determined by BICR Per RECIST 1.1 | 59.8 percentage of participants |
| Pbo+Cap+Tra | Clinical Benefit Rate (CBR) as Determined by BICR Per RECIST 1.1 | 38.1 percentage of participants |
Secondary
Confirmed Objective Response Rate (ORR) Per RECIST 1.1 as Determined by BICR
Defined as achieving a best overall response of confirmed complete response (CR) or confirmed partial response (PR).
Time frame: 34.6 months
Population: ITT - PFS population, subset of participants with measurable disease by BICR at baseline. The ITT-PFS Population includes the first 480 randomized participants in the ITT analysis population (evaluated by their randomized treatment assignment).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tuc+Cap+Tra | Confirmed Objective Response Rate (ORR) Per RECIST 1.1 as Determined by BICR | 40.7 percentage of participants |
| Pbo+Cap+Tra | Confirmed Objective Response Rate (ORR) Per RECIST 1.1 as Determined by BICR | 23.4 percentage of participants |
Secondary
DOR Per RECIST 1.1 as Determined by Investigator Assessment
Defined as the time from the first objective response to documented disease progression or death from any cause, whichever occurred first.
Time frame: 33.2 months
Population: ITT-OS Population: Includes all randomized participants evaluated by their randomized treatment assignment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Tuc+Cap+Tra | DOR Per RECIST 1.1 as Determined by Investigator Assessment | 7.0 months |
| Pbo+Cap+Tra | DOR Per RECIST 1.1 as Determined by Investigator Assessment | 6.9 months |
Secondary
Duration of Response (DOR) Per RECIST 1.1 as Determined by BICR
Defined as the time from the first objective response to documented disease progression or death from any cause, whichever occurred first.
Time frame: 24.6 months
Population: ITT-OS Population: Includes all randomized participants evaluated by their randomized treatment assignment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Tuc+Cap+Tra | Duration of Response (DOR) Per RECIST 1.1 as Determined by BICR | 8.3 months |
| Pbo+Cap+Tra | Duration of Response (DOR) Per RECIST 1.1 as Determined by BICR | 6.3 months |
Secondary
Frequency of Dose Modifications
Time frame: 35.1 months
Population: Safety Analysis Population: Includes all randomized participants who received at least one dose of study treatment (tucatinib/placebo, trastuzumab, or capecitabine), with participants allocated to the treatment group associated with the regimen actually received.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Tuc+Cap+Tra | Frequency of Dose Modifications | TEAEs resulting in tuc/pbo dose modification | 220 Participants |
| Tuc+Cap+Tra | Frequency of Dose Modifications | TEAEs resulting in tucatinib/placebo dose hold | 216 Participants |
| Tuc+Cap+Tra | Frequency of Dose Modifications | TEAEs resulting in tuc/pbo dose reduction | 84 Participants |
| Tuc+Cap+Tra | Frequency of Dose Modifications | TEAEs resulting capecitabine dose modification | 313 Participants |
| Tuc+Cap+Tra | Frequency of Dose Modifications | TEAEs resulting in capecitabine dose hold | 276 Participants |
| Tuc+Cap+Tra | Frequency of Dose Modifications | TEAEs resulting in capecitabine dose reduction | 243 Participants |
| Tuc+Cap+Tra | Frequency of Dose Modifications | TEAEs resulting trastuzumab dose modification | 104 Participants |
| Tuc+Cap+Tra | Frequency of Dose Modifications | TEAEs resulting in trastuzumab dose hold | 104 Participants |
| Pbo+Cap+Tra | Frequency of Dose Modifications | TEAEs resulting in trastuzumab dose hold | 38 Participants |
| Pbo+Cap+Tra | Frequency of Dose Modifications | TEAEs resulting in tuc/pbo dose modification | 81 Participants |
