Trial Outcomes & Findings for Tucatinib, Trastuzumab, Ramucirumab, and Paclitaxel Versus Paclitaxel and Ramucirumab in Previously Treated HER2+ Gastroesophageal Cancer (NCT NCT04499924)

Last Updated: 2025-01-22

Results Overview

DLTs were adverse events (AEs), laboratory abnormalities, or treatment modifications that occurred during the first cycle of treatment in the Phase 2 paclitaxel dose optimization stage that were related to paclitaxel, to tucatinib, or to the combination of tucatinib, trastuzumab, ramucirumab and paclitaxel and that met any of the study protocol specified criteria. The relationship of AEs to study drugs was determined by the investigator. AEs that were attributed only to trastuzumab and/or ramucirumab, but not tucatinib or paclitaxel were not considered DLTs.

Recruitment status

COMPLETED

Study phase

PHASE2/PHASE3

Target enrollment

17 participants

Primary outcome timeframe

Cycle 1 (28 days)

Results posted on

2025-01-22

Participant Flow

Participants with locally-advanced unresectable or metastatic human epidermal growth factor receptor 2 positive (HER2+) gastric or gastroesophageal junction adenocarcinoma (GEC) who had received prior treatment with a HER2-directed antibody, and had received 1 prior line of therapy in the advanced disease setting were included in the study. A total of 17 participants were enrolled and treated in the study.

"Study termination by sponsor" was used as an end of study reason because long-term follow-up was discontinued following the decision to close enrollment. The study status is listed as completed as participants were permitted to receive treatment until they met protocol defined reasons to stop. After treatment discontinuation, participants were followed through the duration of the safety reporting period, and then ended study as no further disease or survival follow-up was required.

Participant milestones

Participant milestones
Measure	Paclitaxel 60 mg/m^2 Participants received paclitaxel 60 milligram per meter square (mg/m\^2) intravenously (IV) on Days 1, 8, and 15 of each 28-day cycle, in combination with tucatinib 300 mg orally twice daily (BID), trastuzumab 6 milligram per kilogram (mg/kg) IV loading dose on Cycle 1 Day 1, 4 mg/kg IV dose on Cycle 1 Day 15 and on Days 1 and 15 of each Cycle thereafter, and ramucirumab 8 mg/kg IV on Days 1 and 15. Participants received treatment until unacceptable toxicity, disease progression, withdrawal of consent, or study closure.	Paclitaxel 80 mg/m^2 Participants received paclitaxel 80 mg/m\^2 IV on Days 1, 8, and 15 of each 28-day Cycle, in combination with tucatinib 300 mg orally BID, trastuzumab 6 mg/kg IV loading dose on Cycle 1 Day 1, 4 mg/kg IV dose on Cycle 1 Day 15 and on Days 1 and 15 of each Cycle thereafter, and ramucirumab 8 mg/kg IV on Days 1 and 15. Participants received treatment until unacceptable toxicity, disease progression, withdrawal of consent, or study closure.
Overall Study STARTED	8	9
Overall Study COMPLETED	3	0
Overall Study NOT COMPLETED	5	9

Reasons for withdrawal

Reasons for withdrawal
Measure	Paclitaxel 60 mg/m^2 Participants received paclitaxel 60 milligram per meter square (mg/m\^2) intravenously (IV) on Days 1, 8, and 15 of each 28-day cycle, in combination with tucatinib 300 mg orally twice daily (BID), trastuzumab 6 milligram per kilogram (mg/kg) IV loading dose on Cycle 1 Day 1, 4 mg/kg IV dose on Cycle 1 Day 15 and on Days 1 and 15 of each Cycle thereafter, and ramucirumab 8 mg/kg IV on Days 1 and 15. Participants received treatment until unacceptable toxicity, disease progression, withdrawal of consent, or study closure.	Paclitaxel 80 mg/m^2 Participants received paclitaxel 80 mg/m\^2 IV on Days 1, 8, and 15 of each 28-day Cycle, in combination with tucatinib 300 mg orally BID, trastuzumab 6 mg/kg IV loading dose on Cycle 1 Day 1, 4 mg/kg IV dose on Cycle 1 Day 15 and on Days 1 and 15 of each Cycle thereafter, and ramucirumab 8 mg/kg IV on Days 1 and 15. Participants received treatment until unacceptable toxicity, disease progression, withdrawal of consent, or study closure.
Overall Study Study termination by sponsor	4	6
Overall Study Withdrawal by Subject	1	3

Baseline Characteristics

Tucatinib, Trastuzumab, Ramucirumab, and Paclitaxel Versus Paclitaxel and Ramucirumab in Previously Treated HER2+ Gastroesophageal Cancer

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Paclitaxel 60 mg/m^2 n=8 Participants Participants received paclitaxel 60 milligram per meter square (mg/m\^2) intravenously (IV) on Days 1, 8, and 15 of each 28-day cycle, in combination with tucatinib 300 mg orally twice daily (BID), trastuzumab 6 milligram per kilogram (mg/kg) IV loading dose on Cycle 1 Day 1, 4 mg/kg IV dose on Cycle 1 Day 15 and on Days 1 and 15 of each Cycle thereafter, and ramucirumab 8 mg/kg IV on Days 1 and 15. Participants received treatment until unacceptable toxicity, disease progression, withdrawal of consent, or study closure.	Paclitaxel 80 mg/m^2 n=9 Participants Participants received paclitaxel 80 mg/m\^2 IV on Days 1, 8, and 15 of each 28-day Cycle, in combination with tucatinib 300 mg orally BID, trastuzumab 6 mg/kg IV loading dose on Cycle 1 Day 1, 4 mg/kg IV dose on Cycle 1 Day 15 and on Days 1 and 15 of each Cycle thereafter, and ramucirumab 8 mg/kg IV on Days 1 and 15. Participants received treatment until unacceptable toxicity, disease progression, withdrawal of consent, or study closure.	Total n=17 Participants Total of all reporting groups
Age, Continuous	53.6 Years STANDARD_DEVIATION 9.5 • n=99 Participants	57.6 Years STANDARD_DEVIATION 8.9 • n=107 Participants	55.7 Years STANDARD_DEVIATION 9.2 • n=206 Participants
Sex: Female, Male Female	0 Participants n=99 Participants	1 Participants n=107 Participants	1 Participants n=206 Participants
Sex: Female, Male Male	8 Participants n=99 Participants	8 Participants n=107 Participants	16 Participants n=206 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	8 Participants n=99 Participants	9 Participants n=107 Participants	17 Participants n=206 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants
Race (NIH/OMB) Asian	5 Participants n=99 Participants	4 Participants n=107 Participants	9 Participants n=206 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants
Race (NIH/OMB) Black or African American	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants
Race (NIH/OMB) White	3 Participants n=99 Participants	5 Participants n=107 Participants	8 Participants n=206 Participants
Race (NIH/OMB) More than one race	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants

PRIMARY outcome

Timeframe: Cycle 1 (28 days)

Population: The safety analysis set included all participants who received any amount of any study drug. Participants were considered evaluable for DLT if they received at least 75 percent (%) of the planned administrations of each study drug and were followed for at least 1 cycle or if they experienced a DLT during the first cycle.

Outcome measures

Outcome measures
Measure	Paclitaxel 60 mg/m^2 n=8 Participants Participants received paclitaxel 60 milligram per meter square (mg/m\^2) intravenously (IV) on Days 1, 8, and 15 of each 28-day cycle, in combination with tucatinib 300 mg orally twice daily (BID), trastuzumab 6 milligram per kilogram (mg/kg) IV loading dose on Cycle 1 Day 1, 4 mg/kg IV dose on Cycle 1 Day 15 and on Days 1 and 15 of each Cycle thereafter, and ramucirumab 8 mg/kg IV on Days 1 and 15. Participants received treatment until unacceptable toxicity, disease progression, withdrawal of consent, or study closure.	Paclitaxel 80 mg/m^2 n=9 Participants Participants received paclitaxel 80 mg/m\^2 IV on Days 1, 8, and 15 of each 28-day Cycle, in combination with tucatinib 300 mg orally BID, trastuzumab 6 mg/kg IV loading dose on Cycle 1 Day 1, 4 mg/kg IV dose on Cycle 1 Day 15 and on Days 1 and 15 of each Cycle thereafter, and ramucirumab 8 mg/kg IV on Days 1 and 15. Participants received treatment until unacceptable toxicity, disease progression, withdrawal of consent, or study closure.
Number of Participants With Dose-limiting Toxicities (DLT) During the First Cycle of Treatment	0 Participants	2 Participants

PRIMARY outcome

Timeframe: From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment (maximum treatment duration= 19.8 months, maximum follow-up duration up to 20.8 months)

Population: The safety analysis set included all participants who received any amount of any study drug.

