Home › Trials › NCT06731478

Combination treatment for advanced HER2-positive gastric cancer

A Multicenter, Randomized, Open-Label, Phase 3 Trial of Trastuzumab Deruxtecan (Enhertu®) Plus Chemotherapy Plus or Minus Pembrolizumab Versus Chemotherapy Plus Trastuzumab Plus or Minus Pembrolizumab as First-Line Treatment in Participants With Unresectable, Locally Advanced or Metastatic HER2-Positive Gastric Or Gastroesophageal Junction (GEJ) Cancer (Destiny-Gastric05)

Phase 3 Interventional Daiichi Sankyo · NCT06731478

This study is testing a new combination treatment for adults with advanced HER2-positive gastric cancer to see if it works better than the standard treatment.

Quick facts

PhasePhase 3
Study typeInterventional
Enrollment726 (estimated)
Ages18 Years and up
SexAll
SponsorDaiichi Sankyo Industry-sponsored
Drugs / interventionstrastuzumab, chemotherapy, pembrolizumab
Locations250 sites (New Haven, Connecticut and 249 other locations)
Trial IDNCT06731478 on ClinicalTrials.gov

What this trial studies

This clinical trial evaluates the effectiveness and safety of a combination therapy involving trastuzumab deruxtecan, chemotherapy, and pembrolizumab compared to standard chemotherapy and trastuzumab in patients with unresectable, locally advanced, or metastatic HER2-positive gastric or gastroesophageal junction cancer. The study includes a main cohort for patients with PD-L1 CPS ≥1 and an exploratory cohort for those with PD-L1 CPS <1. Participants must be adults aged 18 and older and have not received prior treatment for their condition.

Who should consider this trial

Good fit: Ideal candidates are adults with unresectable, locally advanced, or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma who have not received prior treatment.

Not a fit: Patients with resectable tumors or those who have received prior treatment for their condition may not benefit from this study.

Why it matters

Potential benefit: If successful, this treatment could provide a more effective first-line therapy option for patients with advanced HER2-positive gastric cancer.

How similar studies have performed: Other studies have shown promising results with similar combination therapies in treating HER2-positive cancers, indicating potential for success in this approach.

Eligibility criteria

Show full inclusion / exclusion criteria 
Inclusion

1. Sign and date the Tissue Prescreening ICF, prior to HER2 and PD-L1 CPS central 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.
2. 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.
3. 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.
4. 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.
5. 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 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.
6. 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.
7. LVEF ≥50% within 28 days before randomization.

exclusion criteria

1. Prior exposure to other HER2-targeting therapies (including ADCs).
2. 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 (ie, capecitabine).
3. Known 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.
4. Contraindications to trastuzumab, 5-FU, capecitabine, cisplatin, or oxaliplatin treatment as per local label.
5. 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.
6. 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.
7. 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
8. 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 this trial is running

New Haven, Connecticut and 249 other locations

+200 more sites — see ClinicalTrials.gov for the full list.

Study contacts

How to participate

  1. Review the eligibility criteria above with your treating physician.
  2. Visit the official trial page on ClinicalTrials.gov for the most current contact information and recruitment status.
  3. Contact the listed study coordinator or principal investigator to request pre-screening. Pre-screening is free and never obligates you to enroll.
View on ClinicalTrials.gov → Find more trials like this →
Conditions Gastric CancerGastroesophageal Junction CancerEnhertuTrastuzumab DeruxtecanChemotherapyDS-8201aHER2 positive
Last reviewed 2026-06-13 by the Find a Trial editorial team. Information on this page is for educational purposes and is not medical advice. Always consult qualified healthcare professionals about clinical trial participation.