HER2-positive Breast Cancer
Conditions
Keywords
Seattle Genetics, Seagen
Brief summary
This study is being done to see if tucatinib with ado-trastuzumab emtansine (T-DM1) works better than T-DM1 alone 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. Patients in this study will be randomly assigned to get either tucatinib or placebo (a pill with no medicine). This is a blinded study, so neither patients nor their doctors will know whether a patient gets tucatinib or placebo. All patients in the study will get T-DM1, a drug that is often used to treat this cancer. Each treatment cycle lasts 21 days. Patients will swallow tucatinib pills or placebo pills two times every day. Patients will get T-DM1 injections from the study site staff on the first day of every cycle.
Detailed description
This study is designed to evaluate the efficacy and safety of tucatinib in combination with T-DM1 in participants with unresectable locally-advanced or metastatic HER2+ breast cancer who have had prior treatment with a taxane and trastuzumab in any setting. Prior pertuzumab treatment is permitted, but not required. Participants will be randomized in a 1:1 manner to receive 21-day cycles of either tucatinib or placebo in combination with T-DM1. While on study treatment, participants will be assessed for progression every 6 weeks for the first 24 weeks, and every 9 weeks thereafter, irrespective of dose holds or interruptions. Study treatment will continue until unacceptable toxicity, disease progression, withdrawal of consent, or study closure. After completion of study treatment and after occurrence of disease progression, participants in both arms of the study will continue to be followed for survival until study closure or withdrawal of consent.
Interventions
DRUGtucatinib
300mg given twice per day by mouth (orally)
DRUGplacebo
Given twice per day orally
DRUGT-DM1
3.6 mg/kg given into the vein (IV; intravenously) every 21 days
Sponsors
Seagen, a wholly owned subsidiary of Pfizer
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Inclusion Criteria: * Histologically confirmed HER2+ breast carcinoma as determined by a sponsor-designated central laboratory * History of prior treatment with a taxane and trastuzumab in any setting, separately or in combination * Have progression of unresectable locally advanced/metastatic breast cancer after last systemic therapy, or be intolerant of last systemic therapy * Measurable or non-measurable disease assessable by RECIST v1.1 * ECOG performance status score of 0 or 1 * CNS Inclusion - Based on screening contrast brain magnetic resonance imaging (MRI), participants must have at least one of the following: (a) No evidence of brain metastases (b) Untreated brain metastases not needing immediate local therapy (c) Previously treated brain metastases 1. Brain metastases previously treated with local therapy may either be stable since treatment or may have progressed since prior local CNS therapy, provided that there is no clinical indication for immediate re-treatment with local therapy 2. Participants treated with CNS local therapy for newly identified lesions or previously treated and progressing lesions may be eligible to enroll if all of the following criteria are met: (i) Time since SRS is at least 7 days prior to first dose of study treatment, time since WBRT is at least 14 days prior to first dose, or time since surgical resection is at least 28 days. (ii) Other sites of evaluable disease are present 3. Relevant records of any CNS treatment must be available to allow for classification of target and non-target lesions *
Exclusion criteria
* Prior treatment with tucatinib, afatinib, trastuzumab deruxtecan (DS-8201a), or any other investigational anti-HER2, anti-EGFR, or HER2 TKI agent. Prior treatment with lapatinib or neratinib within 12 months of starting study treatment (except in cases where they were given for ≤21 days and was discontinued for reasons other than disease progression or severe toxicity). Prior treatment with pyrotinib for recurrent of mBC (except in cases where pyrotinib was given for ≤21 days and was discontinued for reasons other than disease progression or severe toxicity). * CNS Exclusion - Based on screening contrast brain magnetic resonance imaging (MRI), participants must not have any of the following: 1. Any untreated brain lesions \>2 cm in size 2. Ongoing use of 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 4. Known or concurrent leptomeningeal disease as documented by the investigator 5. Poorly controlled generalized or complex partial seizures
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival (PFS) as Per Response Evaluation Criteria in Solid Tumors (RECIST) Version (v)1.1 Based on Investigator Assessment | From the date of randomization to the date of PD or death from any cause or censoring date, whichever occurred first (maximum up to 43 months) | PFS as per investigator was defined as the time from the date of randomization to the investigator assessment of disease progression (PD) as per RECIST v1.1 or death from any cause, whichever occurred first. PD: at least a 20 percent (%) increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 millimiter (mm). Participants without documentation of PD, or death at the time of analysis were censored at the date of the last tumor assessment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | Up to approximately 5 years | OS was defined as the time from randomization to death due to any cause. For a participant who was not known to have died by the end of study follow-up, observation of OS was censored on the date the participant was last known to be alive (i.e., the date of last contact). |
