Tucatinib Plus Trastuzumab and Oxaliplatin-based Chemotherapy or Pembrolizumab-containing Combinations for HER2+ Gastrointestinal Cancers

An SAE was any untoward medical occurrence at any dose that was fatal; life-threatening; required hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity; was a congenital anomaly/birth defect or was medically significant.

Time frame: From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment, end of study date, death date, or data cutoff date, whichever was earlier (maximum of 21 months)

Population: The safety analysis set included all participants who were enrolled in the study and received any amount of study treatment.

An SAE was any untoward medical occurrence at any dose that was fatal; life-threatening; required hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity; was a congenital anomaly/birth defect or was medically significant.

Time frame: From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment, end of study date, death date, or data cutoff date, whichever was earlier (maximum of 20.9 months)

Population: The safety analysis set included all participants who were enrolled in the study and received any amount of study treatment.

An SAE was any untoward medical occurrence at any dose that was fatal; life-threatening; required hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity; was a congenital anomaly/birth defect or was medically significant.

Time frame: From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment, end of study date, death date, or data cutoff date, whichever was earlier (maximum of 20.7 months)

Population: The safety analysis set included all participants who were enrolled in the study and received any amount of study treatment.

An SAE was any untoward medical occurrence at any dose that was fatal; life-threatening; required hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity; was a congenital anomaly/birth defect or was medically significant. Treatment related SAEs were SAEs related to any study treatment and relatedness was judged by investigator.

Time frame: From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment, end of study date, death date, or data cutoff date, whichever was earlier (maximum of 21 months)

Population: The safety analysis set included all participants who were enrolled in the study and received any amount of study treatment.

An SAE was any untoward medical occurrence at any dose that was fatal; life-threatening; required hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity; was a congenital anomaly/birth defect or was medically significant. Treatment related SAEs were SAEs related to any study treatment and relatedness was judged by investigator.

Time frame: From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment, end of study date, death date, or data cutoff date, whichever was earlier (maximum of 20.7 months)

Population: The safety analysis set included all participants who were enrolled in the study and received any amount of study treatment.

An SAE was any untoward medical occurrence at any dose that was fatal; life-threatening; required hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity; was a congenital anomaly/birth defect or was medically significant. Treatment related SAEs were SAEs related to any study treatment and relatedness was judged by investigator.

Time frame: From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment, end of study date, death date, or data cutoff date, whichever was earlier (maximum of 20.9 months)

Population: The safety analysis set included all participants who were enrolled in the study and received any amount of study treatment.

Vital signs included temperature, blood pressure, heart rate and respiratory rate. Clinically significant vital signs were defined as: temperature \>= 38 degrees Celsius, respiratory rate \> 20 breaths per minute, SBP \>= 120 mmHg or DBP \>= 80 mmHg, SBP \>= 140 mmHg or DBP \>= 90 mmHg and heart rate \> 100 beats per minute (bpm).

Time frame: From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment, end of study date, death date, or data cutoff date, whichever was earlier (maximum of 21 months)

Population: The safety analysis set included all participants who were enrolled in the study and received any amount of study treatment.

Vital signs included temperature, blood pressure, heart rate and respiratory rate. Clinically significant vital signs were defined as: temperature greater than or equal to (\>=) 38 degrees Celsius, respiratory rate greater than (\>) 20 breaths per minute, systolic blood pressure (SBP) \>= 120 millimeter of mercury (mmHg) or diastolic blood pressure (DBP) \>= 80 mmHg, SBP \>= 140 mmHg or DBP \>= 90 mmHg and heart rate \> 100 beats per minute (bpm).

Time frame: From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment, end of study date, death date, or data cutoff date, whichever was earlier (maximum of 20.7 months)

Population: The safety analysis set included all participants who were enrolled in the study and received any amount of study treatment.

Vital signs included temperature, blood pressure and heart rate. Clinically significant vital signs were defined as: temperature \>= 38 degrees Celsius, respiratory rate \> 20 breaths per minute, SBP \>= 120 mmHg or DBP \>= 80 mmHg, SBP \>= 140 mmHg or DBP \>= 90 mmHg and heart rate \> 100 bpm.

Time frame: From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment, end of study date, death date, or data cutoff date, whichever was earlier (maximum of 20.9 months)

Population: The safety analysis set included all participants who were enrolled in the study and received any amount of study treatment.

DLTs were AEs/ laboratory abnormalities that were considered to be related to tucatinib/ tucatinib in combination with chemotherapy (mFOLFOX6/CAPOX) and/ or trastuzumab and/ or pembrolizumab. DLTs was defined any of following: a-) Hepatic- any instance of AST/ ALT \>3\*ULN and total bilirubin \>2\*ULN that is not thought to be due to PD/ other medical illness. PD: at least 20% increase in sum of diameters of target lesions, taking as reference smallest sum on study. In addition to relative increase of 20%, sum must also demonstrate an absolute increase of at least 5 mm. b-) Non-hematologic- any clinically significant, non-hematologic treatment-related AE\>= grade 3, with following exceptions: grade 3 fatigue=\< 7days, grade 3 diarrhea, nausea/vomiting without optimal use of anti-emetics/antidiarrheals c-) hematologic: \>= grade 3 febrile neutropenia and ANC decreased grade 4 for \>7days.

