Trastuzumab Deruxtecan for Subjects With HER2-Positive Gastric Cancer or Gastro-Esophageal Junction Adenocarcinoma After Progression on or After a Trastuzumab-Containing Regimen (DESTINY-Gastric04)

Inclusion Criteria:

• Adults (according to local regulation) and able to provide informed consent forstudy participation.

• Pathologically documented gastric and GEJ adenocarcinoma that has been previouslytreated in the metastatic setting (unresectable, locally advanced, or metastaticdisease).

• Progression on or after first-line therapy with a trastuzumab or approvedtrastuzumab biosimilar-containing regimen. Note: Prior neoadjuvant or adjuvanttherapy with a trastuzumab-containing regimen can be counted as a line of therapy ifthe subject progressed on or within 6 months of completing neoadjuvant or adjuvanttherapy. Prior neoadjuvant or adjuvant therapy that does not include trastuzumabwill not be counted as a line of therapy regardless of the progression status of thesubject.

• Locally or centrally confirmed HER2-positive (IHC 3+ or IHC 2+ and evidence of HER2amplification by ISH) as classified by ASCO-CAP on a tumor biopsy obtained afterprogression on or after a first-line trastuzumab or approved trastuzumabbiosimilar-containing regimen.

• Eastern Cooperative Oncology Group performance status of 0 or 1 at Screening.

• Adequate bone marrow, renal, hepatic function, and blood clotting function within 14days of randomization.

Exclusion Criteria:

• Use of anticancer therapy after trastuzumab-containing treatment

• Medical history of myocardial infarction (MI) within 6 months beforerandomization/enrollment, symptomatic congestive heart failure (New York HeartAssociation Class II to IV).

• Has a QT interval corrected by Fridericia's formula (QTcF) prolongation to >470 msec (female subjects) or >450 msec (male subjects) based on average of the Screeningtriplicate12-lead ECG.

• Has a history of (non-infectious) interstitial lung disease (ILD/pneumonitis) thatrequired steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitiscannot be ruled out by imaging at Screening.

• Any autoimmune, connective tissue or inflammatory disorders (eg, rheumatoidarthritis, Sjögren syndrome, sarcoidosis, etc.) where there is documented (or asuspicion of) pulmonary involvement at the time of Screening.

• Prior complete pneumonectomy.

• Spinal cord compression or clinically active central nervous system metastases,defined as untreated and symptomatic or requiring therapy with corticosteroids oranticonvulsants to control associated symptoms.

• Has multiple primary malignancies within 3 years, except adequately resectednon-melanoma skin cancer, curatively treated in-situ disease, other solid tumorscuratively treated.

• History of severe hypersensitivity reactions to either the T-DXd or inactiveingredients in T-DXd.

• History of severe hypersensitivity reactions to other monoclonal antibodies,including ramucirumab or to any of its excipients.

• Known allergy or hypersensitivity to paclitaxel or any components used in thepaclitaxel preparation or other contraindication for taxane therapy.

• Current uncontrolled infection requiring antibiotics, antivirals, or antifungals oran unexplained fever >38.0°C during Screening visits or on the first scheduled dayof dosing (at the discretion of the Investigator, participants with tumor fever maybe enrolled), which in the Investigator's opinion might compromise the participant'sparticipation in the study or affect the study outcome

• Clinically significant gastrointestinal disorder (eg, including hepatic disorders,bleeding, inflammation, occlusion, ileus, diarrhea Grade >1, jaundice, intestinalparalysis, malabsorption syndrome, ulcerative colitis, inflammatory bowel disease,or partial bowel obstruction) in the opinion of Investigator

• Has history of receiving live, attenuated vaccine (mRNA and replication deficientadenoviral vaccines are not considered attenuated live vaccines) within 30 daysprior to the first exposure to study intervention