| Pbo+Cap+Tra | Frequency of Dose Modifications | TEAEs resulting in capecitabine dose hold | 113 Participants |
| Pbo+Cap+Tra | Frequency of Dose Modifications | TEAEs resulting in tucatinib/placebo dose hold | 80 Participants |
| Pbo+Cap+Tra | Frequency of Dose Modifications | TEAEs resulting trastuzumab dose modification | 38 Participants |
| Pbo+Cap+Tra | Frequency of Dose Modifications | TEAEs resulting in tuc/pbo dose reduction | 21 Participants |
| Pbo+Cap+Tra | Frequency of Dose Modifications | TEAEs resulting in capecitabine dose reduction | 77 Participants |
| Pbo+Cap+Tra | Frequency of Dose Modifications | TEAEs resulting capecitabine dose modification | 122 Participants |
Secondary
Frequency of Dose Modifications at Time of Final Analysis
Time frame: Up to 60.1 months
Population: Safety Analysis Population: Includes all randomized participants who received at least one dose of study treatment (tucatinib/placebo, trastuzumab, or capecitabine), with participants allocated to the treatment group associated with the regimen actually received.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Tuc+Cap+Tra | Frequency of Dose Modifications at Time of Final Analysis | TEAEs resulting in capecitabine dose hold | 288 Participants |
| Tuc+Cap+Tra | Frequency of Dose Modifications at Time of Final Analysis | TEAEs resulting in tuc/pbo dose modification | 237 Participants |
| Tuc+Cap+Tra | Frequency of Dose Modifications at Time of Final Analysis | TEAEs resulting in capecitabine dose reduction | 251 Participants |
| Tuc+Cap+Tra | Frequency of Dose Modifications at Time of Final Analysis | TEAEs resulting in tuc/pbo dose reduction | 92 Participants |
| Tuc+Cap+Tra | Frequency of Dose Modifications at Time of Final Analysis | TEAEs resulting trastuzumab dose modification | 117 Participants |
| Tuc+Cap+Tra | Frequency of Dose Modifications at Time of Final Analysis | TEAEs resulting capecitabine dose modification | 322 Participants |
| Tuc+Cap+Tra | Frequency of Dose Modifications at Time of Final Analysis | TEAEs resulting in trastuzumab dose hold | 117 Participants |
| Tuc+Cap+Tra | Frequency of Dose Modifications at Time of Final Analysis | TEAEs resulting in tucatinib/placebo dose hold | 232 Participants |
| Pbo+Cap+Tra | Frequency of Dose Modifications at Time of Final Analysis | TEAEs resulting in trastuzumab dose hold | 41 Participants |
| Pbo+Cap+Tra | Frequency of Dose Modifications at Time of Final Analysis | TEAEs resulting in tuc/pbo dose modification | 85 Participants |
| Pbo+Cap+Tra | Frequency of Dose Modifications at Time of Final Analysis | TEAEs resulting in tucatinib/placebo dose hold | 84 Participants |
| Pbo+Cap+Tra | Frequency of Dose Modifications at Time of Final Analysis | TEAEs resulting capecitabine dose modification | 125 Participants |
| Pbo+Cap+Tra | Frequency of Dose Modifications at Time of Final Analysis | TEAEs resulting in capecitabine dose hold | 117 Participants |
| Pbo+Cap+Tra | Frequency of Dose Modifications at Time of Final Analysis | TEAEs resulting in capecitabine dose reduction | 79 Participants |
| Pbo+Cap+Tra | Frequency of Dose Modifications at Time of Final Analysis | TEAEs resulting trastuzumab dose modification | 41 Participants |
| Pbo+Cap+Tra | Frequency of Dose Modifications at Time of Final Analysis | TEAEs resulting in tuc/pbo dose reduction | 21 Participants |
Secondary
Incidence of Adverse Events (AEs) at Time of Final Analysis
As determined by assessment of AEs, clinical laboratory tests, and vital signs measurements. AEs were classified by system organ class (SOC) and preferred term using the Medical Dictionary for Regulatory Activities (MedDRA) Version 22.0 or higher; AE severities were classified using Version 4.03 of the (Common Terminology Criteria for Adverse Events) CTCAE criteria.
