This is a phase 1/2, multicenter, open-label umbrella platform study that will evaluate the safety and tolerability of investigational agents with pembrolizumab and fluoropyrimidine chemotherapy for the first-line (1L) treatment of participants with locally advanced unresectable or metastatic human epidermal growth factor receptor 2 (HER2)-negative gastric, gastroesophageal junction, or esophageal adenocarcinoma.
This substudy will have two phases: a safety lead-in phase and an efficacy phase. The safety lead-in phase will be used to evaluate the safety and tolerability, and to establish a recommended Phase 2 dose (RP2D) for investigational agents in combination with chemotherapy and immunotherapy. There is no formal hypothesis in this study.
Has histologically and/or cytologically confirmed diagnosis of previously untreated locally advanced unresectable or metastatic first-line (1L) gastroesophageal adenocarcinoma
Is not expected to require tumor resection during the treatment course
Tumor tissue must be confirmed as negative for human epidermal growth factor receptor 2 (HER2) expression as classified by American Society of Clinical Oncology/College of American Pathologists (ASCO-CAP) guidelines
Core/excisional biopsy of a tumor lesion not previously irradiated has been provided
Has squamous cell or undifferentiated gastroesophageal cancer.
Has had previous therapy for locally advanced unresectable or metastatic gastric/gastroesophageal junction (GEJ)/esophageal adenocarcinoma
Has experienced weight loss >20% over 3 months before the first dose of study intervention
Has a history of documented severe dry eye syndrome, severe Meibomian gland disease and/or blepharitis, or severe corneal disease that prevents/delays corneal healing
Parallel
Pembrolizumab
Biological/VaccineAdministered via intravenous (IV) infusion.
Sacituzumab Tirumotecan (sac-TMT)
Biological/VaccineAdministered via IV infusion.
Capecitabine
DrugAdministered via oral tablet.
Leucovorin
DrugAdministered via IV infusion.
Levoleucovorin
DrugAdministered via IV infusion.
5-Fluorouracil (5-FU)
DrugAdministered via IV infusion
Oxaliplatin
DrugAdministered via IV infusion
Patritumab Deruxtecan
Biological/VaccineAdministered via IV infusion
Safety Lead-in Phase: Number of Participants Who Experience One or More Dose-Limiting Toxicities (DLTs)
DLTs are defined as any treatment-emergent adverse events (TEAEs) not attributable to disease or disease-related processes that occur during the DLT evaluation period and are a Grade 3 or higher according to the National Cancer Institute Common Terminology for Adverse Events (NCI CTCAE) Version 5.0. The percentage of participants who experience at least one DLT will be reported.
Safety Lead-in Phase: Number of Participants Who Experienced an Adverse Event (AE)
An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention.
Safety Lead-in Phase: Number of Participants Who Discontinued Study Intervention Due to an AE
An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention.
Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR)
ORR is defined as the percentage of participants in the analysis population who have a Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1. The percentage of participants who experience CR or PR as assessed by BICR will be presented.
Progression-Free Survival (PFS) per RECIST 1.1 as Assessed by BICR
PFS is defined as the time from randomization to the first documented progressive disease (PD) or death from any cause, whichever occurs first. Per RECIST 1.1, PD is defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered PD. PFS as assessed by BICR will be presented.
Duration of Response (DOR) Per RECIST 1.1 as Assessed by BICR
For participants who demonstrate a confirmed Complete Response (CR: disappearance of all target lesions) or Partial Response (PR: at least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1, DOR is defined as the time from first documented evidence of CR or PR until PD or death. Per RECIST 1.1, PD is defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered PD. DOR as assessed by BICR will be presented.
Overall Survival (OS)
OS is defined as the time from randomization to the date of death from any cause.
Number of Participants Who Experience an Adverse Event (AE)
An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention.
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