Biliary Tract Neoplasms, Carcinoma, Non-Small-Cell Lung, HER2 Mutations Breast Neoplasms, Urologic Neoplasms, Uterine Cervical Neoplasms, Uterine Neoplasms
Conditions
Keywords
Cervical cancer, Uterine cancer, Biliary tract cancer, Urothelial cancer, Non-squamous non-small cell lung cancer, Non-squamous NSCLC, Breast cancer, Colorectal cancer, Ampullary cancer, Solid tumors, Solid tumors harboring somatic HER2 mutations, Seattle Genetics
Brief summary
This trial studies how well tucatinib works for solid tumors that make either more HER2 or a different type of HER2 than usual (HER2 alterations) The solid tumors studied in this trial have either spread to other parts of the body (metastatic) or cannot be removed completely with surgery (unresectable). All participants will get both tucatinib and trastuzumab. People with hormone-receptor positive breast cancer will also get a drug called fulvestrant. The trial will also look at what side effects happen. A side effect is anything a drug does besides treating cancer.
Detailed description
There are multiple cohorts in this trial: * 5 tumor specific cohorts with HER2 overexpression/amplification (cervical cancer, uterine cancer, biliary tract cancer, urothelial cancer, and non-squamous non-small cell lung cancer \[NSCLC\]) * 2 tumor specific cohorts with HER2 mutations (non-squamous NSCLC and breast cancer) * 2 cohorts which will enroll all other HER2 amplified/overexpressed solid tumor types (except breast cancer, gastric or gastroesophageal junction adenocarcinoma \[GEC\], and colorectal cancer \[CRC\]) or HER2-mutated solid tumor types.
Interventions
DRUGtucatinib
300 mg orally twice daily
DRUGtrastuzumab
Given into the vein (intravenously; IV). 8mg/kg IV on Cycle 1 Day 1, and 6mg/kg every 21 days starting on Cycle 2 Day 1
DRUGfulvestrant
Given into the muscle (intramuscular; IM) once every 4 weeks starting from Cycle 1 Day 1, plus one dose on Cycle 1 Day 15. Only administered to participants with hormone-receptor positive breast cancer.
Sponsors
Seagen, a wholly owned subsidiary of Pfizer
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically or cytologically confirmed diagnosis of locally-advanced unresectable or metastatic solid tumor, including primary brain tumors * Participants with non-squamous NSCLC must have progressed during or after standard treatment or for which no standard treatment is available * Participants with other disease types must have progressed during or after ≥1 prior line of systemic therapy for locally-advanced unresectable or metastatic disease * Disease progression during or after, or intolerance of, the most recent line of systemic therapy * Disease demonstrating HER2 alterations (overexpression/amplification or HER2 activating mutations), as determined by local or central testing processed in a Clinical Laboratory Improvement Amendments (CLIA)- or International Organization for Standardization (ISO) accredited laboratory, according to one of the following: * HER2 overexpression/amplification from fresh or archival tumor tissue or blood * Known activating HER2 mutations detected in fresh or archival tumor tissue or blood * Have measurable disease per RECIST v1.1 criteria according to investigator assessment * Have Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
Exclusion criteria
* Participants with breast cancer, gastric or gastroesophageal junction adenocarcinoma, or CRC whose disease shows HER2 amplification/overexpression. * Previous treatment with HER2-directed therapy; participants with uterine serous carcinoma or HER2-mutated gastric or gastroesophageal junction adenocarcinoma without HER2-overexpression/amplification may have received prior trastuzumab * Known hypersensitivity to any component of the drug formulation of tucatinib or trastuzumab (drug substance, excipients, murine proteins), or any component of the drug formulation of fulvestrant in participants with HR+ HER2-mutated breast cancer * History of exposure to a 360 mg/m² doxorubicin-equivalent or \>720 mg/m\^2 epirubicin-equivalent cumulative dose of anthracyclines * Treatment with any systemic anti-cancer therapy, radiation therapy, major surgery, or experimental agent within ≤3 weeks of first dose of study treatment or are currently participating in another interventional clinical trial. There are additional inclusion and