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. AEs were defined as treatment emergent if they were newly occurring or worsened following study treatment. A TEAE was defined as a newly occurring or worsening AE after the first dose of study treatment (tucatinib, trastuzumab, ramucirumab, or paclitaxel) and up to 30 days after the last dose of study treatment (tucatinib, trastuzumab, ramucirumab, or paclitaxel, whichever was later).

Outcome measures

Outcome measures
Measure	Paclitaxel 60 mg/m^2 n=8 Participants Participants received paclitaxel 60 milligram per meter square (mg/m\^2) intravenously (IV) on Days 1, 8, and 15 of each 28-day cycle, in combination with tucatinib 300 mg orally twice daily (BID), trastuzumab 6 milligram per kilogram (mg/kg) IV loading dose on Cycle 1 Day 1, 4 mg/kg IV dose on Cycle 1 Day 15 and on Days 1 and 15 of each Cycle thereafter, and ramucirumab 8 mg/kg IV on Days 1 and 15. Participants received treatment until unacceptable toxicity, disease progression, withdrawal of consent, or study closure.	Paclitaxel 80 mg/m^2 n=9 Participants Participants received paclitaxel 80 mg/m\^2 IV on Days 1, 8, and 15 of each 28-day Cycle, in combination with tucatinib 300 mg orally BID, trastuzumab 6 mg/kg IV loading dose on Cycle 1 Day 1, 4 mg/kg IV dose on Cycle 1 Day 15 and on Days 1 and 15 of each Cycle thereafter, and ramucirumab 8 mg/kg IV on Days 1 and 15. Participants received treatment until unacceptable toxicity, disease progression, withdrawal of consent, or study closure.
Number of Participants With Treatment-emergent Adverse Events (TEAEs)	8 Participants	9 Participants

PRIMARY outcome

Timeframe: From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment (maximum treatment duration= 19.8 months, maximum follow-up duration up to 20.8 months)

Population: The safety analysis set included all participants who received any amount of any study drug. Here, 'Number Analyzed' signifies participants evaluable for the specified rows.

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. Laboratory abnormalities included: 1) Blood chemistry: alanine aminotransferase increased, albumin decreased, alkaline phosphatase increased, aspartate aminotransferase increased, calcium corrected for albumin decreased, calcium corrected for albumin increased, creatinine increased, glomerular filtration rate estimated decreased, glucose decreased, lactate dehydrogenase increased, magnesium decreased, magnesium increased, potassium decreased, potassium increased, sodium decreased, sodium increased, and total bilirubin increased; 2) Hematological: hemoglobin decreased, leukocytes decreased, lymphocytes decreased, neutrophils decreased, and platelets decreased.

Outcome measures

Outcome measures
Measure	Paclitaxel 60 mg/m^2 n=8 Participants Participants received paclitaxel 60 milligram per meter square (mg/m\^2) intravenously (IV) on Days 1, 8, and 15 of each 28-day cycle, in combination with tucatinib 300 mg orally twice daily (BID), trastuzumab 6 milligram per kilogram (mg/kg) IV loading dose on Cycle 1 Day 1, 4 mg/kg IV dose on Cycle 1 Day 15 and on Days 1 and 15 of each Cycle thereafter, and ramucirumab 8 mg/kg IV on Days 1 and 15. Participants received treatment until unacceptable toxicity, disease progression, withdrawal of consent, or study closure.	Paclitaxel 80 mg/m^2 n=9 Participants Participants received paclitaxel 80 mg/m\^2 IV on Days 1, 8, and 15 of each 28-day Cycle, in combination with tucatinib 300 mg orally BID, trastuzumab 6 mg/kg IV loading dose on Cycle 1 Day 1, 4 mg/kg IV dose on Cycle 1 Day 15 and on Days 1 and 15 of each Cycle thereafter, and ramucirumab 8 mg/kg IV on Days 1 and 15. Participants received treatment until unacceptable toxicity, disease progression, withdrawal of consent, or study closure.
Number of Participants With Treatment-emergent Laboratory Abnormalities Neutrophils decreased	5 Participants	7 Participants
Number of Participants With Treatment-emergent Laboratory Abnormalities Platelets decreased	1 Participants	7 Participants
Number of Participants With Treatment-emergent Laboratory Abnormalities Aspartate aminotransferase increased	6 Participants	4 Participants
Number of Participants With Treatment-emergent Laboratory Abnormalities Lactate dehydrogenase increased	1 Participants	5 Participants
Number of Participants With Treatment-emergent Laboratory Abnormalities Magnesium increased	0 Participants	1 Participants
Number of Participants With Treatment-emergent Laboratory Abnormalities Potassium decreased	1 Participants	6 Participants
Number of Participants With Treatment-emergent Laboratory Abnormalities Potassium increased	1 Participants	0 Participants
Number of Participants With Treatment-emergent Laboratory Abnormalities Sodium decreased	2 Participants	4 Participants
Number of Participants With Treatment-emergent Laboratory Abnormalities Sodium increased	1 Participants	1 Participants
Number of Participants With Treatment-emergent Laboratory Abnormalities Albumin decreased	4 Participants	4 Participants
Number of Participants With Treatment-emergent Laboratory Abnormalities Hemoglobin decreased	3 Participants	7 Participants
Number of Participants With Treatment-emergent Laboratory Abnormalities Leukocytes decreased	4 Participants	9 Participants
Number of Participants With Treatment-emergent Laboratory Abnormalities Lymphocytes decreased	2 Participants	8 Participants
Number of Participants With Treatment-emergent Laboratory Abnormalities Alanine aminotransferase increased	5 Participants	5 Participants
Number of Participants With Treatment-emergent Laboratory Abnormalities Alkaline phosphatase increased	2 Participants	0 Participants
Number of Participants With Treatment-emergent Laboratory Abnormalities Calcium corrected for albumin decreased	1 Participants	5 Participants
Number of Participants With Treatment-emergent Laboratory Abnormalities Calcium corrected for albumin increased	0 Participants	2 Participants
Number of Participants With Treatment-emergent Laboratory Abnormalities Creatinine increased	3 Participants	2 Participants
Number of Participants With Treatment-emergent Laboratory Abnormalities Glomerular filtration rate, estimated decreased	0 Participants	1 Participants
Number of Participants With Treatment-emergent Laboratory Abnormalities Glucose decreased	1 Participants	2 Participants
Number of Participants With Treatment-emergent Laboratory Abnormalities Magnesium decreased	0 Participants	7 Participants
Number of Participants With Treatment-emergent Laboratory Abnormalities Total bilirubin increased	3 Participants	2 Participants

PRIMARY outcome

Timeframe: From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment (maximum treatment duration= 19.8 months, maximum follow-up duration up to 20.8 months)

Population: The safety analysis set included all participants who received any amount of any study drug.

Vital sign examinations included systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate. Criteria: SBP greater than or equal to (\>=) 120 millimeters of mercury (mm Hg) or DBP \>= 80 mm Hg; SBP \>= 140 mm Hg or DBP \>= 90 mm Hg; SBP \>= 160 mm Hg or DBP \>= 100 mm Hg), heart rate greater than (\>) 100 beats per minute (min). Clinical significance in vital signs abnormalities was judged by investigator. In this outcome measure number of participants with at least 1 clinically significant abnormality in any vital sign are reported.

Outcome measures

Outcome measures
Measure	Paclitaxel 60 mg/m^2 n=8 Participants Participants received paclitaxel 60 milligram per meter square (mg/m\^2) intravenously (IV) on Days 1, 8, and 15 of each 28-day cycle, in combination with tucatinib 300 mg orally twice daily (BID), trastuzumab 6 milligram per kilogram (mg/kg) IV loading dose on Cycle 1 Day 1, 4 mg/kg IV dose on Cycle 1 Day 15 and on Days 1 and 15 of each Cycle thereafter, and ramucirumab 8 mg/kg IV on Days 1 and 15. Participants received treatment until unacceptable toxicity, disease progression, withdrawal of consent, or study closure.	Paclitaxel 80 mg/m^2 n=9 Participants Participants received paclitaxel 80 mg/m\^2 IV on Days 1, 8, and 15 of each 28-day Cycle, in combination with tucatinib 300 mg orally BID, trastuzumab 6 mg/kg IV loading dose on Cycle 1 Day 1, 4 mg/kg IV dose on Cycle 1 Day 15 and on Days 1 and 15 of each Cycle thereafter, and ramucirumab 8 mg/kg IV on Days 1 and 15. Participants received treatment until unacceptable toxicity, disease progression, withdrawal of consent, or study closure.
Number of Participants With Clinically Significant Vital Signs Values SBP >= 120 mm Hg or DBP >= 80 mm Hg	8 Participants	9 Participants
Number of Participants With Clinically Significant Vital Signs Values Heart rate > 100 beats per min	1 Participants	4 Participants
Number of Participants With Clinically Significant Vital Signs Values SBP >= 140 mm Hg or DBP >= 90 mm Hg	7 Participants	9 Participants
Number of Participants With Clinically Significant Vital Signs Values SBP >= 160 mm Hg or DBP >= 100 mm Hg	2 Participants	3 Participants

PRIMARY outcome

Timeframe: From Baseline (Day 1) up to 30 days after the last dose of study treatment (maximum treatment duration= 19.8 months, maximum follow-up duration up to 20.8 months)

Population: The safety analysis set included all participants who received any amount of any study drug.