Time frame: Cycle 1 (Up to 28 days)

Population: The DLT-evaluable analysis set for Cohort 1D included all participants who met one of the following criteria: had a DLT or had taken at least 75% of planned fluorouracil, oxaliplatin, trastuzumab, and tucatinib doses and were followed for at least 28 days.

DLTs were AEs/ laboratory abnormalities that were considered to be related to tucatinib/ tucatinib in combination with chemotherapy(mFOLFOX6/CAPOX) and/or trastuzumab and/or pembrolizumab. DLTs was defined any of following: a-)Hepatic- any instance of aspartate aminotransferase(AST)/ alanine aminotransferase(ALT)\>3\*upper limit of normal(ULN) and total bilirubin \>2\*ULN that is not thought to be due to progressive disease(PD)/other medical illness. PD:at least 20% increase in sum of diameters of target lesions,taking as reference smallest sum on study. In addition to relative increase of 20%,sum must also demonstrate an absolute increase of at least 5 millimeters(mm). b-) Non-hematologic- any clinically significant, non-hematologic treatment-related AE\>= grade(G)3, with following exceptions:G3 fatigue=\< 7days,G3 diarrhea,nausea/vomiting without optimal use of anti-emetics/antidiarrheals c-)hematologic:\>=G3 febrile neutropenia and absolute neutrophil count(ANC) decreased G4 for \>7days.

Time frame: Cycle 1 (Up to 21 days)

Population: The DLT evaluable analysis set for cohort 1E included all participants who met one of following criteria: had a DLT or had taken at least 75% of planned study treatment for first 21 days of study treatment and were followed for at least 21 days of study treatment.

DLTs were AEs/ laboratory abnormalities that were considered to be related to tucatinib/ tucatinib in combination with chemotherapy (mFOLFOX6/CAPOX) and/ or trastuzumab and/ or pembrolizumab. DLTs was defined any of following: a-) Hepatic- any instance of AST/ ALT \>3\*ULN and total bilirubin \>2\*ULN that is not thought to be due to PD/ other medical illness. PD: at least 20% increase in sum of diameters of target lesions, taking as reference smallest sum on study. In addition to relative increase of 20%, sum must also demonstrate an absolute increase of at least 5 mm. b-) Non-hematologic- any clinically significant, non-hematologic treatment-related AE\>= grade 3, with following exceptions: grade 3 fatigue=\< 7days, grade 3 diarrhea, nausea/vomiting without optimal use of anti-emetics/antidiarrheals c-) hematologic: \>= grade 3 febrile neutropenia and ANC decreased grade 4 for \>7days.

Time frame: Cycle 1 (Up to 28 days)

Population: The DLT evaluable analysis set for cohort 1F included all participants who met one of following criteria: had a DLT or had taken at least 75% of planned study treatment for first 28 days of study treatment and were followed for at least 28 days of study treatment.

An AE was defined was any untoward medical occurrence in a clinical investigational participant administered a medicinal product and which did not necessarily have a causal relationship with this treatment. TEAE was defined as a newly occurring or worsening AE after the first dose of study treatment (tucatinib, trastuzumab, leucovorin, fluorouracil and oxaliplatin) through 30 days after the last dose of study treatment. TEAEs were graded according to NCI-CTCAE v 5.0 where grade 1= mild, grade 2= moderate, grade 3= severe and grade 4= life-threatening. Number of participants with \>= grade 3 TEAEs are reported in this outcome measure.

Time frame: From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment, end of study date, death date, or data cutoff date, whichever was earlier (maximum of 21 months)

Population: The safety analysis set included all participants who were enrolled in the study and received any amount of study treatment.

An AE was defined was any untoward medical occurrence in a clinical investigational participant administered a medicinal product and which did not necessarily have a causal relationship with this treatment. TEAE was defined as a newly occurring or worsening AE after the first dose of study treatment (tucatinib, trastuzumab, leucovorin, fluorouracil and oxaliplatin) through 30 days after the last dose of study treatment. TEAEs were graded according to NCI-CTCAE v 5.0 (grade 1= mild, grade 2= moderate, grade 3= severe and grade 4= life-threatening). Number of participants with \>= grade 3 TEAEs are reported in this outcome measure.

Time frame: From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment, end of study date, death date, or data cutoff date, whichever was earlier (maximum of 20.9 months)

Population: The safety analysis set included all participants who were enrolled in the study and received any amount of study treatment.