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Confirmed Objective Response Rate (cORR) as Assessed by Investigator | From the first dose of study treatment until the first documented CR or PR on or before the first documented PD or new anti-cancer therapies or death, whichever occurred first (up to 28.3 months) | Confirmed ORR was defined as the percentage of participants with best overall response of complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria version (v)1.1 as assessed by investigator and was considered as confirmed when subsequent response was at least 4 weeks after initial response. As per RECIST v1.1, CR: disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to less than (\<)10 millimeter (mm). PR: at least a greater than or equal to (\>=)30 % decrease in the sum of diameters (SOD) of target lesions (longest for non-nodal target lesions and the short axes for nodal target lesions), taking as reference the baseline sum diameters. Disease progression (PD): at least \>=20% relative increase in SOD of target lesion taking as reference the smallest sum on study (including baseline sum if that is the smallest on study). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Confirmed Disease Control Rate (DCR) as Assessed by Investigator | From the first dose study treatment until PD or death, whichever occurred first (approximately 52.7 months) | DCR was defined as the percentage of participants with confirmed CR, PR, or stable disease (SD or non-CR/non-PD) according to RECIST v1.1 as assessed by investigator. As per RECIST v1.1, CR: disappearance of all target (T) lesions and non-target (NT) lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR: at least \>=30 % decrease in the SOD of target lesions (longest for non-nodal target lesions and the short axes for nodal target lesions), taking as reference the baseline sum diameters. PD: at least \>=20% relative increase in SOD of target lesions taking as reference the smallest sum on study (including baseline sum if that is the smallest on study). SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest SOD while on study and cannot have met criteria for PD previously. |
| Duration of Response (DOR) as Assessed by Investigator | From the first documented CR or PR until the first documentation of PD or death or censoring date, whichever occurred first (approximately 52.7 months) | DOR: time from first documentation of confirmed CR/PR to first documentation of PD according to RECIST v1.1 or death from any cause, whichever occurred earlier. Per RECIST v1.1, CR: disappearance of all T/NT lesions(L). Any pathological lymph nodes (whether T/NT) must have reduction in short axis to \<10 mm. PR: at least \>=30 % decrease in SOD of TL, taking reference baseline sum diameters. PD: at least \>=20% relative increase in SOD of TL taking reference smallest sum on study. Participants who do not have PD \& were still on study at time of an analysis/ who have started new anticancer treatment/discontinue prior to documentation of PD were censored at date of last adequate response assessment documenting absence of PD. Participants who had PD/death occurred after two/more consecutive missing scheduled response assessments were censored at date of last adequate response assessment of CR, PR, SD,/non-CR/non-PD. Kaplan-Meier method was used for evaluation. |
| Progression-Free Survival (PFS) as Assessed by Investigator | From the first documented CR or PR until the first documentation of PD or death or censoring date, whichever occurred first (approximately 52.7 months) | PFS was defined as time from the date of treatment initiation to date of PD as per RECIST v1.1 or death from any cause, whichever occurred first . As per RECIST v1.1, PD: least \>=20% relative increase in SOD of target lesions taking as reference the smallest sum on study (including baseline sum if that is smallest on study). Participants who do not have PD and were still on study at time of an analysis/ who have started new anticancer treatment/discontinue prior to documentation of PD were censored at date of last adequate response assessment documenting absence of PD. Participants who had PD or death occurred after two or more consecutive missing scheduled response assessments were censored at date of last adequate response assessment of CR, PR, SD,/non-CR/non-PD. Kaplan-Meier method was used for evaluation. |