Time frame: Up to 60.1 months
Population: Safety Analysis Population: Includes all randomized participants who received at least one dose of study treatment (tucatinib/placebo, trastuzumab, or capecitabine), with participants allocated to the treatment group associated with the regimen actually received.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Tuc+Cap+Tra | Incidence of Adverse Events (AEs) at Time of Final Analysis | Any treatment-emergent AE (TEAE) | 401 Participants |
| Tuc+Cap+Tra | Incidence of Adverse Events (AEs) at Time of Final Analysis | Any Grade 3 or higher TEAE | 248 Participants |
| Tuc+Cap+Tra | Incidence of Adverse Events (AEs) at Time of Final Analysis | Any treatment-emergent serious AE | 123 Participants |
| Tuc+Cap+Tra | Incidence of Adverse Events (AEs) at Time of Final Analysis | TEAE leading to death | 8 Participants |
| Pbo+Cap+Tra | Incidence of Adverse Events (AEs) at Time of Final Analysis | TEAE leading to death | 6 Participants |
| Pbo+Cap+Tra | Incidence of Adverse Events (AEs) at Time of Final Analysis | Any treatment-emergent AE (TEAE) | 191 Participants |
| Pbo+Cap+Tra | Incidence of Adverse Events (AEs) at Time of Final Analysis | Any treatment-emergent serious AE | 58 Participants |
| Pbo+Cap+Tra | Incidence of Adverse Events (AEs) at Time of Final Analysis | Any Grade 3 or higher TEAE | 101 Participants |
Secondary
Incidence of Adverse Events (AEs) at Time of Primary Analysis
As determined by assessment of AEs, clinical laboratory tests, and vital signs measurements. AEs were classified by system organ class (SOC) and preferred term using the Medical Dictionary for Regulatory Activities (MedDRA) Version 22.0 or higher; AE severities were classified using Version 4.03 of the (Common Terminology Criteria for Adverse Events) CTCAE criteria.
Time frame: 36.1 months
Population: Safety Analysis Population: Includes all randomized participants who received at least one dose of study treatment (tucatinib/placebo, trastuzumab, or capecitabine), with participants allocated to the treatment group associated with the regimen actually received.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Tuc+Cap+Tra | Incidence of Adverse Events (AEs) at Time of Primary Analysis | Any treatment-emergent AE (TEAE) | 401 Participants |
| Tuc+Cap+Tra | Incidence of Adverse Events (AEs) at Time of Primary Analysis | Any Grade 3 or higher TEAE | 223 Participants |
| Tuc+Cap+Tra | Incidence of Adverse Events (AEs) at Time of Primary Analysis | Any treatment-emergent serious AE | 104 Participants |
| Tuc+Cap+Tra | Incidence of Adverse Events (AEs) at Time of Primary Analysis | TEAE leading to death | 8 Participants |
| Pbo+Cap+Tra | Incidence of Adverse Events (AEs) at Time of Primary Analysis | TEAE leading to death | 6 Participants |
| Pbo+Cap+Tra | Incidence of Adverse Events (AEs) at Time of Primary Analysis | Any treatment-emergent AE (TEAE) | 191 Participants |
| Pbo+Cap+Tra | Incidence of Adverse Events (AEs) at Time of Primary Analysis | Any treatment-emergent serious AE | 53 Participants |
| Pbo+Cap+Tra | Incidence of Adverse Events (AEs) at Time of Primary Analysis | Any Grade 3 or higher TEAE | 96 Participants |
Secondary
Incidence of Health Resources Utilization
Cumulative incidence of health resource utilization, including length of stay, hospitalizations, and ER visits using the EQ-5D-5L questionnaire.