An AE was defined was any untoward medical occurrence in a clinical investigational participant administered a medicinal product and which did not necessarily have a causal relationship with this treatment. TEAE was defined as a newly occurring or worsening AE after the first dose of study treatment (tucatinib, trastuzumab, leucovorin, fluorouracil and oxaliplatin) through 30 days after the last dose of study treatment. TEAEs were graded according to NCI-CTCAE v 5.0 where grade 1= mild, grade 2= moderate, grade 3= severe and grade 4= life-threatening. Treatment related TEAEs were AEs related to study treatment and relatedness was judged by investigator. Number of participants with \>= grade 3 treatment related TEAEs are reported in this outcome measure.

Time frame: From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment, end of study date, death date, or data cutoff date, whichever was earlier (maximum of 21 months)

Population: The safety analysis set included all participants who were enrolled in the study and received any amount of study treatment.

An AE was defined was any untoward medical occurrence in a clinical investigational participant administered a medicinal product and which did not necessarily have a causal relationship with this treatment. TEAE was defined as a newly occurring or worsening AE after the first dose of study treatment (tucatinib, trastuzumab, leucovorin, fluorouracil, oxaliplatin and pembrolizumab) through 30 days after the last dose of study treatment. TEAEs were graded according to NCI-CTCAE v 5.0 where grade 1= mild, grade 2= moderate, grade 3= severe and grade 4= life-threatening. Treatment related TEAEs were AEs related to study treatment and relatedness was judged by investigator. Number of participants with \>= grade 3 treatment related TEAEs are reported in this outcome measure.

Time frame: From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment, end of study date, death date, or data cutoff date, whichever was earlier (maximum of 20.7 months)

Population: The safety analysis set included all participants who were enrolled in the study and received any amount of study treatment.

An AE was defined was any untoward medical occurrence in a clinical investigational participant administered a medicinal product and which did not necessarily have a causal relationship with this treatment. TEAE was defined as a newly occurring or worsening AE after the first dose of study treatment (tucatinib, trastuzumab, leucovorin, fluorouracil and oxaliplatin) through 30 days after the last dose of study treatment. TEAEs were graded according to NCI-CTCAE v 5.0 (grade 1= mild, grade 2= moderate, grade 3= severe and grade 4= life-threatening). Treatment related TEAEs were AEs related to study treatment and relatedness was judged by investigator. Number of participants with \>= grade 3 treatment related TEAEs are reported in this outcome measure.

Time frame: From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment, end of study date, death date, or data cutoff date, whichever was earlier (maximum of 20.9 months)

Population: The safety analysis set included all participants who were enrolled in the study and received any amount of study treatment.

An AE was defined was any untoward medical occurrence in a clinical investigational participant administered a medicinal product and which did not necessarily have a causal relationship with this treatment. TEAE was defined as a newly occurring or worsening AE after the first dose of study treatment (tucatinib, trastuzumab, leucovorin, fluorouracil, oxaliplatin and pembrolizumab) through 30 days after the last dose of study treatment. TEAEs were graded according to National Cancer Institute, Common Terminology Criteria for Adverse Events (NCI-CTCAE) version (v) 5.0 where grade 1= mild, grade 2= moderate, grade 3= severe and grade 4= life-threatening. Number of participants with \>= grade 3 TEAEs are reported in this outcome measure.

Time frame: From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment, end of study date, death date, or data cutoff date, whichever was earlier (maximum of 20.7 months)

Population: The safety analysis set included all participants who were enrolled in the study and received any amount of study treatment.

A renal DLT was defined as an increase in serum cystatin C \>1.5\* baseline that was not related to pre-renal or post-renal etiologies (including disease progression, dehydration and intercurrent illness) and occurred during the period of treatment with tucatinib in combination with trastuzumab and FOLFOX between the first dose of tucatinib and the end of Cycle 3. Increased serum cystatin C for which there was an alternative clinical explanation (eg, clearly related to an intercurrent illness or disease progression) was not considered renal DLTs.

Time frame: From first dose of tucatinib until end of Cycle 3 (up to 42 days)

Population: The DLT-evaluable analysis set for cohort 1A and 1B included all participants in cohort 1A or 1B who met one of the following criteria: had a renal DLT or had taken at least 75% of planned oxaliplatin and tucatinib doses per cycle and were followed for at least 2 cycles of study treatment (through the end of Cycle 3 for FOLFOX regimens), inclusive of dose delays.

An AE was defined as any untoward medical occurrence in a clinical investigational participant administered a medicinal product and which did not necessarily have a causal relationship with this treatment. TEAE was defined as a newly occurring or worsening AE after the first dose of study treatment (tucatinib, trastuzumab, leucovorin, fluorouracil and oxaliplatin) through 30 days after the last dose of study treatment. Number of participants with TEAEs leading to dose discontinuations (i.e. permanent withdrawal of tucatinib, trastuzumab, oxaliplatin, fluorouracil and leucovorin) are reported in this outcome measure.

Time frame: From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment, end of study date, death date, or data cutoff date, whichever was earlier (maximum of 21 months)

Population: The safety analysis set included all participants who were enrolled in the study and received any amount of study treatment.