| Overall Survival (OS) | From date of start of study treatment until date of death or censoring date (approximately 52.7 months) | OS was defined as the time from treatment initiation 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). Participants lacking data beyond the day of treatment initiation were censored on the date of treatment initiation (i.e., OS duration of 1 day). Kaplan-Meier method was used for evaluation. |
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) | From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment (approximately 52.7 months) | An AE was any untoward medical occurrence in a participant or clinical investigational participant administered a medicinal product and which did not necessarily have a causal relationship with this treatment. A TEAE was defined as a newly occurring or worsening AE after the first dose of study treatment. |
| Number of Participants With Treatment Emergent Laboratory Test Abnormalities | From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment (approximately 52.7 months) | Treatment-emergent laboratory abnormalities were defined as abnormalities that are new or worsened on or after receiving the first dose of study treatment up to 30 days after the last dose of study treatment. The following laboratory abnormalities were assessed: A-) Hematology: hemoglobin decreased, leukocytes decreased, lymphocytes decreased and increased, neutrophils decreased and platelets decreased; B-) Chemistry: alanine aminotransferase increased, albumin decreased, alkaline phosphatase increased, aspartate aminotransferase increased, calcium corrected for albumin decreased and increased, creatinine increased, glomerular filtration rate estimated decreased, glucose decreased, lactate dehydrogenase increased, magnesium increased and decreased, potassium increased and decreased, sodium increased and decreased and total bilirubin increased. |
| Number of Participants With Any Dose Modifications Due to AEs | From first dose of the study treatment (Day 1) up to the last dose of study treatment (approximately 52.7 months) | Dose modification included dose hold, dose reduction, or discontinuation of drugs. Dose reductions or treatment interruption/discontinuation were made at the discretion of the investigator. |
| Number of Participants With TEAEs of Special Interest | From first dose of the study treatment (Day 1) up to the last dose of study treatment (approximately 52.7 months) | An adverse event of special interest (AESI) were any serious or nonserious AE that were of scientific or medical concern as defined by the sponsor and specific to the program, for which ongoing monitoring and rapid communication to the sponsor were appropriate. A TEAE was defined as a newly occurring or worsening AE after the first dose of study treatment (tucatinib, trastuzumab or fulvestrant). AESIs for this study were related to hepatoxicity. |
| Maximum Concentration (Cmax) of Tucatinib | Cycle 3 Day 1: anytime within 1-4 hours post-dose | — |
| Trough Concentration (Ctrough) of Tucatinib | Cycle 3 Day 1: Predose | — |
Countries
Belgium, Germany, Italy, Japan, South Korea, Spain, United Kingdom, United States
Contacts
STUDY_DIRECTORPfizer CT.gov Call Center
Pfizer
Participant flow
Recruitment details
Participants with locally-advanced (LA) unresectable or metastatic solid tumors driven by human epidermal growth factor receptor 2 (HER2) alterations, who were previously treated, were enrolled to receive tucatinib in combination with trastuzumab in this study. Participants with hormone-receptor positive breast cancer also received fulvestrant.
Pre-assignment details
A total of 217 participants were enrolled into 9 separate cohorts based on tumor histology and HER2 alteration status. All 217 participants were treated. Results reported are based on the primary completion date (PCD) of the study; data for only those secondary outcome measures are reported for which analyses were complete at PCD. Remaining outcome measures would be reported upon completion of their analyses at study completion.