Maximum percentage decrease from baseline in weight is reported in this outcome measure.

Outcome measures

Outcome measures
Measure	Paclitaxel 60 mg/m^2 n=8 Participants Participants received paclitaxel 60 milligram per meter square (mg/m\^2) intravenously (IV) on Days 1, 8, and 15 of each 28-day cycle, in combination with tucatinib 300 mg orally twice daily (BID), trastuzumab 6 milligram per kilogram (mg/kg) IV loading dose on Cycle 1 Day 1, 4 mg/kg IV dose on Cycle 1 Day 15 and on Days 1 and 15 of each Cycle thereafter, and ramucirumab 8 mg/kg IV on Days 1 and 15. Participants received treatment until unacceptable toxicity, disease progression, withdrawal of consent, or study closure.	Paclitaxel 80 mg/m^2 n=9 Participants Participants received paclitaxel 80 mg/m\^2 IV on Days 1, 8, and 15 of each 28-day Cycle, in combination with tucatinib 300 mg orally BID, trastuzumab 6 mg/kg IV loading dose on Cycle 1 Day 1, 4 mg/kg IV dose on Cycle 1 Day 15 and on Days 1 and 15 of each Cycle thereafter, and ramucirumab 8 mg/kg IV on Days 1 and 15. Participants received treatment until unacceptable toxicity, disease progression, withdrawal of consent, or study closure.
Maximum Percentage Change From Baseline in Weight	0.34 Percent Change Interval -4.3 to 9.9	6.21 Percent Change Interval -4.8 to 21.0

PRIMARY outcome

Timeframe: From first dose of the study treatment (Day 1) up to the last dose of study treatment (maximum treatment duration up to 19.8 months)

Population: The full analysis set included all participants who received any amount of any study drug.

Dose modification included dose hold, dose reduction, dose error and unplanned dose adjustments. Number of participants with any dose treatment modifications for paclitaxel, ramucirumab, trastuzumab, and tucatinib are reported in this outcome measure.

Outcome measures

Outcome measures
Measure	Paclitaxel 60 mg/m^2 n=8 Participants Participants received paclitaxel 60 milligram per meter square (mg/m\^2) intravenously (IV) on Days 1, 8, and 15 of each 28-day cycle, in combination with tucatinib 300 mg orally twice daily (BID), trastuzumab 6 milligram per kilogram (mg/kg) IV loading dose on Cycle 1 Day 1, 4 mg/kg IV dose on Cycle 1 Day 15 and on Days 1 and 15 of each Cycle thereafter, and ramucirumab 8 mg/kg IV on Days 1 and 15. Participants received treatment until unacceptable toxicity, disease progression, withdrawal of consent, or study closure.	Paclitaxel 80 mg/m^2 n=9 Participants Participants received paclitaxel 80 mg/m\^2 IV on Days 1, 8, and 15 of each 28-day Cycle, in combination with tucatinib 300 mg orally BID, trastuzumab 6 mg/kg IV loading dose on Cycle 1 Day 1, 4 mg/kg IV dose on Cycle 1 Day 15 and on Days 1 and 15 of each Cycle thereafter, and ramucirumab 8 mg/kg IV on Days 1 and 15. Participants received treatment until unacceptable toxicity, disease progression, withdrawal of consent, or study closure.
Number of Participants With Any Dose Modifications Trastuzumab	7 Participants	8 Participants
Number of Participants With Any Dose Modifications Tucatinib	6 Participants	8 Participants
Number of Participants With Any Dose Modifications Paclitaxel	7 Participants	9 Participants
Number of Participants With Any Dose Modifications Ramucirumab	7 Participants	8 Participants

SECONDARY outcome

Timeframe: 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 19.8 months)

Population: The response evaluable analysis set included all participants who had baseline disease assessment, received study treatment, had post baseline disease assessment or discontinued treatment due to documented disease progression, clinical progression, AEs, or death.

ORR was defined as the percentage of participants with best overall response of complete response (CR) or partial response (PR) according to RECIST v 1.1 by investigator assessment. As per RECIST v1.1, CR was defined as disappearance of all target and non-target lesions and normalization of tumor markers. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to less than (\<) 10 millimeter (mm). PR was defined as at least a 30 % decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. As per RECIST v1.1, disease progression (PD) was defined as one of the following: at least a 20% increase in the sum of diameters of target lesions (taking as reference the smallest sum on study) with an absolute increase of at least 5mm, unequivocal progression of existing non-target lesions, or the appearance of one or more new lesions.

Outcome measures

Outcome measures
Measure	Paclitaxel 60 mg/m^2 n=8 Participants Participants received paclitaxel 60 milligram per meter square (mg/m\^2) intravenously (IV) on Days 1, 8, and 15 of each 28-day cycle, in combination with tucatinib 300 mg orally twice daily (BID), trastuzumab 6 milligram per kilogram (mg/kg) IV loading dose on Cycle 1 Day 1, 4 mg/kg IV dose on Cycle 1 Day 15 and on Days 1 and 15 of each Cycle thereafter, and ramucirumab 8 mg/kg IV on Days 1 and 15. Participants received treatment until unacceptable toxicity, disease progression, withdrawal of consent, or study closure.	Paclitaxel 80 mg/m^2 n=9 Participants Participants received paclitaxel 80 mg/m\^2 IV on Days 1, 8, and 15 of each 28-day Cycle, in combination with tucatinib 300 mg orally BID, trastuzumab 6 mg/kg IV loading dose on Cycle 1 Day 1, 4 mg/kg IV dose on Cycle 1 Day 15 and on Days 1 and 15 of each Cycle thereafter, and ramucirumab 8 mg/kg IV on Days 1 and 15. Participants received treatment until unacceptable toxicity, disease progression, withdrawal of consent, or study closure.
Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors (RECIST) Version (v) 1.1 By Investigator Assessment	50.0 Percentage of participants Interval 15.7 to 84.3	100.0 Percentage of participants Interval 66.4 to 100.0

SECONDARY outcome

Timeframe: From the first dose of study treatment until the first documented confirmed CR or PR or before the first documented PD or new anti-cancer therapies or death, whichever occurred first (up to 19.8 months)

Confirmed ORR was defined as the percentage of participants with best overall response of confirmed CR or PR according to RECIST v1.1 by investigator assessment. For a response to be confirmed, the subsequent response needs to be at least 4 weeks after the initial response. As per RECIST v1.1, CR was defined as disappearance of all target and non-target lesions and normalization of tumor markers. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \< 10 mm. PR was defined as at least a 30 % decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. As per RECIST v1.1, disease progression (PD) was defined as one of the following: at least a 20% increase in the sum of diameters of target lesions (taking as reference the smallest sum on study) with an absolute increase of at least 5mm, unequivocal progression of existing non-target lesions, or the appearance of one or more new lesions.