An AE was defined as any untoward medical occurrence in a clinical investigational participant administered a medicinal product and which did not necessarily have a causal relationship with this treatment. TEAE was defined as a newly occurring or worsening AE after the first dose of study treatment (tucatinib, trastuzumab, leucovorin, fluorouracil and oxaliplatin) through 30 days after the last dose of study treatment. Dose hold was considered as dose delay and dose elimination. Number of participants with TEAEs leading to dose holds are reported in this outcome measure.

Time frame: From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment, end of study date, death date, or data cutoff date, whichever was earlier (maximum of 21 months)

Population: The safety analysis set included all participants who were enrolled in the study and received any amount of study treatment.

An AE was defined as any untoward medical occurrence in a clinical investigational participant administered a medicinal product and which did not necessarily have a causal relationship with this treatment. TEAE was defined as a newly occurring or worsening AE after the first dose of study treatment (tucatinib, trastuzumab, leucovorin, fluorouracil and oxaliplatin) through 30 days after the last dose of study treatment. Number of participants with TEAEs leading to dose reductions are reported in this outcome measure.

Time frame: From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment, end of study date, death date, or data cutoff date, whichever was earlier (maximum of 21 months)

Population: The safety analysis set included all participants who were enrolled in the study and received any amount of study treatment.

An AE was defined as any untoward medical occurrence in a clinical investigational participant administered a medicinal product and which did not necessarily have a causal relationship with this treatment. TEAE was defined as a newly occurring or worsening AE after the first dose of study treatment (tucatinib, trastuzumab, leucovorin, fluorouracil and oxaliplatin) through 30 days after the last 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, end of study date, death date, or data cutoff date, whichever was earlier (maximum of 21 months)

Population: The safety analysis set included all participants who were enrolled in the study and received any amount of study treatment.

An AE was defined was any untoward medical occurrence in a clinical investigational participant administered a medicinal product and which did not necessarily have a causal relationship with this treatment. TEAE was defined as a newly occurring or worsening AE after the first dose of study treatment (tucatinib, trastuzumab, leucovorin, fluorouracil and oxaliplatin) through 30 days after the last 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, end of study date, death date, or data cutoff date, whichever was earlier (maximum of 20.9 months)

Population: The safety analysis set included all participants who were enrolled in the study and received any amount of study treatment.

An adverse event (AE) was defined as any untoward medical occurrence in a clinical investigational participant administered a medicinal product and which did not necessarily have a causal relationship with this treatment. TEAE was defined as a newly occurring or worsening AE after the first dose of study treatment (tucatinib, trastuzumab, leucovorin, fluorouracil, oxaliplatin and pembrolizumab) through 30 days after the last 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, end of study date, death date, or data cutoff date, whichever was earlier (maximum of 20.7 months)

Population: The safety analysis set included all participants who were enrolled in the study and received any amount of study treatment.

The following chemistry parameters were assessed: ALT increased, albumin decreased, alkaline phosphatase increased, AST increased, calcium corrected for albumin decreased, creatinine increased, lactate dehydrogenase increased, potassium decreased, potassium increased, sodium decreased and sodium increased. TEAE was defined as a newly occurring or worsening AE after the first dose of study treatment (tucatinib, trastuzumab, leucovorin, fluorouracil and oxaliplatin) through 30 days after the last dose of study treatment. Chemistry laboratory parameters abnormalities were graded according to NCI CTCAE v 5.0 (grade 1= mild, grade 2= moderate, grade 3= severe and grade 4= life-threatening). Participants with chemistry abnormalities of any grade were reported.

Time frame: From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment, end of study date, death date, or data cutoff date, whichever was earlier (maximum of 21 months)

Population: The safety analysis set included all participants who were enrolled in the study and received any amount of study treatment.

The following chemistry laboratory parameters were assessed: alanine aminotransferase (ALT) increased, albumin decreased, alkaline phosphatase increased, aspartate aminotransferase (AST) increased, calcium corrected for albumin decreased, creatinine increased, calcium corrected for albumin increased, lactate dehydrogenase increased, potassium decreased, potassium increased, sodium decreased, sodium increased and total bilirubin increased. TEAE was defined as a newly occurring or worsening AE after the first dose of study treatment (tucatinib, trastuzumab, leucovorin, fluorouracil, oxaliplatin and pembrolizumab) through 30 days after the last dose of study treatment Chemistry laboratory abnormalities were graded according to NCI CTCAE v 5.0 (grade 1= mild, grade 2= moderate, grade 3= severe and grade 4= life-threatening). Participants with chemistry abnormalities of any grade were reported.

Time frame: From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment, end of study date, death date, or data cutoff date, whichever was earlier (maximum of 20.7 months)

Population: The safety analysis set included all participants who were enrolled in the study and received any amount of study treatment.

Following chemistry parameters were assessed: ALT increased, albumin decreased, alkaline phosphatase increased, AST increased, creatinine increased, glomerular filtration rate (GFR) estimated decreased, lactate dehydrogenase increased, potassium decreased, potassium increased, sodium decreased, sodium increased and total bilirubin increased. TEAE was defined as a newly occurring or worsening AE after the first dose of study treatment (tucatinib, trastuzumab, leucovorin, fluorouracil and oxaliplatin) through 30 days after the last dose of study treatment. Chemistry abnormalities were graded according to NCI CTCAE v 5.0; where, grade 1= mild, grade 2= moderate, grade 3= severe and grade 4= life-threatening. Participants with chemistry abnormalities of any grade were reported.

