• Progression-Free Survival (PFS), based on Independent Central Review using RECIST v1.1 [ Time Frame: within approximately 30 months ]
  PFS is defined as the time from enrollment until objective tumor progression or withdrawing from the study for other reasons, whichever occurs first.
• PFS, based on Investigator Assessment [ Time Frame: within approximately 30 months ]
  The time from enrollment until disease progression or withdrawing from the study for other reasons, whichever occurs first, as assessed by the Investigator
• ORR, based on Investigator Assessment [ Time Frame: within approximately 30 months ]
  The percentage of participants with Best Response of Complete Response (CR) or Partial Response (PR), assessed by the Investigator
• Overall Survival (OS) [ Time Frame: within approximately 30 months ]
  Overall survival is defined as the time from enrollment until death from any cause, and is measured in the intent-to-treat population.
• Duration of Response (DoR) [ Time Frame: within approximately 30 months ]
  DoR is defined as the length of time the Best Response of CR or PR continued

This study will find out if trastuzumab deruxtecan is safe and works for participants with certain kinds of cancer.

They must have HER2-positive gastric or gastro-esophageal junction (GEJ) cancer:

• that cannot be removed surgically
• that has moved to other parts of the body
• that got worse during or after treatment that included trastuzumab

The study will enroll about 72 participants at about 25 to 30 sites. Sites will be in North America, Australia, Israel, and the European Union. There might be other countries as well.

• Adenocarcinoma Gastric Stage IV With Metastases
• Adenocarcinoma - GEJ

Inclusion Criteria:

• Men or women ≥18 years old (local regulatory guidelines apply)
• Has pathologically documented HER2-positive gastric or GEJ cancer that is unresectable or metastatic, and that progressed during or after treatment regimen containing trastuzumab
• Has at least one measurable lesion per RECIST v1.1, as confirmed by independent central review
• If of reproductive potential, agrees to use a highly effective form of contraception or avoid intercourse during and upon completion of the study and for at least 4.5 months after the last dose of study drug
• Has protocol-defined adequate cardiac, renal and hepatic function

Exclusion Criteria:

• Has had anticancer therapy after first-line treatment regimen containing trastuzumab
• Has uncontrolled cardiovascular disease, including any of the following: history of myocardial infarction (MI) within 6 months of enrollment or symptomatic congestive heart failure (New York Heart Association Class II to IV), troponin levels consistent with MI as defined according to the manufacturer within 28 days prior to enrollment, history of unstable angina or serious cardiac arrhythmia requiring treatment, or corrected QT interval (QTc) prolongation to >470 ms (females) or >450 ms (male) based on screening triplicate 12-lead electrocardiogram (ECG)
• Has history of non-infectious interstitial lung disease (ILD) or pneumonitis that required corticosteroid therapy, or current ILD/pneumonitis that cannot be ruled out at screening
• Has clinically significant corneal disease or any other condition or disease that, per protocol or in the opinion of the investigator, precludes participation
• Has pleural effusion, ascites, or pericardial effusion that requires drainage, peritoneal shunt, or Cell-free and Concentrated Ascites Reinfusion Therapy (CART)
• Has spinal cord compression or clinically active central nervous system metastases, defined as untreated and symptomatic or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms (Note: participants with clinically inactive brain metastases may be included in the study as well as participants with treated brain metastases who are no longer symptomatic and no longer require treatment with corticosteroids or anticonvulsants.