This study will assess the efficacy and safety of T-DXd compared with Ram + PTX in
participants with HER2-positive (defined as immunohistochemistry [IHC] 3+ or IHC 2+/in situ
hybridization [ISH]+) gastric or GEJ adenocarcinoma (based on [American Society of Clinical
Oncology (ASCO) College of American Pathologists (CAP) guidelines and confirmed by central
assessment of tumor tissue) who have progressed on or after a trastuzumab-containing regimen
and have not received any additional systemic therapy. Participants will be randomized 1:1 to
either T-DXd or Ram + PTX treatment. The primary objective will assess overall survival.
Secondary objectives will further assess progression-free survival, objective response rate,
duration of response, disease control rate, safety, pharmacokinetics, and immunogenicity of
- Adults (according to local regulation) and able to provide informed consent for study
- Pathologically documented gastric and GEJ adenocarcinoma that has been previously
treated in the metastatic setting (unresectable, locally advanced, or metastatic
- Progression on or after first-line therapy with a trastuzumab or approved trastuzumab
biosimilar-containing regimen. Note: Prior adjuvant therapy with a
trastuzumab-containing regimen can be counted as a line of therapy if the subject
progressed on or within 6 months of completing adjuvant therapy.
- Centrally confirmed HER2-positive (IHC 3+ or IHC 2+ and evidence of HER2 amplification
by ISH) as classified by ASCO-CAP on a tumor biopsy obtained after progression on or
after a first-line trastuzumab or approved trastuzumab biosimilar-containing regimen.
- Eastern Cooperative Oncology Group performance status of 0 or 1 at both Screening and
within 3 days prior to randomization.
- Adequate bone marrow, renal, and hepatic function within 14 days of randomization.
- Use of anticancer therapy after trastuzumab-containing treatment
- Medical history of myocardial infarction (MI) within 6 months before
randomization/enrollment, symptomatic congestive heart failure (New York Heart
Association 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 Screening
- Has a pleural effusion, ascites, or pericardial effusion that requires drainage,
peritoneal shunt, or cell-free and concentrated ascites reinfusion therapy (CART).
Drainage and CART must be at least 2 weeks prior to Screening.
- Has a history of (non-infectious) interstitial lung disease (ILD/pneumonitis) that
required steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis
cannot be ruled out by imaging at Screening.
- Any autoimmune, connective tissue or inflammatory disorders (eg, rheumatoid arthritis,
Sjögren syndrome, sarcoidosis, etc.) where there is documented (or a suspicion of)
pulmonary involvement at the time of Screening.
- Prior pneumonectomy.
- 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.
- Has multiple primary malignancies within 3 years, except adequately resected
non-melanoma skin cancer, curatively treated in-situ disease, other solid tumors
- History of severe hypersensitivity reactions to either the T-DXd or inactive
ingredients in T-DXd.
- History of severe hypersensitivity reactions to other monoclonal antibodies or any
components used in the ramucirumab drug product preparation
- Known allergy or hypersensitivity to paclitaxel or any components used in the
paclitaxel preparation or other contraindication for taxane therapy such as peripheral
neuropathy, Grade 2.
- Current uncontrolled infection requiring antibiotics, antivirals, or antifungals or an
unexplained fever >38.0°C during Screening visits or on the first scheduled day of
dosing (at the discretion of the Investigator, participants with tumor fever may be
enrolled), which in the Investigator's opinion might compromise the participant's
participation in the study or affect the study outcome
- Clinically significant gastrointestinal disorder (eg, including hepatic disorders,
bleeding, inflammation, occlusion, ileus, diarrhea Grade >1, jaundice, intestinal
paralysis, malabsorption syndrome, ulcerative colitis, inflammatory bowel disease, or
partial bowel obstruction) in the opinion of Investigator