Time frame: From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment, end of study date, death date, or data cutoff date, whichever was earlier (maximum of 20.9 months)

Population: The safety analysis set included all participants who were enrolled in the study and received any amount of study treatment. Here, 'Number Analyzed' signifies number of participants evaluable for the specified rows.

The following hematological parameters were assessed: hemoglobin decreased, leukocytes decreased, lymphocytes decreased, neutrophils decreased and platelets decreased. TEAE was defined as a newly occurring or worsening AE after the first dose of study treatment (tucatinib, trastuzumab, leucovorin, fluorouracil and oxaliplatin) through 30 days after the last dose of study treatment. Hematological laboratory abnormalities were graded according to NCI CTCAE v 5.0 (grade 1= mild, grade 2= moderate, grade 3= severe and grade 4= life-threatening). Participants with hematological abnormalities of any grade were reported.

Time frame: From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment, end of study date, death date, or data cutoff date, whichever was earlier (maximum of 21 months)

Population: The safety analysis set included all participants who were enrolled in the study and received any amount of study treatment.

The following hematological parameters were assessed: hemoglobin decreased, leukocytes decreased, lymphocytes decreased, neutrophils decreased and platelets decreased. TEAE was defined as a newly occurring or worsening AE after the first dose of study treatment (tucatinib, trastuzumab, leucovorin, fluorouracil, oxaliplatin and pembrolizumab) through 30 days after the last dose of study treatment. Hematological laboratory abnormalities were graded according to NCI CTCAE v 5.0 (grade 1= mild, grade 2= moderate, grade 3= severe and grade 4= life-threatening). Participants with hematological abnormalities of any grade were reported.

Time frame: From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment, end of study date, death date, or data cutoff date, whichever was earlier (maximum of 20.7 months)

Population: The safety analysis set included all participants who were enrolled in the study and received any amount of study treatment.

Following hematological parameters were assessed: hemoglobin decreased, leukocytes decreased, lymphocytes decreased, neutrophils decreased and platelets decreased. TEAE was defined as a newly occurring or worsening AE after the first dose of study treatment (tucatinib, trastuzumab, leucovorin, fluorouracil and oxaliplatin) through 30 days after the last dose of study treatment. Hematological abnormalities were graded according to NCI CTCAE v 5.0; where, grade 1= mild, grade 2= moderate, grade 3= severe and grade 4= life-threatening). Participants with hematologic abnormalities of any grade were reported.

Time frame: From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment, end of study date, death date, or data cutoff date, whichever was earlier (maximum of 20.9 months)

Population: The safety analysis set included all participants who were enrolled in the study and received any amount of study treatment.

An AE was defined was any untoward medical occurrence in a clinical investigational participant administered a medicinal product and which did not necessarily have a causal relationship with this treatment. TEAE was defined as a newly occurring or worsening AE after the first dose of study treatment (tucatinib, trastuzumab, leucovorin, fluorouracil and oxaliplatin) through 30 days after the last dose of study treatment. Treatment related TEAEs were AEs related to study treatment and relatedness was judged by investigator.

Time frame: From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment, end of study date, death date, or data cutoff date, whichever was earlier (maximum of 21 months)

Population: The safety analysis set included all participants who were enrolled in the study and received any amount of study treatment.

An AE was defined was any untoward medical occurrence in a clinical investigational participant administered a medicinal product and which did not necessarily have a causal relationship with this treatment. TEAE was defined as a newly occurring or worsening AE after the first dose of study treatment (tucatinib, trastuzumab, leucovorin, fluorouracil, oxaliplatin and pembrolizumab) through 30 days after the last dose of study treatment. Treatment related TEAEs were AEs related to any study treatment and relatedness was judged by investigator.

Time frame: From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment, end of study date, death date, or data cutoff date, whichever was earlier (maximum of 20.7 months)

Population: The safety analysis set included all participants who were enrolled in the study and received any amount of study treatment.

An AE was defined was any untoward medical occurrence in a clinical investigational participant administered a medicinal product and which did not necessarily have a causal relationship with this treatment. TEAE was defined as a newly occurring or worsening AE after the first dose of study treatment (tucatinib, trastuzumab, leucovorin, fluorouracil and oxaliplatin) through 30 days after the last dose of study treatment. Treatment related TEAEs were AEs related to study treatment and relatedness was judged by investigator.

Time frame: From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment, end of study date, death date, or data cutoff date, whichever was earlier (maximum of 20.9 months)

Population: The safety analysis set included all participants who were enrolled in the study and received any amount of study treatment.

PK parameters were determined using noncompartmental analysis.