Participants by arm
| Arm | Count |
|---|---|
| Tucatinib+Trastuzumab (Cohort 1) Participants with cervical cancer with HER2 amplification/over expression, received tucatinib 300 mg PO BID from Day 1 of Cycle 1 onwards and trastuzumab 8 mg/kg IV on Day 1 of Cycle 1 and then 6 mg/kg every 21 days starting on Day 1 of Cycle 2 (1 Cycle = 21 Days). Participants received treatment until unacceptable toxicity, occurrence of radiographic progression or clinical progression, withdrawal of consent, death, or study closure. | 11 |
| Tucatinib+Trastuzumab (Cohort 2) Participants with uterine cancer with HER2 amplification/over expression, received tucatinib 300 mg PO BID from Day 1 of Cycle 1 onwards and trastuzumab 8 mg/kg IV on Day 1 of Cycle 1 and then 6 mg/kg every 21 days starting on Day 1 of Cycle 2 (1 Cycle = 21 Days). Participants received treatment until unacceptable toxicity, occurrence of radiographic progression or clinical progression, withdrawal of consent, death, or study closure. | 31 |
| Tucatinib+Trastuzumab (Cohort 3) Participants with biliary tract cancer with HER2 amplification/over expression, received tucatinib 300 mg PO BID from Day 1 of Cycle 1 onwards and trastuzumab 8 mg/kg IV on Day 1 of Cycle 1 and then 6 mg/kg every 21 days starting on Day 1 of Cycle 2 (1 Cycle = 21 Days). Participants received treatment until unacceptable toxicity, occurrence of radiographic progression or clinical progression, withdrawal of consent, death, or study closure. | 30 |
| Tucatinib+Trastuzumab (Cohort 4) Participants with urothelial cancer with HER2 amplification/over expression, received tucatinib 300 mg PO BID from Day 1 of Cycle 1 onwards and trastuzumab 8 mg/kg IV on Day 1 of Cycle 1 and then 6 mg/kg every 21 days starting on Day 1 of Cycle 2 (1 Cycle = 21 Days). Participants received treatment until unacceptable toxicity, occurrence of radiographic progression or clinical progression, withdrawal of consent, death, or study closure. | 25 |
| Tucatinib+Trastuzumab (Cohort 5) Participants with NSCLC with HER2 amplification/over expression, received tucatinib 300 mg PO BID from Day 1 of Cycle 1 onwards and trastuzumab 8 mg/kg IV on Day 1 of Cycle 1 and then 6 mg/kg every 21 days starting on Day 1 of Cycle 2 (1 Cycle = 21 Days). Participants received treatment until unacceptable toxicity, occurrence of radiographic progression or clinical progression, withdrawal of consent, death, or study closure. | 12 |
| Tucatinib+Trastuzumab (Cohort 6) Participants with solid tumor types (except breast, gastric or GEC, and CRC) with HER2 amplification/over expression, received tucatinib 300 mg PO BID from Day 1 of Cycle 1 onwards and trastuzumab 8 mg/kg IV on Day 1 of Cycle 1 and then 6 mg/kg every 21 days starting on Day 1 of Cycle 2 (1 Cycle = 21 Days). Participants received treatment until unacceptable toxicity, occurrence of radiographic progression or clinical progression, withdrawal of consent, death, or study closure. | 31 |
| Tucatinib+Trastuzumab (Cohort 7) Participants with non-squamous NSCLC with HER2 mutations, received tucatinib 300 mg PO BID from Day 1 of Cycle 1 onwards and trastuzumab 8 mg/kg IV on Day 1 of Cycle 1 and then 6 mg/kg every 21 days starting on Day 1 of Cycle 2 (1 Cycle = 21 Days). Participants received treatment until unacceptable toxicity, occurrence of radiographic progression or clinical progression, withdrawal of consent, death, or study closure. | 13 |
| Tucatinib+Trastuzumab+ Fulvestrant (Cohort 8) Participants with breast cancer with HER2 mutations, received tucatinib 300 mg PO BID from Day 1 of Cycle 1 onwards and trastuzumab 8 mg/kg IV on Day 1 of Cycle 1 and then 6 mg/kg every 21 days starting on Day 1 of Cycle 2 (1 Cycle = 21 Days). Participants with hormone-receptor positive breast cancer also received fulvestrant 500 mg IM once every 4 weeks starting from Day 1 of Cycle 1, and on Day 15 of Cycle 1. Participants received treatment until unacceptable toxicity, occurrence of radiographic progression or clinical progression, withdrawal of consent, death, or study closure. | 31 |
