This clinical trial is designed to assess the efficacy and safety of the triplet combination of trastuzumab deruxtecan (ENHERTU, T-DXd, DS-8201a) plus a fluoropyrimidine plus pembrolizumab versus standard of care (SoC) chemotherapy plus trastuzumab plus pembrolizumab as first-line therapy in participants with unresectable, locally advanced or metastatic HER2-positive tumor PD-L1 CPS ≥1 gastric or GEJ cancer in the Main Cohort. An Exploratory Cohort will also be evaluated to assess the efficacy and safety of T-DXd plus a fluoropyrimidine versus SoC chemotherapy plus trastuzumab in participants with unresectable, locally advanced or metastatic HER2-positive tumor PD-L1 CPS \<1 gastric or GEJ cancer.
Sign and date the Tissue Prescreening ICF, prior to central HER2 and PD-L1 CPS testing. Sign and date the Main Screening ICF, prior to the start of any trial-specific qualification procedures. Sign and date the Optional PGx ICF (included in the Main Screening ICF) prior to any PGx procedure.
Adults ≥18 years of age on the day of signing the ICF. Follow local regulatory requirements if the legal age of consent for trial participation is >18 years old.
Previously untreated, unresectable, locally advanced or metastatic gastric or GEJ adenocarcinoma histologically confirmed by pathology report. Prior treatment in the perioperative and/or adjuvant setting is permissible, provided there is >6 months between the end of perioperative or neoadjuvant treatment and the diagnosis of recurrent disease.
Centrally determined HER2-positive (IHC 3+ or IHC 2+/ISH-positive) gastric or GEJ cancer as classified by the American Society of Clinical Oncology-College of American Pathologists for GC on a tumor biopsy as detected by prospective central test on new (core, incisional, excisional biopsy) or existing tumor tissue taken at the time of diagnosis of locally advanced or metastatic disease.
Prior exposure to other HER2-targeting therapies (including ADCs).
Lack of physiological integrity of the upper gastrointestinal tract (ie, severe Crohn disease that results in malabsorption) or malabsorption syndrome that would preclude feasibility of oral chemotherapy for participants planned to be offered capecitabine as part of the study treatment.
Known total or partial DPD enzyme deficiency. Note: Screening for DPD enzyme deficiency is required only in regions/countries where DPD testing is SoC and with unknown DPD status. For regions/countries where DPD testing is not SoC, local practice should be followed. In Spain and Italy, screening for DPD enzyme deficiency is mandatory for all participants with unknown DPD status.
Contraindications to trastuzumab, 5-FU, capecitabine, cisplatin, or oxaliplatin treatment as per local label.
Parallel
Trastuzumab Deruxtecan
DrugT-DXd will be administered at a dose of 5.4 mg/kg intravenously (IV) every 3 weeks (Q3W)
pembrolizumab
DrugPembrolizumab will be administered at a dose of 200 mg IV Q3W
Trastuzumab
DrugTrastuzumab will be administered at a loading dose of 8 mg/kg IV followed by 6 mg/kg IV Q3W
Chemotherapy
DrugFor Arms M1 and E1: 5-FU or capecitabine will be administered. For Arms M2 and E2: Cisplatin plus 5-FU or oxaliplatin plus capecitabine will be administered.
Progression Free Survival (PFS)
PFS is defined as the time interval from the date of randomization to the date of radiographic disease progression as assessed by blinded independent central review (BICR) based on RECIST v1.1 or death due to any cause.
Overall Survival (OS)
OS is defined as the time interval from the date of randomization to the date of death due to any cause.
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Daiichi Sankyo
Lead sponsor
Merck Sharp & Dohme LLC
Collaborator