Outcome measures

Outcome measures
Measure	Paclitaxel 60 mg/m^2 n=8 Participants Participants received paclitaxel 60 milligram per meter square (mg/m\^2) intravenously (IV) on Days 1, 8, and 15 of each 28-day cycle, in combination with tucatinib 300 mg orally twice daily (BID), trastuzumab 6 milligram per kilogram (mg/kg) IV loading dose on Cycle 1 Day 1, 4 mg/kg IV dose on Cycle 1 Day 15 and on Days 1 and 15 of each Cycle thereafter, and ramucirumab 8 mg/kg IV on Days 1 and 15. Participants received treatment until unacceptable toxicity, disease progression, withdrawal of consent, or study closure.	Paclitaxel 80 mg/m^2 n=9 Participants Participants received paclitaxel 80 mg/m\^2 IV on Days 1, 8, and 15 of each 28-day Cycle, in combination with tucatinib 300 mg orally BID, trastuzumab 6 mg/kg IV loading dose on Cycle 1 Day 1, 4 mg/kg IV dose on Cycle 1 Day 15 and on Days 1 and 15 of each Cycle thereafter, and ramucirumab 8 mg/kg IV on Days 1 and 15. Participants received treatment until unacceptable toxicity, disease progression, withdrawal of consent, or study closure.
Confirmed ORR Per RECIST v1.1 By Investigator Assessment	37.5 Percentage of participants Interval 8.5 to 75.5	100.0 Percentage of participants Interval 66.4 to 100.0

SECONDARY outcome

Timeframe: From the date of first dose until the first documentation of PD or death or censoring date, whichever occurred first (up to 19.8 months)

PFS was defined as the time from the date of treatment initiation to the date of documented PD or death from any cause, whichever occurred first per RECIST version 1.1 by investigator assessment. As per RECIST v1.1, disease progression (PD) was defined as one of the following: at least a 20% increase in the sum of diameters (SOD) of target lesions (taking as reference the smallest sum on study) with an absolute increase of at least 5mm, unequivocal progression of existing non-target lesions, or the appearance of one or more new lesions. Participants without documentation of PD or death at the time of analysis were censored at the date of the last tumor assessment. Kaplan-Meier method was used for evaluation.

Outcome measures

Outcome measures
Measure	Paclitaxel 60 mg/m^2 n=8 Participants Participants received paclitaxel 60 milligram per meter square (mg/m\^2) intravenously (IV) on Days 1, 8, and 15 of each 28-day cycle, in combination with tucatinib 300 mg orally twice daily (BID), trastuzumab 6 milligram per kilogram (mg/kg) IV loading dose on Cycle 1 Day 1, 4 mg/kg IV dose on Cycle 1 Day 15 and on Days 1 and 15 of each Cycle thereafter, and ramucirumab 8 mg/kg IV on Days 1 and 15. Participants received treatment until unacceptable toxicity, disease progression, withdrawal of consent, or study closure.	Paclitaxel 80 mg/m^2 n=9 Participants Participants received paclitaxel 80 mg/m\^2 IV on Days 1, 8, and 15 of each 28-day Cycle, in combination with tucatinib 300 mg orally BID, trastuzumab 6 mg/kg IV loading dose on Cycle 1 Day 1, 4 mg/kg IV dose on Cycle 1 Day 15 and on Days 1 and 15 of each Cycle thereafter, and ramucirumab 8 mg/kg IV on Days 1 and 15. Participants received treatment until unacceptable toxicity, disease progression, withdrawal of consent, or study closure.
Progression-Free Survival (PFS) Per RECIST v1.1 By Investigator Assessment	4.1 Months Interval 1.5 to 12.5	12.2 Months Interval 7.0 to 14.4

SECONDARY outcome

Timeframe: From the first documented CR or PR until the first documentation of PD or death or censoring date, whichever occurred first (up to 19.8 months)

DOR: time from first documentation of objective response of CR or PR to first documentation of PD or death from any cause, whichever occurred first according to RECIST v1.1 by investigator assessment. As per RECIST v1.1, CR: disappearance of all target and non-target lesions and normalization of tumor markers. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10mm. PR: at least a 30% decrease in sum of diameters of target lesions, taking as reference baseline sum diameters. PD was defined as one of the following: at least a 20% increase in sum of diameters of target lesions (taking as reference the smallest sum on study) with an absolute increase of at least 5mm, unequivocal progression of existing non-target lesions, or appearance of one or more new lesions. Participants without documentation of PD or death at time of analysis were censored at the date of last tumor assessment. Kaplan-Meier method was used for evaluation.

Outcome measures

Outcome measures
Measure	Paclitaxel 60 mg/m^2 n=4 Participants Participants received paclitaxel 60 milligram per meter square (mg/m\^2) intravenously (IV) on Days 1, 8, and 15 of each 28-day cycle, in combination with tucatinib 300 mg orally twice daily (BID), trastuzumab 6 milligram per kilogram (mg/kg) IV loading dose on Cycle 1 Day 1, 4 mg/kg IV dose on Cycle 1 Day 15 and on Days 1 and 15 of each Cycle thereafter, and ramucirumab 8 mg/kg IV on Days 1 and 15. Participants received treatment until unacceptable toxicity, disease progression, withdrawal of consent, or study closure.	Paclitaxel 80 mg/m^2 n=9 Participants Participants received paclitaxel 80 mg/m\^2 IV on Days 1, 8, and 15 of each 28-day Cycle, in combination with tucatinib 300 mg orally BID, trastuzumab 6 mg/kg IV loading dose on Cycle 1 Day 1, 4 mg/kg IV dose on Cycle 1 Day 15 and on Days 1 and 15 of each Cycle thereafter, and ramucirumab 8 mg/kg IV on Days 1 and 15. Participants received treatment until unacceptable toxicity, disease progression, withdrawal of consent, or study closure.
Duration of Response (DOR) Per RECIST v1.1 By Investigator Assessment	10.6 Months Interval 2.8 to Upper limit of 95% CI could not be estimated due to insufficient number of participants with event.	11.0 Months Interval 2.9 to 12.9

SECONDARY outcome

Timeframe: From the first dose study treatment until PD or death, whichever occurred first (up to 19.8 months)

DCR was defined as percentage of participants with CR, PR, or stable disease (SD or non-CR/non-progressive disease) according to RECIST v1.1 by investigator assessment. As per RECIST v1.1, CR was defined as disappearance of all target and non-target lesions and normalization of tumor markers. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \< 10 mm. PR was defined as at least a 30 % decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters. PD was defined as one of following: at least a 20% increase in the sum of diameters of target lesions (taking as reference the smallest sum on study) with an absolute increase of at least 5mm, unequivocal progression of existing non-target lesions, or appearance of one or more new lesions. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference smallest sum of diameters.

Outcome measures

Outcome measures
Measure	Paclitaxel 60 mg/m^2 n=8 Participants Participants received paclitaxel 60 milligram per meter square (mg/m\^2) intravenously (IV) on Days 1, 8, and 15 of each 28-day cycle, in combination with tucatinib 300 mg orally twice daily (BID), trastuzumab 6 milligram per kilogram (mg/kg) IV loading dose on Cycle 1 Day 1, 4 mg/kg IV dose on Cycle 1 Day 15 and on Days 1 and 15 of each Cycle thereafter, and ramucirumab 8 mg/kg IV on Days 1 and 15. Participants received treatment until unacceptable toxicity, disease progression, withdrawal of consent, or study closure.	Paclitaxel 80 mg/m^2 n=9 Participants Participants received paclitaxel 80 mg/m\^2 IV on Days 1, 8, and 15 of each 28-day Cycle, in combination with tucatinib 300 mg orally BID, trastuzumab 6 mg/kg IV loading dose on Cycle 1 Day 1, 4 mg/kg IV dose on Cycle 1 Day 15 and on Days 1 and 15 of each Cycle thereafter, and ramucirumab 8 mg/kg IV on Days 1 and 15. Participants received treatment until unacceptable toxicity, disease progression, withdrawal of consent, or study closure.
Disease Control Rate (DCR) Per RECIST v1.1 By Investigator Assessment	87.5 Percentage of participants Interval 47.3 to 99.7	100.0 Percentage of participants Interval 66.4 to 100.0

SECONDARY outcome

Timeframe: Tucatinib and ONT-993- Cycle 1 Day 8, Cycle 2 Day 1: Pre-dose, 2, 4, 6, 8 hours post-dose; Paclitaxel and its metabolites- Cycle 1 Days 1 and 8, Cycle 2 Day 1: Pre-dose, 2, 4, 6, 8 hours post-dose (each cycle length=28 days)

Population: The pharmacokinetics (PK) analysis set included participants in the full analysis set who received at least one dose of tucatinib or paclitaxel and have at least one evaluable PK assessment. All participants reported under "Number of Participants Analyzed" contributed data to the table; however, may not have evaluable data for every row. Here, "Number Analyzed" signifies participants evaluable for the specified rows.

AUClast was reported for tucatinib, tucatinib metabolite (ONT-993), paclitaxel and paclitaxel metabolites (6 alpha-hydroxy-paclitaxel, 3'-p-hydroxy-paclitaxel and 6 alpha-3'-p-Dihydroxy-paclitaxel).

Outcome measures

SECONDARY outcome

Timeframe: Tucatinib and ONT-993- Cycle 1 Day 8, Cycle 2 Day 1: Pre-dose, 2, 4, 6, 8 hours post-dose (each cycle length=28 days)

Population: The PK analysis set included participants in the full analysis set who received at least one dose of tucatinib or paclitaxel and have at least one evaluable PK assessment. All participants reported under "Number of Participants Analyzed" contributed data to the table; however, may not have evaluable data for every row. Here, "Number Analyzed" signifies participants evaluable for the specified rows.