| Tucatinib+Trastuzumab (Cohort 9) Participants with all solid tumor cancers (except breast and non-squamous NSCLC) with HER2 mutations, received tucatinib 300 mg PO BID from Day 1 of Cycle 1 onwards and trastuzumab 8 mg/kg IV on Day 1 of Cycle 1 and then 6 mg/kg every 21 days starting on Day 1 of Cycle 2 (1 Cycle = 21 Days). Participants received treatment until unacceptable toxicity, occurrence of radiographic progression or clinical progression, withdrawal of consent, death, or study closure. | 33 |
| Total | 217 |
Baseline characteristics
| Characteristic | Tucatinib+Trastuzumab (Cohort 1) | Tucatinib+Trastuzumab (Cohort 2) | Tucatinib+Trastuzumab (Cohort 3) | Tucatinib+Trastuzumab (Cohort 4) | Tucatinib+Trastuzumab (Cohort 5) | Tucatinib+Trastuzumab (Cohort 6) | Tucatinib+Trastuzumab (Cohort 7) | Tucatinib+Trastuzumab+ Fulvestrant (Cohort 8) | Tucatinib+Trastuzumab (Cohort 9) | Total |
|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 53.6 Years STANDARD_DEVIATION 15.3 | 67.6 Years STANDARD_DEVIATION 7.4 | 66.4 Years STANDARD_DEVIATION 10.1 | 67.5 Years STANDARD_DEVIATION 11.6 | 69.7 Years STANDARD_DEVIATION 11.1 | 62.7 Years STANDARD_DEVIATION 10.7 | 71.3 Years STANDARD_DEVIATION 9.5 | 61.3 Years STANDARD_DEVIATION 10.3 | 63.8 Years STANDARD_DEVIATION 10.5 | 64.9 Years STANDARD_DEVIATION 11 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 1 Participants | 2 Participants | 1 Participants | 2 Participants | 0 Participants | 2 Participants | 1 Participants | 10 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 11 Participants | 29 Participants | 26 Participants | 17 Participants | 8 Participants | 25 Participants | 9 Participants | 24 Participants | 30 Participants | 179 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 3 Participants | 6 Participants | 3 Participants | 4 Participants | 4 Participants | 5 Participants | 2 Participants | 28 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 6 Participants | 9 Participants | 23 Participants | 5 Participants | 3 Participants | 20 Participants | 1 Participants | 11 Participants | 23 Participants | 101 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 4 Participants | 1 Participants | 2 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 10 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 3 Participants | 6 Participants | 3 Participants | 6 Participants | 4 Participants | 4 Participants | 2 Participants | 28 Participants |
| Race (NIH/OMB) White | 4 Participants | 18 Participants | 3 Participants | 12 Participants | 6 Participants | 5 Participants | 7 Participants | 15 Participants | 8 Participants | 78 Participants |
| Sex: Female, Male Female | 11 Participants | 31 Participants | 15 Participants | 6 Participants | 4 Participants | 20 Participants | 6 Participants | 31 Participants | 16 Participants | 140 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 15 Participants | 19 Participants | 8 Participants | 11 Participants | 7 Participants | 0 Participants | 17 Participants | 77 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 9 / 11 | 22 / 31 | 22 / 30 | 17 / 25 | 6 / 12 | 21 / 31 | 10 / 13 | 11 / 31 | 25 / 33 |
| other Total, other adverse events | 10 / 11 | 30 / 31 | 29 / 30 | 23 / 25 | 12 / 12 | 29 / 31 | 13 / 13 | 31 / 31 | 30 / 33 |
| serious Total, serious adverse events | 5 / 11 | 11 / 31 | 13 / 30 | 9 / 25 | 2 / 12 | 9 / 31 | 7 / 13 | 8 / 31 | 14 / 33 |
Outcome results
Primary
Confirmed Objective Response Rate (cORR) as Assessed by Investigator
Confirmed ORR was defined as the percentage of participants with best overall response of complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria version (v)1.1 as assessed by investigator and was considered as confirmed when subsequent response was at least 4 weeks after initial response. As per RECIST v1.1, CR: disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to less than (\<)10 millimeter (mm). PR: at least a greater than or equal to (\>=)30 % decrease in the sum of diameters (SOD) of target lesions (longest for non-nodal target lesions and the short axes for nodal target lesions), taking as reference the baseline sum diameters. Disease progression (PD): at least \>=20% relative increase in SOD of target lesion taking as reference the smallest sum on study (including baseline sum if that is the smallest on study).
