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

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.

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).

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.

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.

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

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.

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.

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.

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.

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.

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.

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).

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

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

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

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.