Cmax was reported for tucatinib and tucatinib metabolite ONT-993.

Outcome measures

Outcome measures
Measure	Paclitaxel 60 mg/m^2 n=8 Participants Participants received paclitaxel 60 milligram per meter square (mg/m\^2) intravenously (IV) on Days 1, 8, and 15 of each 28-day cycle, in combination with tucatinib 300 mg orally twice daily (BID), trastuzumab 6 milligram per kilogram (mg/kg) IV loading dose on Cycle 1 Day 1, 4 mg/kg IV dose on Cycle 1 Day 15 and on Days 1 and 15 of each Cycle thereafter, and ramucirumab 8 mg/kg IV on Days 1 and 15. Participants received treatment until unacceptable toxicity, disease progression, withdrawal of consent, or study closure.	Paclitaxel 80 mg/m^2 n=9 Participants Participants received paclitaxel 80 mg/m\^2 IV on Days 1, 8, and 15 of each 28-day Cycle, in combination with tucatinib 300 mg orally BID, trastuzumab 6 mg/kg IV loading dose on Cycle 1 Day 1, 4 mg/kg IV dose on Cycle 1 Day 15 and on Days 1 and 15 of each Cycle thereafter, and ramucirumab 8 mg/kg IV on Days 1 and 15. Participants received treatment until unacceptable toxicity, disease progression, withdrawal of consent, or study closure.
Maximum Observed Plasma Concentration (Cmax) Cycle 1 Day 8: Tucatinib	769 Nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 30.9	615 Nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 56.1
Maximum Observed Plasma Concentration (Cmax) Cycle 1 Day 8: ONT-993	112 Nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 65.2	130 Nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 99.9
Maximum Observed Plasma Concentration (Cmax) Cycle 2 Day 1: ONT-993	79.0 Nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 35.7	84.2 Nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 80.3
Maximum Observed Plasma Concentration (Cmax) Cycle 2 Day 1: Tucatinib	482 Nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 21.4	553 Nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 52.3

SECONDARY outcome

Timeframe: Tucatinib and ONT-993- Cycle 1 Day 8, Cycle 2 Day 1: Pre-dose, 2, 4, 6, 8 hours post-dose (each cycle length=28 days)

Tmax was reported for tucatinib and tucatinib metabolite ONT-993.

Outcome measures

Outcome measures
Measure	Paclitaxel 60 mg/m^2 n=8 Participants Participants received paclitaxel 60 milligram per meter square (mg/m\^2) intravenously (IV) on Days 1, 8, and 15 of each 28-day cycle, in combination with tucatinib 300 mg orally twice daily (BID), trastuzumab 6 milligram per kilogram (mg/kg) IV loading dose on Cycle 1 Day 1, 4 mg/kg IV dose on Cycle 1 Day 15 and on Days 1 and 15 of each Cycle thereafter, and ramucirumab 8 mg/kg IV on Days 1 and 15. Participants received treatment until unacceptable toxicity, disease progression, withdrawal of consent, or study closure.	Paclitaxel 80 mg/m^2 n=9 Participants Participants received paclitaxel 80 mg/m\^2 IV on Days 1, 8, and 15 of each 28-day Cycle, in combination with tucatinib 300 mg orally BID, trastuzumab 6 mg/kg IV loading dose on Cycle 1 Day 1, 4 mg/kg IV dose on Cycle 1 Day 15 and on Days 1 and 15 of each Cycle thereafter, and ramucirumab 8 mg/kg IV on Days 1 and 15. Participants received treatment until unacceptable toxicity, disease progression, withdrawal of consent, or study closure.
Time to Maximum Observed Plasma Concentration (Tmax) Cycle 1 Day 8: Tucatinib	3.5 Hours Interval 2.0 to 6.6	3.9 Hours Interval 1.7 to 7.5
Time to Maximum Observed Plasma Concentration (Tmax) Cycle 2 Day 1: Tucatinib	3.0 Hours Interval 1.4 to 4.9	3.9 Hours Interval 1.5 to 5.9
Time to Maximum Observed Plasma Concentration (Tmax) Cycle 1 Day 8: ONT-993	1.2 Hours Interval 1.0 to 2.2	1.9 Hours Interval 1.0 to 3.9
Time to Maximum Observed Plasma Concentration (Tmax) Cycle 2 Day 1: ONT-993	1.3 Hours Interval 1.1 to 2.0	2.8 Hours Interval 1.1 to 4.0

SECONDARY outcome

Timeframe: Tucatinib and ONT-993- Cycle 1 Day 8, Cycle 2 Day 1: Predose (each cycle length=28 days)

Ctrough was calculated for tucatinib and tucatinib metabolite ONT-993.

Outcome measures

Outcome measures
Measure	Paclitaxel 60 mg/m^2 n=8 Participants Participants received paclitaxel 60 milligram per meter square (mg/m\^2) intravenously (IV) on Days 1, 8, and 15 of each 28-day cycle, in combination with tucatinib 300 mg orally twice daily (BID), trastuzumab 6 milligram per kilogram (mg/kg) IV loading dose on Cycle 1 Day 1, 4 mg/kg IV dose on Cycle 1 Day 15 and on Days 1 and 15 of each Cycle thereafter, and ramucirumab 8 mg/kg IV on Days 1 and 15. Participants received treatment until unacceptable toxicity, disease progression, withdrawal of consent, or study closure.	Paclitaxel 80 mg/m^2 n=9 Participants Participants received paclitaxel 80 mg/m\^2 IV on Days 1, 8, and 15 of each 28-day Cycle, in combination with tucatinib 300 mg orally BID, trastuzumab 6 mg/kg IV loading dose on Cycle 1 Day 1, 4 mg/kg IV dose on Cycle 1 Day 15 and on Days 1 and 15 of each Cycle thereafter, and ramucirumab 8 mg/kg IV on Days 1 and 15. Participants received treatment until unacceptable toxicity, disease progression, withdrawal of consent, or study closure.
Trough Concentration (Ctrough) Cycle 1 Day 8: Tucatinib	71.0 Nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 2010	156 Nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 64.3
Trough Concentration (Ctrough) Cycle 2 Day 1: Tucatinib	67.4 Nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 1180	62.0 Nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 1320
Trough Concentration (Ctrough) Cycle 1 Day 8: ONT-993	9.64 Nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 289	17.4 Nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 75.7
Trough Concentration (Ctrough) Cycle 2 Day 1: ONT-993	8.23 Nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 203	8.45 Nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 251

SECONDARY outcome

Timeframe: Paclitaxel and its metabolites- Cycle 1 Days 1 and 8, Cycle 2 Day 1: Pre-dose, 2, 4, 6, 8 hours post-dose (each cycle length=28 days)

Population: The PK analysis set included participants in the full analysis set who received at least one dose of tucatinib or paclitaxel and have at least one evaluable PK assessment. All participants reported under "Number of Participants Analyzed" contributed data to the table; however, may not have evaluable data for every row. Here, "Number Analyzed' signifies participants evaluable for the specified rows. Only non-zero values for each time point have been reported in this outcome measure.

MRAUClast was defined as metabolic ratio, that is, ratio of the AUClast of a given paclitaxel metabolite over the AUClast of paclitaxel. MRAUClast for 6 alpha-hydroxypaclitaxel, 3-p-hydroxy-paclitaxel and 6 alpha-3-p-dihydroxy-paclitaxel was reported in this outcome measure.