| Progression-Free Survival as Per RECIST v1.1 in Participants With Brain Metastases at Baseline Based on Investigator Assessment | From the date of randomization to the date of PD or death from any cause or censoring date, whichever occurred first (maximum up to 45 months) | PFS as per investigator was defined as the time from the date of randomization to the investigator assessment of PD as per RECIST v1.1 or death from any cause, whichever occurred first. PD: at least a 20 % increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Participants without documentation of PD, or death at the time of analysis were censored at the date of the last tumor assessment. PFS was analyzed in participants with presence or history of brain metastases. |
| Objective Response Rate (ORR) as Per RECIST v1.1 Based on Investigator Assessment | From the date of first CR or PR until the date of the first documentation of PD or death, whichever occurred first (maximum up to 43 months) | ORR was defined as the percentage of participants with confirmed complete response (CR) or partial response (PR) according to RECIST v1.1. CR: disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to less than (\<)10 mm. PR: a greater than equal (\>=) 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. For a response to be considered as confirmed, the subsequent response needs to be at least 4 weeks after the initial response. ORR by investigator assessment is based on investigator response assessments. Two-sided 95% exact confidence interval, computed using the Clopper-Pearson method. |
| Overall Survival in Participants With Brain Metastases at Baseline | Up to approximately 5 years | OS was defined as the time from randomization to death due to any cause. For a participant who was not known to have died by the end of study follow-up, observation of OS was censored on the date the participant was last known to be alive (i.e., the date of last contact). OS was analyzed in participants with presence or history of brain metastases. |
| Progression-Free Survival as Per RECIST v1.1 Determined by Blinded Independent Committee Review (BICR) | From the date of randomization to the date of PD or death from any cause or censoring date, whichever occurred first (maximum up to 43 months) | PFS as per BICR was defined as the time from the date of randomization to the centrally-reviewed documented PD as per RECIST v1.1 or death from any cause, whichever occurred first. PD: at least a 20 % increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Participants without documented progression of PD or death at the time of analysis were censored at the date of the last tumor assessment. |
| Progression-Free Survival in Participants With Brain Metastases at Baseline as Per RECIST v1.1 Determined by BICR | From the date of randomization to the date of PD or death from any cause or censoring date, whichever occurred first (maximum up to 43 months) | PFS as per BICR was defined as the time from the date of randomization to the centrally-reviewed documented PD as per RECIST v1.1 or death from any cause, whichever occurred first. PD: at least a 20 % increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. PFS was analyzed in participants with presence or history of brain metastases. |
| Objective Response Rate as Per RECIST v1.1 Determined by BICR | From the date of randomization to the date of PD or death from any cause or censoring date, whichever occurred first (maximum up to 43 months) | ORR was defined as the percentage of participants with confirmed CR or PR according to RECIST v1.1. CR: Disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to \<10 mm. PR: A \>= 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. ORR per BICR is based on BICR response assessments. |
| Duration of Response (DOR) as Per RECIST v1.1 Based on Investigator Assessment | Up to approximately 5 years | DOR was defined as the time from first documentation of objective response (CR or PR that is subsequently confirmed) to the first documentation of PD as per RECIST v1.1 PD: at least a 20 % increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Participants without documentation of PD, or death at the time of analysis were censored at the date of the last tumor assessment. CR: disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to \<10 mm. PR: A\>=30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. DOR per investigator was based on investigator response assessments. |