Time frame: Predose, 1 hour intra-dose, end of dose, 1, 2, 4, 6 hours after end of 2 hour oxaliplatin infusion (8 hours) on Day 1 of Cycle 1 and 2

Population: The pharmacokinetic (PK) analysis set included all participants in the safety set from whom at least one PK assessment was reported. Here, 'Overall Number of Participants Analyzed' signifies number of participants evaluable for this outcome measure.

PK parameters were determined using noncompartmental analysis.

Time frame: Predose, 1 hour intra-dose, end of dose, 1, 2, 4, 6 hours after end of 2 hour oxaliplatin infusion (8 hours) on Day 1 of Cycle 1 and 2

Population: The PK analysis set included all participants in the safety set from whom at least one PK assessment was reported. Here, 'Overall Number of Participants Analyzed' signifies number of participants evaluable for the outcome measure.

GFR value was estimated using serum Cystatin C. Baseline was considered as the most recent non-missing measurement prior to the first dose of any study treatment.

Time frame: Baseline, Cycle 1 Day 3, Cycle 1 Day 8, Cycle 2 Day 1, Cycle 2 Day 3, Cycle 2 Day 8 (each cycle=14 days)

Population: The safety analysis set included all participants who were enrolled in the study and received any amount of study treatment. Here Number of Participants Analyzed signifies number of participants evaluable for this outcome measure.

PK parameters were determined using noncompartmental analysis.

Time frame: Predose, 1 hour intra-dose, end of dose, 1, 2, 4, 6 hours after end of 2 hour oxaliplatin infusion (8 hours) on Day 1 of Cycle 1 and 2

Population: The PK analysis set included all participants in the safety set from whom at least one PK assessment was reported. Here, 'Overall Number of Participants Analyzed' signifies number of participants evaluable for the outcome measure.

cORR was defined as the percentage of participants with a confirmed CR or PR per investigator according to RECIST v1.1. For a response to be considered confirmed, the subsequent response had to be at least 4 weeks after the initial response. CR: complete disappearance of all target lesions with exception of nodal disease and complete disappearance of non-target lesions and normalization of tumor marker level. Any pathological lymph nodes (whether target or non-target) 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 of diameters. 90% exact CI was based on Clopper-Pearson method.

Time frame: From the first dose of study treatment until the first documented CR or PR or before start of any new anti-cancer therapy (up to 20.9 months)

Population: The response evaluable set included all participants who met all following criteria: had measurable disease at baseline, received any amount of study treatment, and had at least one post-baseline disease assessment or discontinued due to clinical progression, toxicity or death.

PK parameters were determined using noncompartmental analysis.

Time frame: Predose on Day 1 of Cycle 2

Population: The PK analysis set included all participants in the safety set from whom at least one PK assessment was reported. Here Number of Participants Analyzed signifies number of participants evaluable for this outcome measure.

DOR was defined as time from first documented objective response (CR or PR that was subsequently confirmed) to first documented PD per RECIST v1.1 or death due to any cause, whichever occurred first. PD: at least a 20 % increase in sum of diameters of target lesions, taking as reference smallest sum on study (this included the baseline sum if that was the smallest on study). In addition to relative increase of 20%, sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered progression. CR: complete disappearance of all target lesions with exception of nodal disease and complete disappearance of non-target lesions and normalization of tumor marker level. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR: a \>= 30 % decrease in sum of diameters of target lesions, taking as reference the baseline sum of diameters. 90% exact CI was based on Clopper-Pearson method.

Time frame: From the first documented objective response until the first documentation of PD or death, whichever occurred first (up to 19.9 months)

Population: The response evaluable set included all participants who met all following criteria- had measurable disease at baseline, received any amount of study treatment, and had at least one post-baseline disease assessment or discontinued due to clinical progression, toxicity or death. Here, 'Overall Number of Participants Analyzed' signifies number of participants evaluable for the outcome measure.

DOR was defined as time from first documented objective response (CR or PR that was subsequently confirmed) to first documented PD per RECIST v1.1 or death due to any cause, whichever occurred first. PD: at least a 20 % increase in sum of diameters of target lesions, taking as reference smallest sum on study (this included the baseline sum if that was the smallest on study). In addition to relative increase of 20%, sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered progression. CR: complete disappearance of all target lesions with exception of nodal disease and complete disappearance of non-target lesions and normalization of tumor marker level. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR: a \>= 30 % decrease in sum of diameters of target lesions, taking as reference the baseline sum of diameters. 90% exact CI was based on Clopper-Pearson method.

Time frame: From the first documented objective response until the first documentation of PD or death due to any cause, whichever occurred first (up to 18.1 months)

Population: The response evaluable set included all participants who met all following criteria: had measurable disease at baseline, received any amount of study treatment, and had at least one post-baseline disease assessment or discontinued due to clinical progression, toxicity or death. Here, 'Overall Number of Participants Analyzed' signifies number of participants evaluable for the outcome measure.

PK parameters were determined using noncompartmental analysis.