Outcome measures

Outcome measures
Measure	Paclitaxel 60 mg/m^2 n=8 Participants Participants received paclitaxel 60 milligram per meter square (mg/m\^2) intravenously (IV) on Days 1, 8, and 15 of each 28-day cycle, in combination with tucatinib 300 mg orally twice daily (BID), trastuzumab 6 milligram per kilogram (mg/kg) IV loading dose on Cycle 1 Day 1, 4 mg/kg IV dose on Cycle 1 Day 15 and on Days 1 and 15 of each Cycle thereafter, and ramucirumab 8 mg/kg IV on Days 1 and 15. Participants received treatment until unacceptable toxicity, disease progression, withdrawal of consent, or study closure.	Paclitaxel 80 mg/m^2 n=9 Participants Participants received paclitaxel 80 mg/m\^2 IV on Days 1, 8, and 15 of each 28-day Cycle, in combination with tucatinib 300 mg orally BID, trastuzumab 6 mg/kg IV loading dose on Cycle 1 Day 1, 4 mg/kg IV dose on Cycle 1 Day 15 and on Days 1 and 15 of each Cycle thereafter, and ramucirumab 8 mg/kg IV on Days 1 and 15. Participants received treatment until unacceptable toxicity, disease progression, withdrawal of consent, or study closure.
Metabolite Ratio Based on AUClast (MRAUClast) Cycle 1 Day 1: 3-p-hydroxypaclitaxel	0.0224 Ratio Geometric Coefficient of Variation 99.4	0.0218 Ratio Geometric Coefficient of Variation 43.0
Metabolite Ratio Based on AUClast (MRAUClast) Cycle 1 Day 1: 6 alpha-3-p-dihydroxypaclitaxel	0.0172 Ratio Geometric Coefficient of Variation 151	0.0115 Ratio Geometric Coefficient of Variation 269
Metabolite Ratio Based on AUClast (MRAUClast) Cycle 1 Day 8: 6 alpha-hydroxypaclitaxel	0.0412 Ratio Geometric Coefficient of Variation 67.3	0.0474 Ratio Geometric Coefficient of Variation 130
Metabolite Ratio Based on AUClast (MRAUClast) Cycle 1 Day 8: 3-p-hydroxypaclitaxel	0.00519 Ratio Geometric Coefficient of Variation 78.3	0.00741 Ratio Geometric Coefficient of Variation 101
Metabolite Ratio Based on AUClast (MRAUClast) Cycle 1 Day 8: 6 alpha-3-p-dihydroxypaclitaxel	0.00330 Ratio Geometric Coefficient of Variation 130	0.00445 Ratio Geometric Coefficient of Variation 205
Metabolite Ratio Based on AUClast (MRAUClast) Cycle 2 Day 1: 6 alpha-hydroxypaclitaxel	0.0212 Ratio Geometric Coefficient of Variation 47.9	0.0428 Ratio Geometric Coefficient of Variation 120
Metabolite Ratio Based on AUClast (MRAUClast) Cycle 2 Day 1: 3-p-hydroxypaclitaxel	0.00467 Ratio Geometric Coefficient of Variation 33.1	0.00772 Ratio Geometric Coefficient of Variation 78.0
Metabolite Ratio Based on AUClast (MRAUClast) Cycle 2 Day 1: 6 alpha-3-p-dihydroxypaclitaxel	0.00222 Ratio Geometric Coefficient of Variation 108	0.00340 Ratio Geometric Coefficient of Variation 304
Metabolite Ratio Based on AUClast (MRAUClast) Cycle 1 Day 1: 6 alpha-hydroxypaclitaxel	0.0532 Ratio Geometric Coefficient of Variation 92.5	0.0373 Ratio Geometric Coefficient of Variation 104