Time frame: From the first dose of study treatment until the first documented CR or PR on or before the first documented PD or new anti-cancer therapies or death, whichever occurred first (up to 28.3 months)
Population: The Response-Evaluable analysis set includes all participants with measurable disease who meet the following 3 criteria: (1) had a baseline disease assessment, (2) received study treatment, and (3) had post-baseline disease assessment or discontinued treatment due to documented disease progression or clinical progression.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tucatinib+Trastuzumab (Cohort 1) | Confirmed Objective Response Rate (cORR) as Assessed by Investigator | 27.3 Percentage of participants |
| Tucatinib+Trastuzumab (Cohort 2) | Confirmed Objective Response Rate (cORR) as Assessed by Investigator | 13.3 Percentage of participants |
| Tucatinib+Trastuzumab (Cohort 3) | Confirmed Objective Response Rate (cORR) as Assessed by Investigator | 46.7 Percentage of participants |
| Tucatinib+Trastuzumab (Cohort 4) | Confirmed Objective Response Rate (cORR) as Assessed by Investigator | 8.0 Percentage of participants |
| Tucatinib+Trastuzumab (Cohort 5) | Confirmed Objective Response Rate (cORR) as Assessed by Investigator | 8.3 Percentage of participants |
| Tucatinib+Trastuzumab (Cohort 6) | Confirmed Objective Response Rate (cORR) as Assessed by Investigator | 22.6 Percentage of participants |
| Tucatinib+Trastuzumab (Cohort 7) | Confirmed Objective Response Rate (cORR) as Assessed by Investigator | 0 Percentage of participants |
| Tucatinib+Trastuzumab+ Fulvestrant (Cohort 8) | Confirmed Objective Response Rate (cORR) as Assessed by Investigator | 41.9 Percentage of participants |
| Tucatinib+Trastuzumab (Cohort 9) | Confirmed Objective Response Rate (cORR) as Assessed by Investigator | 10.3 Percentage of participants |
Secondary
Confirmed Disease Control Rate (DCR) as Assessed by Investigator
DCR was defined as the percentage of participants with confirmed CR, PR, or stable disease (SD or non-CR/non-PD) according to RECIST v1.1 as assessed by investigator. As per RECIST v1.1, CR: disappearance of all target (T) lesions and non-target (NT) lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR: at least \>=30 % decrease in the SOD of target lesions (longest for non-nodal target lesions and the short axes for nodal target lesions), taking as reference the baseline sum diameters. PD: at least \>=20% relative increase in SOD of target lesions taking as reference the smallest sum on study (including baseline sum if that is the smallest on study). SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest SOD while on study and cannot have met criteria for PD previously.
Time frame: From the first dose study treatment until PD or death, whichever occurred first (approximately 52.7 months)
Secondary
Duration of Response (DOR) as Assessed by Investigator
DOR: time from first documentation of confirmed CR/PR to first documentation of PD according to RECIST v1.1 or death from any cause, whichever occurred earlier. Per RECIST v1.1, CR: disappearance of all T/NT lesions(L). Any pathological lymph nodes (whether T/NT) must have reduction in short axis to \<10 mm. PR: at least \>=30 % decrease in SOD of TL, taking reference baseline sum diameters. PD: at least \>=20% relative increase in SOD of TL taking reference smallest sum on study. Participants who do not have PD & were still on study at time of an analysis/ who have started new anticancer treatment/discontinue prior to documentation of PD were censored at date of last adequate response assessment documenting absence of PD. Participants who had PD/death occurred after two/more consecutive missing scheduled response assessments were censored at date of last adequate response assessment of CR, PR, SD,/non-CR/non-PD. Kaplan-Meier method was used for evaluation.