Time frame: 36.1 months
Population: Safety Analysis Population: Includes all randomized participants who received at least one dose of study treatment (tucatinib/placebo, trastuzumab, or capecitabine), with participants allocated to the treatment group associated with the regimen actually received.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Tuc+Cap+Tra | Incidence of Health Resources Utilization | Hospitalization for AE | 124 hospitalizations |
| Tuc+Cap+Tra | Incidence of Health Resources Utilization | Ambulatory Surgery | 3 hospitalizations |
| Tuc+Cap+Tra | Incidence of Health Resources Utilization | Planned hospitalization (other than AE) | 10 hospitalizations |
| Tuc+Cap+Tra | Incidence of Health Resources Utilization | Other | 6 hospitalizations |
| Tuc+Cap+Tra | Incidence of Health Resources Utilization | Total number of hospitalizations | 143 hospitalizations |
| Pbo+Cap+Tra | Incidence of Health Resources Utilization | Other | 5 hospitalizations |
| Pbo+Cap+Tra | Incidence of Health Resources Utilization | Total number of hospitalizations | 75 hospitalizations |
| Pbo+Cap+Tra | Incidence of Health Resources Utilization | Hospitalization for AE | 64 hospitalizations |
| Pbo+Cap+Tra | Incidence of Health Resources Utilization | Planned hospitalization (other than AE) | 6 hospitalizations |
| Pbo+Cap+Tra | Incidence of Health Resources Utilization | Ambulatory Surgery | 0 hospitalizations |
Secondary
ORR Per RECIST 1.1 as Determined by Investigator Assessment
Defined as achieving a best overall response of confirmed CR or confirmed PR.
Time frame: 34.6 months
Population: ITT - PFS population, subset of participants with measurable disease by investigator at baseline. The ITT-PFS Population includes the first 480 randomized participants in the ITT analysis population (evaluated by their randomized treatment assignment).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tuc+Cap+Tra | ORR Per RECIST 1.1 as Determined by Investigator Assessment | 41.4 percentage of participants |
| Pbo+Cap+Tra | ORR Per RECIST 1.1 as Determined by Investigator Assessment | 23.0 percentage of participants |
Secondary
Overall Survival (OS) at Time of Final Analysis
Defined as time from randomization to death from any cause
Time frame: Up to 60.1 months
Population: ITT-OS Population: Includes all randomized participants evaluated by their randomized treatment assignment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Tuc+Cap+Tra | Overall Survival (OS) at Time of Final Analysis | 24.7 months |
| Pbo+Cap+Tra | Overall Survival (OS) at Time of Final Analysis | 19.2 months |
Secondary
Overall Survival (OS) at Time of Primary Analysis
Defined as time from randomization to death from any cause
Time frame: 35.9 months
Population: ITT-OS Population: Includes all randomized participants evaluated by their randomized treatment assignment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Tuc+Cap+Tra | Overall Survival (OS) at Time of Primary Analysis | 21.9 months |
| Pbo+Cap+Tra | Overall Survival (OS) at Time of Primary Analysis | 17.4 months |
Secondary
PFS in Patients With Brain Metastases at Baseline Using RECIST 1.1 as Determined by BICR
Defined as the time from the date of randomization to the date of documented disease progression.