Adverse Events

Paclitaxel 60 mg/m^2

Serious events: 4 serious events

Other events: 8 other events

Deaths: 3 deaths

Paclitaxel 80 mg/m^2

Serious events: 5 serious events

Other events: 9 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Paclitaxel 60 mg/m^2 n=8 participants at risk Participants received paclitaxel 60 milligram per meter square (mg/m\^2) intravenously (IV) on Days 1, 8, and 15 of each 28-day cycle, in combination with tucatinib 300 mg orally twice daily (BID), trastuzumab 6 milligram per kilogram (mg/kg) IV loading dose on Cycle 1 Day 1, 4 mg/kg IV dose on Cycle 1 Day 15 and on Days 1 and 15 of each Cycle thereafter, and ramucirumab 8 mg/kg IV on Days 1 and 15. Participants received treatment until unacceptable toxicity, disease progression, withdrawal of consent, or study closure.	Paclitaxel 80 mg/m^2 n=9 participants at risk Participants received paclitaxel 80 mg/m\^2 IV on Days 1, 8, and 15 of each 28-day Cycle, in combination with tucatinib 300 mg orally BID, trastuzumab 6 mg/kg IV loading dose on Cycle 1 Day 1, 4 mg/kg IV dose on Cycle 1 Day 15 and on Days 1 and 15 of each Cycle thereafter, and ramucirumab 8 mg/kg IV on Days 1 and 15. Participants received treatment until unacceptable toxicity, disease progression, withdrawal of consent, or study closure.
Gastrointestinal disorders Abdominal pain	12.5% 1/8 • Number of events 1 • From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment (maximum treatment duration= 19.8 months, maximum follow-up duration up to 20.8 months) Same event may appear as both non-serious adverse event (SAE) and SAE; however, what is presented are distinct events. An event may be categorized as serious in 1 participant and non-serious in another participant, or a participant may have experienced both SAE and non-SAE. Safety analysis set was evaluated. All-cause mortality: number of deaths are reported from Day 1 of study up to 30 days post last dose and deaths which occurred after 30 days post last dose of study drug are also included.	0.00% 0/9 • From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment (maximum treatment duration= 19.8 months, maximum follow-up duration up to 20.8 months) Same event may appear as both non-serious adverse event (SAE) and SAE; however, what is presented are distinct events. An event may be categorized as serious in 1 participant and non-serious in another participant, or a participant may have experienced both SAE and non-SAE. Safety analysis set was evaluated. All-cause mortality: number of deaths are reported from Day 1 of study up to 30 days post last dose and deaths which occurred after 30 days post last dose of study drug are also included.
Gastrointestinal disorders Enteritis	12.5% 1/8 • Number of events 1 • From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment (maximum treatment duration= 19.8 months, maximum follow-up duration up to 20.8 months) Same event may appear as both non-serious adverse event (SAE) and SAE; however, what is presented are distinct events. An event may be categorized as serious in 1 participant and non-serious in another participant, or a participant may have experienced both SAE and non-SAE. Safety analysis set was evaluated. All-cause mortality: number of deaths are reported from Day 1 of study up to 30 days post last dose and deaths which occurred after 30 days post last dose of study drug are also included.	0.00% 0/9 • From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment (maximum treatment duration= 19.8 months, maximum follow-up duration up to 20.8 months) Same event may appear as both non-serious adverse event (SAE) and SAE; however, what is presented are distinct events. An event may be categorized as serious in 1 participant and non-serious in another participant, or a participant may have experienced both SAE and non-SAE. Safety analysis set was evaluated. All-cause mortality: number of deaths are reported from Day 1 of study up to 30 days post last dose and deaths which occurred after 30 days post last dose of study drug are also included.
Gastrointestinal disorders Gastric haemorrhage	12.5% 1/8 • Number of events 1 • From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment (maximum treatment duration= 19.8 months, maximum follow-up duration up to 20.8 months) Same event may appear as both non-serious adverse event (SAE) and SAE; however, what is presented are distinct events. An event may be categorized as serious in 1 participant and non-serious in another participant, or a participant may have experienced both SAE and non-SAE. Safety analysis set was evaluated. All-cause mortality: number of deaths are reported from Day 1 of study up to 30 days post last dose and deaths which occurred after 30 days post last dose of study drug are also included.	0.00% 0/9 • From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment (maximum treatment duration= 19.8 months, maximum follow-up duration up to 20.8 months) Same event may appear as both non-serious adverse event (SAE) and SAE; however, what is presented are distinct events. An event may be categorized as serious in 1 participant and non-serious in another participant, or a participant may have experienced both SAE and non-SAE. Safety analysis set was evaluated. All-cause mortality: number of deaths are reported from Day 1 of study up to 30 days post last dose and deaths which occurred after 30 days post last dose of study drug are also included.
Gastrointestinal disorders Oesophageal obstruction	0.00% 0/8 • From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment (maximum treatment duration= 19.8 months, maximum follow-up duration up to 20.8 months) Same event may appear as both non-serious adverse event (SAE) and SAE; however, what is presented are distinct events. An event may be categorized as serious in 1 participant and non-serious in another participant, or a participant may have experienced both SAE and non-SAE. Safety analysis set was evaluated. All-cause mortality: number of deaths are reported from Day 1 of study up to 30 days post last dose and deaths which occurred after 30 days post last dose of study drug are also included.	11.1% 1/9 • Number of events 1 • From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment (maximum treatment duration= 19.8 months, maximum follow-up duration up to 20.8 months) Same event may appear as both non-serious adverse event (SAE) and SAE; however, what is presented are distinct events. An event may be categorized as serious in 1 participant and non-serious in another participant, or a participant may have experienced both SAE and non-SAE. Safety analysis set was evaluated. All-cause mortality: number of deaths are reported from Day 1 of study up to 30 days post last dose and deaths which occurred after 30 days post last dose of study drug are also included.
General disorders Pyrexia	0.00% 0/8 • From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment (maximum treatment duration= 19.8 months, maximum follow-up duration up to 20.8 months) Same event may appear as both non-serious adverse event (SAE) and SAE; however, what is presented are distinct events. An event may be categorized as serious in 1 participant and non-serious in another participant, or a participant may have experienced both SAE and non-SAE. Safety analysis set was evaluated. All-cause mortality: number of deaths are reported from Day 1 of study up to 30 days post last dose and deaths which occurred after 30 days post last dose of study drug are also included.	11.1% 1/9 • Number of events 1 • From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment (maximum treatment duration= 19.8 months, maximum follow-up duration up to 20.8 months) Same event may appear as both non-serious adverse event (SAE) and SAE; however, what is presented are distinct events. An event may be categorized as serious in 1 participant and non-serious in another participant, or a participant may have experienced both SAE and non-SAE. Safety analysis set was evaluated. All-cause mortality: number of deaths are reported from Day 1 of study up to 30 days post last dose and deaths which occurred after 30 days post last dose of study drug are also included.
Infections and infestations COVID-19 pneumonia	0.00% 0/8 • From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment (maximum treatment duration= 19.8 months, maximum follow-up duration up to 20.8 months) Same event may appear as both non-serious adverse event (SAE) and SAE; however, what is presented are distinct events. An event may be categorized as serious in 1 participant and non-serious in another participant, or a participant may have experienced both SAE and non-SAE. Safety analysis set was evaluated. All-cause mortality: number of deaths are reported from Day 1 of study up to 30 days post last dose and deaths which occurred after 30 days post last dose of study drug are also included.	11.1% 1/9 • Number of events 1 • From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment (maximum treatment duration= 19.8 months, maximum follow-up duration up to 20.8 months) Same event may appear as both non-serious adverse event (SAE) and SAE; however, what is presented are distinct events. An event may be categorized as serious in 1 participant and non-serious in another participant, or a participant may have experienced both SAE and non-SAE. Safety analysis set was evaluated. All-cause mortality: number of deaths are reported from Day 1 of study up to 30 days post last dose and deaths which occurred after 30 days post last dose of study drug are also included.
Infections and infestations Intestinal sepsis	12.5% 1/8 • Number of events 1 • From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment (maximum treatment duration= 19.8 months, maximum follow-up duration up to 20.8 months) Same event may appear as both non-serious adverse event (SAE) and SAE; however, what is presented are distinct events. An event may be categorized as serious in 1 participant and non-serious in another participant, or a participant may have experienced both SAE and non-SAE. Safety analysis set was evaluated. All-cause mortality: number of deaths are reported from Day 1 of study up to 30 days post last dose and deaths which occurred after 30 days post last dose of study drug are also included.	0.00% 0/9 • From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment (maximum treatment duration= 19.8 months, maximum follow-up duration up to 20.8 months) Same event may appear as both non-serious adverse event (SAE) and SAE; however, what is presented are distinct events. An event may be categorized as serious in 1 participant and non-serious in another participant, or a participant may have experienced both SAE and non-SAE. Safety analysis set was evaluated. All-cause mortality: number of deaths are reported from Day 1 of study up to 30 days post last dose and deaths which occurred after 30 days post last dose of study drug are also included.
Infections and infestations Pneumonia	12.5% 1/8 • Number of events 1 • From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment (maximum treatment duration= 19.8 months, maximum follow-up duration up to 20.8 months) Same event may appear as both non-serious adverse event (SAE) and SAE; however, what is presented are distinct events. An event may be categorized as serious in 1 participant and non-serious in another participant, or a participant may have experienced both SAE and non-SAE. Safety analysis set was evaluated. All-cause mortality: number of deaths are reported from Day 1 of study up to 30 days post last dose and deaths which occurred after 30 days post last dose of study drug are also included.	0.00% 0/9 • From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment (maximum treatment duration= 19.8 months, maximum follow-up duration up to 20.8 months) Same event may appear as both non-serious adverse event (SAE) and SAE; however, what is presented are distinct events. An event may be categorized as serious in 1 participant and non-serious in another participant, or a participant may have experienced both SAE and non-SAE. Safety analysis set was evaluated. All-cause mortality: number of deaths are reported from Day 1 of study up to 30 days post last dose and deaths which occurred after 30 days post last dose of study drug are also included.
Injury, poisoning and procedural complications Hip fracture	0.00% 0/8 • From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment (maximum treatment duration= 19.8 months, maximum follow-up duration up to 20.8 months) Same event may appear as both non-serious adverse event (SAE) and SAE; however, what is presented are distinct events. An event may be categorized as serious in 1 participant and non-serious in another participant, or a participant may have experienced both SAE and non-SAE. Safety analysis set was evaluated. All-cause mortality: number of deaths are reported from Day 1 of study up to 30 days post last dose and deaths which occurred after 30 days post last dose of study drug are also included.	11.1% 1/9 • Number of events 1 • From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment (maximum treatment duration= 19.8 months, maximum follow-up duration up to 20.8 months) Same event may appear as both non-serious adverse event (SAE) and SAE; however, what is presented are distinct events. An event may be categorized as serious in 1 participant and non-serious in another participant, or a participant may have experienced both SAE and non-SAE. Safety analysis set was evaluated. All-cause mortality: number of deaths are reported from Day 1 of study up to 30 days post last dose and deaths which occurred after 30 days post last dose of study drug are also included.
Investigations Alanine aminotransferase increased	12.5% 1/8 • Number of events 1 • From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment (maximum treatment duration= 19.8 months, maximum follow-up duration up to 20.8 months) Same event may appear as both non-serious adverse event (SAE) and SAE; however, what is presented are distinct events. An event may be categorized as serious in 1 participant and non-serious in another participant, or a participant may have experienced both SAE and non-SAE. Safety analysis set was evaluated. All-cause mortality: number of deaths are reported from Day 1 of study up to 30 days post last dose and deaths which occurred after 30 days post last dose of study drug are also included.	0.00% 0/9 • From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment (maximum treatment duration= 19.8 months, maximum follow-up duration up to 20.8 months) Same event may appear as both non-serious adverse event (SAE) and SAE; however, what is presented are distinct events. An event may be categorized as serious in 1 participant and non-serious in another participant, or a participant may have experienced both SAE and non-SAE. Safety analysis set was evaluated. All-cause mortality: number of deaths are reported from Day 1 of study up to 30 days post last dose and deaths which occurred after 30 days post last dose of study drug are also included.
Nervous system disorders Cerebrovascular accident	0.00% 0/8 • From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment (maximum treatment duration= 19.8 months, maximum follow-up duration up to 20.8 months) Same event may appear as both non-serious adverse event (SAE) and SAE; however, what is presented are distinct events. An event may be categorized as serious in 1 participant and non-serious in another participant, or a participant may have experienced both SAE and non-SAE. Safety analysis set was evaluated. All-cause mortality: number of deaths are reported from Day 1 of study up to 30 days post last dose and deaths which occurred after 30 days post last dose of study drug are also included.	11.1% 1/9 • Number of events 1 • From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment (maximum treatment duration= 19.8 months, maximum follow-up duration up to 20.8 months) Same event may appear as both non-serious adverse event (SAE) and SAE; however, what is presented are distinct events. An event may be categorized as serious in 1 participant and non-serious in another participant, or a participant may have experienced both SAE and non-SAE. Safety analysis set was evaluated. All-cause mortality: number of deaths are reported from Day 1 of study up to 30 days post last dose and deaths which occurred after 30 days post last dose of study drug are also included.
Nervous system disorders Syncope	0.00% 0/8 • From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment (maximum treatment duration= 19.8 months, maximum follow-up duration up to 20.8 months) Same event may appear as both non-serious adverse event (SAE) and SAE; however, what is presented are distinct events. An event may be categorized as serious in 1 participant and non-serious in another participant, or a participant may have experienced both SAE and non-SAE. Safety analysis set was evaluated. All-cause mortality: number of deaths are reported from Day 1 of study up to 30 days post last dose and deaths which occurred after 30 days post last dose of study drug are also included.	11.1% 1/9 • Number of events 1 • From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment (maximum treatment duration= 19.8 months, maximum follow-up duration up to 20.8 months) Same event may appear as both non-serious adverse event (SAE) and SAE; however, what is presented are distinct events. An event may be categorized as serious in 1 participant and non-serious in another participant, or a participant may have experienced both SAE and non-SAE. Safety analysis set was evaluated. All-cause mortality: number of deaths are reported from Day 1 of study up to 30 days post last dose and deaths which occurred after 30 days post last dose of study drug are also included.
Respiratory, thoracic and mediastinal disorders Respiratory failure	12.5% 1/8 • Number of events 1 • From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment (maximum treatment duration= 19.8 months, maximum follow-up duration up to 20.8 months) Same event may appear as both non-serious adverse event (SAE) and SAE; however, what is presented are distinct events. An event may be categorized as serious in 1 participant and non-serious in another participant, or a participant may have experienced both SAE and non-SAE. Safety analysis set was evaluated. All-cause mortality: number of deaths are reported from Day 1 of study up to 30 days post last dose and deaths which occurred after 30 days post last dose of study drug are also included.	0.00% 0/9 • From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment (maximum treatment duration= 19.8 months, maximum follow-up duration up to 20.8 months) Same event may appear as both non-serious adverse event (SAE) and SAE; however, what is presented are distinct events. An event may be categorized as serious in 1 participant and non-serious in another participant, or a participant may have experienced both SAE and non-SAE. Safety analysis set was evaluated. All-cause mortality: number of deaths are reported from Day 1 of study up to 30 days post last dose and deaths which occurred after 30 days post last dose of study drug are also included.