Time frame: From the first documented CR or PR until the first documentation of PD or death or censoring date, whichever occurred first (approximately 52.7 months)
Secondary
Maximum Concentration (Cmax) of Tucatinib
Time frame: Cycle 3 Day 1: anytime within 1-4 hours post-dose
Population: The Pharmacokinetic (PK) analysis set included all participants in the safety set from whom at least one evaluable PK assessment was reported.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Tucatinib+Trastuzumab (Cohort 1) | Maximum Concentration (Cmax) of Tucatinib | 488.2 Nanogram per milliliter | Geometric Coefficient of Variation 104.9 |
| Tucatinib+Trastuzumab (Cohort 2) | Maximum Concentration (Cmax) of Tucatinib | 483.1 Nanogram per milliliter | Geometric Coefficient of Variation 53.5 |
| Tucatinib+Trastuzumab (Cohort 3) | Maximum Concentration (Cmax) of Tucatinib | 319.2 Nanogram per milliliter | Geometric Coefficient of Variation 116.2 |
| Tucatinib+Trastuzumab (Cohort 4) | Maximum Concentration (Cmax) of Tucatinib | 275.9 Nanogram per milliliter | Geometric Coefficient of Variation 122.8 |
| Tucatinib+Trastuzumab (Cohort 5) | Maximum Concentration (Cmax) of Tucatinib | 437.2 Nanogram per milliliter | Geometric Coefficient of Variation 60 |
| Tucatinib+Trastuzumab (Cohort 6) | Maximum Concentration (Cmax) of Tucatinib | 330.4 Nanogram per milliliter | Geometric Coefficient of Variation 164.2 |
| Tucatinib+Trastuzumab (Cohort 7) | Maximum Concentration (Cmax) of Tucatinib | 207.7 Nanogram per milliliter | Geometric Coefficient of Variation 344.6 |
| Tucatinib+Trastuzumab+ Fulvestrant (Cohort 8) | Maximum Concentration (Cmax) of Tucatinib | 393.2 Nanogram per milliliter | Geometric Coefficient of Variation 255.6 |
| Tucatinib+Trastuzumab (Cohort 9) | Maximum Concentration (Cmax) of Tucatinib | 242.9 Nanogram per milliliter | Geometric Coefficient of Variation 155.1 |
Secondary
Number of Participants With Any Dose Modifications Due to AEs
Dose modification included dose hold, dose reduction, or discontinuation of drugs. Dose reductions or treatment interruption/discontinuation were made at the discretion of the investigator.
Time frame: From first dose of the study treatment (Day 1) up to the last dose of study treatment (approximately 52.7 months)
Secondary
Number of Participants With TEAEs of Special Interest
An adverse event of special interest (AESI) were any serious or nonserious AE that were of scientific or medical concern as defined by the sponsor and specific to the program, for which ongoing monitoring and rapid communication to the sponsor were appropriate. A TEAE was defined as a newly occurring or worsening AE after the first dose of study treatment (tucatinib, trastuzumab or fulvestrant). AESIs for this study were related to hepatoxicity.
Time frame: From first dose of the study treatment (Day 1) up to the last dose of study treatment (approximately 52.7 months)
Secondary
Number of Participants With Treatment Emergent Adverse Events (TEAEs)
An AE was any untoward medical occurrence in a participant or clinical investigational participant administered a medicinal product and which did not necessarily have a causal relationship with this treatment. A TEAE was defined as a newly occurring or worsening AE after the first dose of study treatment.