Time frame: Predose, 1 hour intra-dose, end of dose, 1, 2, 4, 6 hours after end of 2 hour oxaliplatin infusion (8 hours) on Day 1 of Cycle 1 and 2

Population: The PK analysis set included all participants in the safety set from whom at least one PK assessment was reported. Here, 'Overall Number of Participants Analyzed' signifies number of participants evaluable for the outcome measure.

An SAE was any untoward medical occurrence at any dose that was fatal; life-threatening; required hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity; was a congenital anomaly/birth defect or was medically significant.

Time frame: From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment, end of study date, death date, or data cutoff date, whichever was earlier (maximum of 38.2 months)

Population: The safety analysis set included all participants who were enrolled in the study and received any amount of study treatment.

An SAE was any untoward medical occurrence at any dose that was fatal; life-threatening; required hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity; was a congenital anomaly/birth defect or was medically significant. Treatment related SAEs were SAEs related to any study treatment and relatedness was judged by investigator.

Time frame: From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment, end of study date, death date, or data cutoff date, whichever was earlier (maximum of 38.2 months)

Population: The safety analysis set included all participants who were enrolled in the study and received any amount of study treatment.

Vital signs included temperature, blood pressure, heart rate and respiratory rate. Clinically significant vital signs were defined as: temperature \>= 38 degrees Celsius, respiratory rate \> 20 breaths per minute, SBP \>= 120 mmHg or DBP \>= 80 mmHg, SBP \>= 140 mmHg or DBP \>= 90 mmHg and heart rate \> 100 bpm.

Time frame: From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment, end of study date, death date, or data cutoff date, whichever was earlier (maximum of 38.2 months)

Population: The safety analysis set included all participants who were enrolled in the study and received any amount of study treatment.

An AE was defined was any untoward medical occurrence in a clinical investigational participant administered a medicinal product and which did not necessarily have a causal relationship with this treatment. TEAE was defined as a newly occurring or worsening AE after the first dose of study treatment (tucatinib, trastuzumab, leucovorin, fluorouracil and oxaliplatin) through 30 days after the last dose of study treatment. TEAEs were graded according to NCI-CTCAE v 5.0 where grade 1= mild, grade 2= moderate, grade 3= severe and grade 4= life-threatening. Number of participants with \>= grade 3 TEAEs are reported in this outcome measure.

Time frame: From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment, end of study date, death date, or data cutoff date, whichever was earlier (maximum of 38.2 months)

Population: The safety analysis set included all participants who were enrolled in the study and received any amount of study treatment.

An AE was defined was any untoward medical occurrence in a clinical investigational participant administered a medicinal product and which did not necessarily have a causal relationship with this treatment. TEAE was defined as a newly occurring or worsening AE after the first dose of study treatment (tucatinib, trastuzumab, leucovorin, fluorouracil and oxaliplatin) through 30 days after the last dose of study treatment. TEAEs were graded according to NCI-CTCAE v 5.0 where grade 1= mild, grade 2= moderate, grade 3= severe and grade 4= life-threatening. Treatment related TEAEs were AEs related to study treatment and relatedness was judged by investigator. Number of participants with \>= grade 3 treatment related TEAEs are reported in this outcome measure.

Time frame: From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment, end of study date, death date, or data cutoff date, whichever was earlier (maximum of 38.2 months)

Population: The safety analysis set included all participants who were enrolled in the study and received any amount of study treatment.

An AE was defined as any untoward medical occurrence in a clinical investigational participant administered a medicinal product and which did not necessarily have a causal relationship with this treatment. TEAE was defined as a newly occurring or worsening AE after the first dose of study treatment (tucatinib, trastuzumab, leucovorin, fluorouracil and oxaliplatin) through 30 days after the last 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, end of study date, death date, or data cutoff date, whichever was earlier (maximum of 38.2 months)

Population: The safety analysis set included all participants who were enrolled in the study and received any amount of study treatment.

Following chemistry parameters were assessed: ALT increased, albumin decreased, alkaline phosphatase increased, AST increased, calcium corrected for albumin decreased, calcium corrected for albumin increased, creatinine increased, Cystatin C increased, GFR estimated decreased, lactate dehydrogenase increased, potassium decreased, potassium increased, sodium decreased and total bilirubin increased. TEAE was defined as a newly occurring or worsening AE after the first dose of study treatment (tucatinib, trastuzumab, leucovorin, fluorouracil and oxaliplatin) through 30 days after the last dose of study treatment. Chemistry laboratory abnormalities were graded according to NCI CTCAE v 5.0 grade 1= mild, grade 2= moderate, grade 3= severe and grade 4= life-threatening. Participants with chemistry abnormalities of any grade were reported.

Time frame: From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment, end of study date, death date, or data cutoff date, whichever was earlier (maximum of 38.2 months)

Population: The safety analysis set included all participants who were enrolled in the study and received any amount of study treatment. Here, 'Number Analyzed' signifies number of participants evaluable for the specified rows.