Other adverse events

Additional Information

Chief Medical Officer

Seagen Inc.

Phone: (855) 473-2436

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Paclitaxel 60 mg/m^2 n=8 Participants Participants received paclitaxel 60 milligram per meter square (mg/m\^2) intravenously (IV) on Days 1, 8, and 15 of each 28-day cycle, in combination with tucatinib 300 mg orally twice daily (BID), trastuzumab 6 milligram per kilogram (mg/kg) IV loading dose on Cycle 1 Day 1, 4 mg/kg IV dose on Cycle 1 Day 15 and on Days 1 and 15 of each Cycle thereafter, and ramucirumab 8 mg/kg IV on Days 1 and 15. Participants received treatment until unacceptable toxicity, disease progression, withdrawal of consent, or study closure.	Paclitaxel 80 mg/m^2 n=9 Participants Participants received paclitaxel 80 mg/m\^2 IV on Days 1, 8, and 15 of each 28-day Cycle, in combination with tucatinib 300 mg orally BID, trastuzumab 6 mg/kg IV loading dose on Cycle 1 Day 1, 4 mg/kg IV dose on Cycle 1 Day 15 and on Days 1 and 15 of each Cycle thereafter, and ramucirumab 8 mg/kg IV on Days 1 and 15. Participants received treatment until unacceptable toxicity, disease progression, withdrawal of consent, or study closure.
Area Under the Plasma Concentration-time Curve to the Time of the Last Quantifiable Concentration (AUClast) of Paclitaxel, Tucatinib and Their Metabolites Cycle 1 Day 1: Paclitaxel	2180 Hour*nanograms per milliliter Geometric Coefficient of Variation 45.5	3500 Hour*nanograms per milliliter Geometric Coefficient of Variation 10.1
Area Under the Plasma Concentration-time Curve to the Time of the Last Quantifiable Concentration (AUClast) of Paclitaxel, Tucatinib and Their Metabolites Cycle 1 Day 1: 6 alpha-hydroxy-paclitaxel	118 Hour*nanograms per milliliter Geometric Coefficient of Variation 117	133 Hour*nanograms per milliliter Geometric Coefficient of Variation 100
Area Under the Plasma Concentration-time Curve to the Time of the Last Quantifiable Concentration (AUClast) of Paclitaxel, Tucatinib and Their Metabolites Cycle 1 Day 1: 3'-p-hydroxy-paclitaxel	49.7 Hour*nanograms per milliliter Geometric Coefficient of Variation 123	77.8 Hour*nanograms per milliliter Geometric Coefficient of Variation 40.8
Area Under the Plasma Concentration-time Curve to the Time of the Last Quantifiable Concentration (AUClast) of Paclitaxel, Tucatinib and Their Metabolites Cycle 1 Day 1: 6 alpha-3'-p-dihydroxy-paclitaxel	38.9 Hour*nanograms per milliliter Geometric Coefficient of Variation 194	42.0 Hour*nanograms per milliliter Geometric Coefficient of Variation 242
Area Under the Plasma Concentration-time Curve to the Time of the Last Quantifiable Concentration (AUClast) of Paclitaxel, Tucatinib and Their Metabolites Cycle 1 Day 8: Paclitaxel	2210 Hour*nanograms per milliliter Geometric Coefficient of Variation 54.6	3220 Hour*nanograms per milliliter Geometric Coefficient of Variation 41.5
Area Under the Plasma Concentration-time Curve to the Time of the Last Quantifiable Concentration (AUClast) of Paclitaxel, Tucatinib and Their Metabolites Cycle 1 Day 8: 6 alpha-hydroxy-paclitaxel	92.7 Hour*nanograms per milliliter Geometric Coefficient of Variation 109	155 Hour*nanograms per milliliter Geometric Coefficient of Variation 88.3
Area Under the Plasma Concentration-time Curve to the Time of the Last Quantifiable Concentration (AUClast) of Paclitaxel, Tucatinib and Their Metabolites Cycle 1 Day 8: 3'-p-hydroxy-paclitaxel	11.7 Hour*nanograms per milliliter Geometric Coefficient of Variation 106	24.3 Hour*nanograms per milliliter Geometric Coefficient of Variation 89.6
Area Under the Plasma Concentration-time Curve to the Time of the Last Quantifiable Concentration (AUClast) of Paclitaxel, Tucatinib and Their Metabolites Cycle 1 Day 8: 6 alpha-3'-p-dihydroxy-paclitaxel	7.56 Hour*nanograms per milliliter Geometric Coefficient of Variation 175	14.1 Hour*nanograms per milliliter Geometric Coefficient of Variation 128
Area Under the Plasma Concentration-time Curve to the Time of the Last Quantifiable Concentration (AUClast) of Paclitaxel, Tucatinib and Their Metabolites Cycle 2 Day 1: Paclitaxel	2380 Hour*nanograms per milliliter Geometric Coefficient of Variation 45.9	3120 Hour*nanograms per milliliter Geometric Coefficient of Variation 31.4
Area Under the Plasma Concentration-time Curve to the Time of the Last Quantifiable Concentration (AUClast) of Paclitaxel, Tucatinib and Their Metabolites Cycle 2 Day 1: 6 alpha-hydroxy-paclitaxel	51.2 Hour*nanograms per milliliter Geometric Coefficient of Variation 56.9	136 Hour*nanograms per milliliter Geometric Coefficient of Variation 116
Area Under the Plasma Concentration-time Curve to the Time of the Last Quantifiable Concentration (AUClast) of Paclitaxel, Tucatinib and Their Metabolites Cycle 2 Day 1: 3'-p-hydroxy-paclitaxel	11.3 Hour*nanograms per milliliter Geometric Coefficient of Variation 77.0	24.5 Hour*nanograms per milliliter Geometric Coefficient of Variation 97.5
Area Under the Plasma Concentration-time Curve to the Time of the Last Quantifiable Concentration (AUClast) of Paclitaxel, Tucatinib and Their Metabolites Cycle 2 Day 1: 6 alpha-3'-p-dihydroxy-paclitaxel	5.48 Hour*nanograms per milliliter Geometric Coefficient of Variation 251	12.6 Hour*nanograms per milliliter Geometric Coefficient of Variation 250
Area Under the Plasma Concentration-time Curve to the Time of the Last Quantifiable Concentration (AUClast) of Paclitaxel, Tucatinib and Their Metabolites Cycle 1 Day 8: Tucatinib	4210 Hour*nanograms per milliliter Geometric Coefficient of Variation 37.7	3210 Hour*nanograms per milliliter Geometric Coefficient of Variation 60.0
Area Under the Plasma Concentration-time Curve to the Time of the Last Quantifiable Concentration (AUClast) of Paclitaxel, Tucatinib and Their Metabolites Cycle 1 Day 8: ONT-993	550 Hour*nanograms per milliliter Geometric Coefficient of Variation 65.3	521 Hour*nanograms per milliliter Geometric Coefficient of Variation 92.1
Area Under the Plasma Concentration-time Curve to the Time of the Last Quantifiable Concentration (AUClast) of Paclitaxel, Tucatinib and Their Metabolites Cycle 2 Day 1: Tucatinib	2810 Hour*nanograms per milliliter Geometric Coefficient of Variation 34.7	3130 Hour*nanograms per milliliter Geometric Coefficient of Variation 35.8
Area Under the Plasma Concentration-time Curve to the Time of the Last Quantifiable Concentration (AUClast) of Paclitaxel, Tucatinib and Their Metabolites Cycle 2 Day 1: ONT-993	348 Hour*nanograms per milliliter Geometric Coefficient of Variation 10.1	423 Hour*nanograms per milliliter Geometric Coefficient of Variation 50.4