| Duration of Response as Per RECIST v1.1 by BICR | Up to approximately 5 years | DOR was defined as the time from first documentation of objective response (CR or PR that is subsequently confirmed) to the first documentation of PD as per RECIST v1.1 PD: at least a 20 % increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Participants without documentation of PD, or death at the time of analysis were censored at the date of the last tumor assessment. CR: disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to \<10 mm. PR: A\>=30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. DOR per BICR was based on BICR response assessments. |
| Clinical Benefit Rate (CBR) Per RECIST v1.1 Based on Investigator Assessment | Up to approximately 5 years | CBR was defined as the percentage of participants with stable disease (SD) or non-CR or non-PD \>= 6 months or best response of CR or PR according to RECIST v1.1. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. CR: disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to \<10 mm. PR: A \>= 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. CBR was based on investigator assessment. |
| Clinical Benefit Rate as Per RECIST v1.1 by BICR | Up to approximately 5 years | CBR was defined as the percentage of participants with SD or non-CR or non-PD \>= 6 months or best response of CR or PR according to RECIST v1.1. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. CR: disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to \<10 mm. PR: A \>= 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. CBR per BICR is based on BICR response assessments. |
| Number of Participants With Treatment Emergent Adverse Events (AEs) | From start of treatment up to 30 days after the last study treatment (approximately 43 months) | An AE was any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. TEAE was defined as AE that is newly occurred or worsened after the start of study treatment. |
Countries
Australia, Austria, Belgium, Canada, China, Denmark, France, Germany, Israel, Italy, Japan, Netherlands, Singapore, South Korea, Spain, Sweden, Switzerland, Taiwan, United Kingdom, United States
Contacts
STUDY_DIRECTORPfizer CT.gov Call Center
Pfizer
Participant flow
Recruitment details
Participants diagnosed with locally advanced (LA) or metastatic human epidermal growth factor receptor 2 positive (HER2+) breast cancer who received prior treatment with a taxane and trastuzumab in any setting, were evaluated for efficacy and safety of tucatinib in combination with ado-trastuzumab emtansine (T-DM1) in this study.
Pre-assignment details
A total of 618 participants were screened of which 152 failed screening and 466 participants were enrolled in the study.
Participants by arm
| Arm | Count |
|---|---|
| Tucatinib+ Ado-trastuzumab Emtansine Participants with HER2+ LA/mBC were treated with tucatinib 300 mg orally BID and T-DM1 3.6 mg/kg IV every 21 days in each 21-day cycle. Participants received treatment until unacceptable toxicity, disease progression, withdrawal of consent, or study closure. | 228 |
| Placebo+ Ado-trastuzumab Emtansine Participants with HER2+ LA/mBC were treated with placebo orally BID, and T-DM1 3.6 mg/kg IV every 21 days in each 21-day cycle. Participants received treatment until unacceptable toxicity, disease progression, withdrawal of consent, or study closure. | 235 |
| Total | 463 |
Baseline characteristics
| Characteristic | Placebo+ Ado-trastuzumab Emtansine | Total | Tucatinib+ Ado-trastuzumab Emtansine |
|---|---|---|---|
| Age, Continuous | 52.9 Years STANDARD_DEVIATION 10.9 | 53.4 Years STANDARD_DEVIATION 11.1 | 53.8 Years STANDARD_DEVIATION 11.4 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 13 Participants | 21 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 163 Participants | 334 Participants | 171 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 59 Participants | 108 Participants | 49 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 65 Participants | 131 Participants | 66 Participants |
| Race (NIH/OMB) Black or African American | 8 Participants | 19 Participants | 11 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 6 Participants | 5 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 3 Participants | 3 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 58 Participants | 100 Participants | 42 Participants |
| Race (NIH/OMB) White | 102 Participants | 203 Participants | 101 Participants |
| Sex: Female, Male Female | 235 Participants | 461 Participants | 226 Participants |
| Sex: Female, Male Male | 0 Participants | 2 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 63 / 233 | 71 / 231 |
| other Total, other adverse events | 227 / 233 | 230 / 231 |
| serious Total, serious adverse events | 52 / 233 | 70 / 231 |
Outcome results
Primary
Progression-Free Survival (PFS) as Per Response Evaluation Criteria in Solid Tumors (RECIST) Version (v)1.1 Based on Investigator Assessment
PFS as per investigator was defined as the time from the date of randomization to the investigator assessment of disease progression (PD) as per RECIST v1.1 or death from any cause, whichever occurred first. PD: at least a 20 percent (%) increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 millimiter (mm). Participants without documentation of PD, or death at the time of analysis were censored at the date of the last tumor assessment.