Time frame: 34.6 months
Population: ITT-PFSBrainMets population: included all randomized participants with brain metastases (evaluated by their random treatment assignment).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Tuc+Cap+Tra | PFS in Patients With Brain Metastases at Baseline Using RECIST 1.1 as Determined by BICR | 7.6 months |
| Pbo+Cap+Tra | PFS in Patients With Brain Metastases at Baseline Using RECIST 1.1 as Determined by BICR | 5.4 months |
Secondary
PFS Per RECIST 1.1 as Determined by Investigator Assessment at Time of Final Analysis
Defined as the time from the date of randomization to the date of documented disease progression
Time frame: Up to 58.0 months
Population: ITT-OS Population: Includes all randomized participants evaluated by their randomized treatment assignment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Tuc+Cap+Tra | PFS Per RECIST 1.1 as Determined by Investigator Assessment at Time of Final Analysis | 7.6 months |
| Pbo+Cap+Tra | PFS Per RECIST 1.1 as Determined by Investigator Assessment at Time of Final Analysis | 4.9 months |
Secondary
PFS Per RECIST 1.1 as Determined by Investigator Assessment at Time of Primary Analysis
Defined as the time from the date of randomization to the date of documented disease progression
Time frame: 34.6 months
Population: ITT-PFS Population: Includes the first 480 randomized participants in the ITT analysis population (evaluated by their randomized treatment assignment).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Tuc+Cap+Tra | PFS Per RECIST 1.1 as Determined by Investigator Assessment at Time of Primary Analysis | 7.5 months |
| Pbo+Cap+Tra | PFS Per RECIST 1.1 as Determined by Investigator Assessment at Time of Primary Analysis | 4.3 months |
Secondary
Pharmacokinetic Measure: Ctrough of Tucatinib
Individual plasma tucatinib concentrations at each sampling time
Time frame: 3.5 months
Population: Pharmacokinetics (PK) Analysis Set: Includes all randomized participants who received at least one dose of tucatinib and who had at least one evaluable PK assessment. Participants were evaluated by the treatment actually received.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tuc+Cap+Tra | Pharmacokinetic Measure: Ctrough of Tucatinib | Cycle 2, Day 1 (Pre-dose) | 246.1 ng/mL | Standard Deviation 260.9 |
| Tuc+Cap+Tra | Pharmacokinetic Measure: Ctrough of Tucatinib | Cycle 3, Day 1 (Pre-dose) | 227.6 ng/mL | Standard Deviation 210.8 |
| Tuc+Cap+Tra | Pharmacokinetic Measure: Ctrough of Tucatinib | Cycle 3, Day 1 (Post-dose) | 507.1 ng/mL | Standard Deviation 357.1 |
| Tuc+Cap+Tra | Pharmacokinetic Measure: Ctrough of Tucatinib | Cycle 4, Day 1 (Pre-dose) | 253.2 ng/mL | Standard Deviation 236.1 |
| Tuc+Cap+Tra | Pharmacokinetic Measure: Ctrough of Tucatinib | Cycle 5, Day 1 (Pre-dose) | 257.6 ng/mL | Standard Deviation 286.9 |
| Tuc+Cap+Tra | Pharmacokinetic Measure: Ctrough of Tucatinib | Cycle 6, Day 1 (Pre-dose) | 247.8 ng/mL | Standard Deviation 225.1 |
Secondary
Pharmacokinetic Measure: ONT-993
Individual plasma primary metabolite concentrations at each sampling time
Time frame: 3.5 months
Population: PK Analysis Set: Includes all randomized participants who received at least one dose of tucatinib and who had at least one evaluable PK assessment. Participants were evaluated by the treatment actually received.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tuc+Cap+Tra | Pharmacokinetic Measure: ONT-993 | Cycle 2, Day 1 (Pre-dose) | 25.5 ng/mL | Standard Deviation 24.4 |
| Tuc+Cap+Tra | Pharmacokinetic Measure: ONT-993 | Cycle 3, Day 1 (Pre-dose) | 22.6 ng/mL | Standard Deviation 20.6 |
| Tuc+Cap+Tra | Pharmacokinetic Measure: ONT-993 | Cycle 3, Day 1 (Post-dose) | 47.7 ng/mL | Standard Deviation 47.2 |
| Tuc+Cap+Tra | Pharmacokinetic Measure: ONT-993 | Cycle 4, Day 1 (Pre-dose) | 25.2 ng/mL | Standard Deviation 24.3 |
| Tuc+Cap+Tra | Pharmacokinetic Measure: ONT-993 | Cycle 5, Day 1 (Pre-dose) | 24.5 ng/mL | Standard Deviation 30.6 |
| Tuc+Cap+Tra | Pharmacokinetic Measure: ONT-993 | Cycle 6, Day 1 (Pre-dose) | 20.9 ng/mL | Standard Deviation 18 |