Study of TDXd, Chemotherapy, Pembrolizumab, and Trastuzumab in First-Line Metastatic HER2-Positive Gastric or Gastroesophageal Junction Cancer

Recruiting now · Phase 3

Conditions studied: Gastric Cancer, Gastroesophageal Junction Cancer

In brief

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.

Key facts

Study ID: NCT06731478
Run by: Daiichi Sankyo
People needed: 726
Starts: 2025-02-27
Expected to finish: 2030-02-01
Last updated by the study team: 2026-07-15

Who can join

Age: 18 and older. Sex: any. Healthy volunteers: not accepted.

You may qualify if…

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.
Note: Prior use of IO (ie, anti-PD-1/PD-L1) therapy in the (neo)adjuvant setting is allowed as long as there is >6 months between the end of IO therapy 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.
Note: Archival samples taken from a previous diagnostic or surgical biopsy not previously irradiated can be accepted. Details pertaining to tumor tissue submission can be found in the Study Laboratory Manual.
Centrally determined tumor PD-L1 CPS using the PD-L1 assay:
For the Main Cohort: PD-L1 CPS ≥1
For the Exploratory Cohort: PD-L1 CPS <1
All participants must provide a tumor sample for tissue-based IHC staining to centrally determine HER2 expression, PD-L1 CPS, and other correlatives. The mandatory FFPE or new biopsy tumor sample can be from either the primary tumor or metastatic biopsy. Specimens with limited tumor content (as centrally determined) and cytology samples are inadequate for defining tumor HER2 and PD-L1 status.
At least 1 target measurable lesion on CT or MRI, assessed by the investigator based on RECIST v1.1. Lesions situated in a previously irradiated area are considered measurable if progression has been shown in such lesions.
LVEF ≥50% within 28 days before randomization.

You may not qualify if…

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.
Medical history of myocardial infarction within 6 months before randomization or symptomatic CHF (New York Heart Association Class II to IV). Participants with troponin levels above ULN at Screening (as defined by the manufacturer) and without any myocardial infarction -related symptoms should have a cardiologic consultation during the Screening Period to rule out myocardial infarction.
Has a corrected QT interval (QTcF) prolongation to >470 ms (females) or >450 ms (males) based on the average of the screening triplicate 12-lead ECG.
Has a history of (non-infectious) ILD/pneumonitis that required steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at Screening
Lung-specific intercurrent clinically significant illnesses including, but not limited to, any underlying pulmonary disorder (eg, pulmonary emboli within 3 months of the trial randomization, severe asthma, severe chronic obstructive pulmonary disease, restrictive lung disease, pleural effusion, etc).

Where it is running

LKH - Universitaetsklinikum Graz — Graz, Austria (enrolling)
Cliniques Universitaires Saint-Luc — Brussels, Belgium (enrolling)
St John of God Subiaco Hospital — Subiaco, Australia (enrolling)
Wollongong Hospital — Wollongong, Australia (enrolling)
St. Josef Krankenhaus Wien — Vienna, Austria (enrolling)
AZ Sint-Lucas — Bruges, Belgium (enrolling)
Townsville University Hospital — Douglas, Australia (enrolling)
GenesisCare North Shore (Oncology) — St Leonards, Australia (enrolling)
Tufts Medical Center — Boston, Massachusetts, United States (enrolling)
Penn State University Milton S. Hershey Medical Center — Hershey, Pennsylvania, United States (enrolling)
University of Michigan Comprehensive Cancer Center Michigan Medicine — Ann Arbor, Michigan, United States (enrolling)
Medizinische Universität Innsbruck — Innsbruck, Austria (enrolling)
Landesklinikum Wiener Neustadt — Wiener Neustadt, Austria (enrolling)
Institut Jules Bordet — Anderlecht, Belgium (enrolling)
Memorial Sloan Kettering Cancer Center - MAIN — New York, New York, United States (enrolling)
Orchard Healthcare Research Inc. — Skokie, Illinois, United States (enrolling)
Montefiore Medical Center — The Bronx, New York, United States (enrolling)
Peter MacCallum Cancer Centre — North Melbourne, Australia (enrolling)
Providence Portland Medical Center — Portland, Oregon, United States (enrolling)
Clinica Universitaria Privada Reina Fabiola — Córdoba, Argentina (enrolling)
Centro de Investigaciones Medicas Mar del Plata — Mar del Plata, Argentina (enrolling)
Instituto Medico de la Fundacion Estudios Clinicos — Rosario, Argentina (enrolling)
Flinders Medical Centre — Bedford Park, Australia (enrolling)
Monash Medical Centre Clayton — Clayton, Australia (enrolling)
UZ Leuven — Leuven, Belgium (enrolling)

Full record on ClinicalTrials.gov

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