Time frame: From the date of randomization to the date of PD or death from any cause or censoring date, whichever occurred first (maximum up to 43 months)
Population: The ITT analysis set included all participants who were randomized on or before the date of LPI, in the global study.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Tucatinib+ Ado-trastuzumab Emtansine | Progression-Free Survival (PFS) as Per Response Evaluation Criteria in Solid Tumors (RECIST) Version (v)1.1 Based on Investigator Assessment | 9.5 Months |
| Placebo+ Ado-trastuzumab Emtansine | Progression-Free Survival (PFS) as Per Response Evaluation Criteria in Solid Tumors (RECIST) Version (v)1.1 Based on Investigator Assessment | 7.4 Months |
p-value: 0.016395% CI: [0.607, 0.95]Log Rank
Secondary
Clinical Benefit Rate as Per RECIST v1.1 by BICR
CBR was defined as the percentage of participants with SD or non-CR or non-PD \>= 6 months or best response of CR or PR according to RECIST v1.1. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. CR: disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to \<10 mm. PR: A \>= 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. CBR per BICR is based on BICR response assessments.
Time frame: Up to approximately 5 years
Secondary
Clinical Benefit Rate (CBR) Per RECIST v1.1 Based on Investigator Assessment
CBR was defined as the percentage of participants with stable disease (SD) or non-CR or non-PD \>= 6 months or best response of CR or PR according to RECIST v1.1. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. CR: disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to \<10 mm. PR: A \>= 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. CBR was based on investigator assessment.
Time frame: Up to approximately 5 years
Secondary
Duration of Response as Per RECIST v1.1 by BICR
DOR was defined as the time from first documentation of objective response (CR or PR that is subsequently confirmed) to the first documentation of PD as per RECIST v1.1 PD: at least a 20 % increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Participants without documentation of PD, or death at the time of analysis were censored at the date of the last tumor assessment. CR: disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to \<10 mm. PR: A\>=30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. DOR per BICR was based on BICR response assessments.
Time frame: Up to approximately 5 years
Secondary
Duration of Response (DOR) as Per RECIST v1.1 Based on Investigator Assessment
DOR was defined as the time from first documentation of objective response (CR or PR that is subsequently confirmed) to the first documentation of PD as per RECIST v1.1 PD: at least a 20 % increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Participants without documentation of PD, or death at the time of analysis were censored at the date of the last tumor assessment. CR: disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to \<10 mm. PR: A\>=30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. DOR per investigator was based on investigator response assessments.
Time frame: Up to approximately 5 years
Secondary
Number of Participants With Treatment Emergent Adverse Events (AEs)
An AE was any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. TEAE was defined as AE that is newly occurred or worsened after the start of study treatment.
Time frame: From start of treatment up to 30 days after the last study treatment (approximately 43 months)
Population: The safety analysis set included all participants who were randomized or enrolled on or before the date of LPI in the global study and received at least 1 dose of study treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Tucatinib+ Ado-trastuzumab Emtansine | Number of Participants With Treatment Emergent Adverse Events (AEs) | 230 Participants |
| Placebo+ Ado-trastuzumab Emtansine | Number of Participants With Treatment Emergent Adverse Events (AEs) | 233 Participants |
Secondary
Objective Response Rate as Per RECIST v1.1 Determined by BICR
ORR was defined as the percentage of participants with confirmed CR or PR according to RECIST v1.1. CR: Disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to \<10 mm. PR: A \>= 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. ORR per BICR is based on BICR response assessments.
Time frame: From the date of randomization to the date of PD or death from any cause or censoring date, whichever occurred first (maximum up to 43 months)
Population: The ITT analysis set included all participants who were randomized on or before the date of LPI, in the global study. Here Overall Number of Participants Analyzed signifies the number of participants evaluable for this outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tucatinib+ Ado-trastuzumab Emtansine | Objective Response Rate as Per RECIST v1.1 Determined by BICR | 47.3 Percentage of participants |
| Placebo+ Ado-trastuzumab Emtansine | Objective Response Rate as Per RECIST v1.1 Determined by BICR | 41.1 Percentage of participants |
Secondary
Objective Response Rate (ORR) as Per RECIST v1.1 Based on Investigator Assessment
ORR was defined as the percentage of participants with confirmed complete response (CR) or partial response (PR) according to RECIST v1.1. CR: disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to less than (\<)10 mm. PR: a greater than equal (\>=) 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. For a response to be considered as confirmed, the subsequent response needs to be at least 4 weeks after the initial response. ORR by investigator assessment is based on investigator response assessments. Two-sided 95% exact confidence interval, computed using the Clopper-Pearson method.