Time frame: From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment (approximately 52.7 months)
Secondary
Number of Participants With Treatment Emergent Laboratory Test Abnormalities
Treatment-emergent laboratory abnormalities were defined as abnormalities that are new or worsened on or after receiving the first dose of study treatment up to 30 days after the last dose of study treatment. The following laboratory abnormalities were assessed: A-) Hematology: hemoglobin decreased, leukocytes decreased, lymphocytes decreased and increased, neutrophils decreased and platelets decreased; B-) Chemistry: alanine aminotransferase increased, albumin decreased, alkaline phosphatase increased, aspartate aminotransferase increased, calcium corrected for albumin decreased and increased, creatinine increased, glomerular filtration rate estimated decreased, glucose decreased, lactate dehydrogenase increased, magnesium increased and decreased, potassium increased and decreased, sodium increased and decreased and total bilirubin increased.
Time frame: From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment (approximately 52.7 months)
Secondary
Overall Survival (OS)
OS was defined as the time from treatment initiation 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). Participants lacking data beyond the day of treatment initiation were censored on the date of treatment initiation (i.e., OS duration of 1 day). Kaplan-Meier method was used for evaluation.
Time frame: From date of start of study treatment until date of death or censoring date (approximately 52.7 months)
Secondary
Progression-Free Survival (PFS) as Assessed by Investigator
PFS was defined as time from the date of treatment initiation to date of PD as per RECIST v1.1 or death from any cause, whichever occurred first . As per RECIST v1.1, PD: least \>=20% relative increase in SOD of target lesions taking as reference the smallest sum on study (including baseline sum if that is smallest on study). Participants who do not have PD and were still on study at time of an analysis/ who have started new anticancer treatment/discontinue prior to documentation of PD were censored at date of last adequate response assessment documenting absence of PD. Participants who had PD or death occurred after two or more consecutive missing scheduled response assessments were censored at date of last adequate response assessment of CR, PR, SD,/non-CR/non-PD. Kaplan-Meier method was used for evaluation.
Time frame: From the first documented CR or PR until the first documentation of PD or death or censoring date, whichever occurred first (approximately 52.7 months)
Secondary
Trough Concentration (Ctrough) of Tucatinib
Time frame: Cycle 3 Day 1: Predose
Population: The PK analysis set included all participants in the safety set from whom at least one evaluable PK assessment was reported.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Tucatinib+Trastuzumab (Cohort 1) | Trough Concentration (Ctrough) of Tucatinib | 196.6 Nanogram per milliliter | Geometric Coefficient of Variation 100.1 |
| Tucatinib+Trastuzumab (Cohort 2) | Trough Concentration (Ctrough) of Tucatinib | 99.9 Nanogram per milliliter | Geometric Coefficient of Variation 482.9 |
| Tucatinib+Trastuzumab (Cohort 3) | Trough Concentration (Ctrough) of Tucatinib | 145.7 Nanogram per milliliter | Geometric Coefficient of Variation 383 |
| Tucatinib+Trastuzumab (Cohort 4) | Trough Concentration (Ctrough) of Tucatinib | 105.1 Nanogram per milliliter | Geometric Coefficient of Variation 355.1 |
| Tucatinib+Trastuzumab (Cohort 5) | Trough Concentration (Ctrough) of Tucatinib | 46.5 Nanogram per milliliter | Geometric Coefficient of Variation 3312.4 |
| Tucatinib+Trastuzumab (Cohort 6) | Trough Concentration (Ctrough) of Tucatinib | 115.4 Nanogram per milliliter | Geometric Coefficient of Variation 328.3 |
| Tucatinib+Trastuzumab (Cohort 7) | Trough Concentration (Ctrough) of Tucatinib | 267.4 Nanogram per milliliter | Geometric Coefficient of Variation 165.2 |
| Tucatinib+Trastuzumab+ Fulvestrant (Cohort 8) | Trough Concentration (Ctrough) of Tucatinib | 126.9 Nanogram per milliliter | Geometric Coefficient of Variation 234.5 |
| Tucatinib+Trastuzumab (Cohort 9) | Trough Concentration (Ctrough) of Tucatinib | 142.3 Nanogram per milliliter | Geometric Coefficient of Variation 184.1 |