Following hematological parameters were assessed: hemoglobin decreased, leukocytes decreased, lymphocytes decreased, neutrophils decreased and platelets decreased. TEAE was defined as a newly occurring or worsening AE after the first dose of study treatment (tucatinib, trastuzumab, leucovorin, fluorouracil and oxaliplatin) through 30 days after the last dose of study treatment. Hematological laboratory abnormalities were graded according to NCI CTCAE v 5.0; where, grade 1= mild, grade 2= moderate, grade 3= severe and grade 4= life-threatening. Participants with hematological abnormalities of any grade were reported.

Time frame: From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment, end of study date, death date, or data cutoff date, whichever was earlier (maximum of 38.2 months)

Population: The safety analysis set included all participants who were enrolled in the study and received any amount of study treatment.

An AE was defined was any untoward medical occurrence in a clinical investigational participant administered a medicinal product and which did not necessarily have a causal relationship with this treatment. TEAE was defined as a newly occurring or worsening AE after the first dose of study treatment (tucatinib, trastuzumab, leucovorin, fluorouracil and oxaliplatin) through 30 days after the last dose of study treatment. Treatment related TEAEs were AEs related to study treatment and relatedness was judged by investigator.

Time frame: From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment, end of study date, death date, or data cutoff date, whichever was earlier (maximum of 38.2 months)

Population: The safety analysis set included all participants who were enrolled in the study and received any amount of study treatment.

ORR was defined as percentage of participants with confirmed complete response (CR)/ partial response (PR) per investigator according to response evaluation criteria in solid tumors version 1.1 (RECIST) v1.1. For response to be considered confirmed, subsequent response had to be at least 4 weeks after initial response. CR: complete disappearance of all target lesions with exception of nodal disease and complete disappearance of non-target lesions and normalization of tumor marker level. Any pathological lymph nodes(whether target/ non-target) must have reduction in short axis to \<10 mm. PR: \>= 30% decrease in sum of diameters of target lesions, taking as reference baseline sum of diameters. 90% exact confidence interval (CI) was based on Clopper-Pearson method.

Time frame: From the first dose of study treatment until the first documented CR or PR or before start of any new anti-cancer therapy (up to 24.1 months)

Population: The response evaluable set included all participants who met all following criteria: had measurable disease at baseline, received any amount of study treatment, and had at least one post-baseline disease assessment or discontinued due to clinical progression, toxicity or death.

PK parameters were determined using noncompartmental analysis.

Time frame: Predose on Day 1 of Cycle 2

Population: The PK analysis set included all participants in the safety set from whom at least one PK assessment was reported. Here, 'Overall Number of Participants Analyzed' signifies number of participants evaluable for the outcome measure.

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 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 had their survival time censored on date of treatment initiation.

Time frame: From date of start of study treatment until date of death or censoring date

Population: The FAS included all participants who were enrolled in the study and receive any amount of study treatment.

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 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 had their survival time censored on date of treatment initiation.

Time frame: From date of start of study treatment until date of death or censoring date

Population: The full analysis set included all participants who were enrolled in the study and receive any amount of study treatment.

PFS as per INV was defined as time from the date of treatment initiation to date of documented PD as assessed by INV per RECIST version 1.1 or death from any cause, whichever occurred first. Participants without documentation of progression or death at the time of analysis were censored at the date of the last disease assessment. PD: at least 20 % increase in sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to relative increase of 20%, sum must also demonstrate an absolute increase of at least 5 mm. Appearance of one or more new lesions was also considered progression.

Time frame: From the first dose of study treatment until the first documented PD or death from any cause or censoring date, whichever occurred first (up to 20.9 months)

Population: The FAS included all participants who were enrolled in the study and receive any amount of study treatment.

PFS as per INV was defined as time from the date of treatment initiation to date of documented PD as assessed by INV per RECIST version 1.1 or death from any cause, whichever occurred first. Participants without documentation of progression or death at the time of analysis were censored at the date of the last disease assessment. PD: at least 20 % increase in sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to relative increase of 20%, sum must also demonstrate an absolute increase of at least 5 mm. Appearance of one or more new lesions was also considered progression.

Time frame: From the first dose of study treatment until the first documented PD or death from any cause or censoring date, whichever occurred first (up to 24.1 months)

Population: The full analysis set (FAS) included all participants who were enrolled in the study and receive any amount of study treatment.

PK parameters were determined using noncompartmental analysis.

Time frame: Predose, 1 hour intra-dose, end of dose, 1, 2, 4, 6 hours after end of 2 hour oxaliplatin infusion (8 hours) on Day 1 of Cycle 1 and 2

Population: The PK analysis set included all participants in the safety set from whom at least one PK assessment was reported. Here, 'Overall Number of Participants Analyzed' signifies number of participants evaluable for the outcome measure.

PK parameters were determined using noncompartmental analysis.

Time frame: Predose, 1 hour intra-dose, end of dose, 1, 2, 4, 6 hours after end of 2 hour oxaliplatin infusion (8 hours) on Day 1 of Cycle 1 and 2

Population: The PK analysis set included all participants in the safety set from whom at least one PK assessment was reported. Here, 'Overall Number of Participants Analyzed' signifies number of participants evaluable for the outcome measure.