Time frame: From the date of first CR or PR until the date of the first documentation of PD or death, whichever occurred first (maximum up to 43 months)
Population: The ITT analysis set included all participants who were randomized on or before the date of LPI, in the global study. Here Overall Number of Participants Analyzed signifies the number of participants evaluable for this outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tucatinib+ Ado-trastuzumab Emtansine | Objective Response Rate (ORR) as Per RECIST v1.1 Based on Investigator Assessment | 42.0 Percentage of participants |
| Placebo+ Ado-trastuzumab Emtansine | Objective Response Rate (ORR) as Per RECIST v1.1 Based on Investigator Assessment | 36.1 Percentage of participants |
p-value: 0.2055Cochran-Mantel-Haenszel
Secondary
Overall Survival in Participants With Brain Metastases at Baseline
OS was defined as the time from randomization to death due to any cause. For a participant who was not known to have died by the end of study follow-up, observation of OS was censored on the date the participant was last known to be alive (i.e., the date of last contact). OS was analyzed in participants with presence or history of brain metastases.
Time frame: Up to approximately 5 years
Secondary
Overall Survival (OS)
OS was defined as the time from randomization to death due to any cause. For a participant who was not known to have died by the end of study follow-up, observation of OS was censored on the date the participant was last known to be alive (i.e., the date of last contact).
Time frame: Up to approximately 5 years
Secondary
Progression-Free Survival as Per RECIST v1.1 Determined by Blinded Independent Committee Review (BICR)
PFS as per BICR was defined as the time from the date of randomization to the centrally-reviewed documented PD as per RECIST v1.1 or death from any cause, whichever occurred first. PD: at least a 20 % increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Participants without documented progression of PD or death at the time of analysis were censored at the date of the last tumor assessment.
Time frame: From the date of randomization to the date of PD or death from any cause or censoring date, whichever occurred first (maximum up to 43 months)
Population: The ITT analysis set included all participants who were randomized on or before the date of LPI, in the global study.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Tucatinib+ Ado-trastuzumab Emtansine | Progression-Free Survival as Per RECIST v1.1 Determined by Blinded Independent Committee Review (BICR) | 9.6 Months |
| Placebo+ Ado-trastuzumab Emtansine | Progression-Free Survival as Per RECIST v1.1 Determined by Blinded Independent Committee Review (BICR) | 7.4 Months |
Secondary
Progression-Free Survival as Per RECIST v1.1 in Participants With Brain Metastases at Baseline Based on Investigator Assessment
PFS as per investigator was defined as the time from the date of randomization to the investigator assessment of PD as per RECIST v1.1 or death from any cause, whichever occurred first. PD: at least a 20 % increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Participants without documentation of PD, or death at the time of analysis were censored at the date of the last tumor assessment. PFS was analyzed in participants with presence or history of brain metastases.
Time frame: From the date of randomization to the date of PD or death from any cause or censoring date, whichever occurred first (maximum up to 45 months)
Population: The ITT analysis set included all participants who were randomized on or before the date of LPI, in the global study. Here Overall Number of Participants Analyzed signifies the number of participants evaluable for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Tucatinib+ Ado-trastuzumab Emtansine | Progression-Free Survival as Per RECIST v1.1 in Participants With Brain Metastases at Baseline Based on Investigator Assessment | 7.8 Months |
| Placebo+ Ado-trastuzumab Emtansine | Progression-Free Survival as Per RECIST v1.1 in Participants With Brain Metastases at Baseline Based on Investigator Assessment | 5.7 Months |
p-value: 0.007895% CI: [0.459, 0.891]Log Rank
Secondary
Progression-Free Survival in Participants With Brain Metastases at Baseline as Per RECIST v1.1 Determined by BICR
PFS as per BICR was defined as the time from the date of randomization to the centrally-reviewed documented PD as per RECIST v1.1 or death from any cause, whichever occurred first. PD: at least a 20 % increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. PFS was analyzed in participants with presence or history of brain metastases.
Time frame: From the date of randomization to the date of PD or death from any cause or censoring date, whichever occurred first (maximum up to 43 months)
Population: The ITT analysis set included all participants who were randomized on or before the date of LPI, in the global study. Here Overall Number of Participants Analyzed signifies the number of participants evaluable for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Tucatinib+ Ado-trastuzumab Emtansine | Progression-Free Survival in Participants With Brain Metastases at Baseline as Per RECIST v1.1 Determined by BICR | 7.8 Months |
| Placebo+ Ado-trastuzumab Emtansine | Progression-Free Survival in Participants With Brain Metastases at Baseline as Per RECIST v1.1 Determined by BICR | 5.5 Months |