Trial of Trastuzumab Deruxtecan (Enhertu®) Plus Chemotherapy Plus or Minus Pembrolizumab versus Chemotherapy Plus Trastuzumab Plus or Minus Pembrolizumab in First-line Metastatic HER2-positive Gastric or GEJ Cancer

Prior treatment

• Prior exposure to other HER2-targeting therapies (including ADCs).
• Prior pneumonectomy (complete).
• Has spinal cord compression, known clinically active central nervous system metastases (defined as untreated and symptomatic) and/or carcinomatous meningitis. Note: Participants with previously treated brain metastases may participate provided they a) are radiologically stable (ie, without evidence of progression) for at least 4 weeks as confirmed by repeat imaging performed during trial screening, b) are clinically stable (ie, asymptomatic and have not required steroid treatment or anticonvulsant for at least 14 days before the first dose of trial intervention), and c) have recovered from the acute toxic effect of radiotherapy. A minimum of 2 weeks must have elapsed between the end of whole brain radiotherapy and trial randomization.
• Has an active primary immunodeficiency, known active or uncontrolled HIV infection, including HIV-infected participants with a history of Kaposi’s sarcoma and/or Multicentric Castleman’s Disease. Note: HIV testing is required prior to randomization for all participants enrolled in the EU and Japan. For other regions, HIV testing should be performed if required by local regulations or IRB/EC.
• Has history of receiving live, attenuated vaccine (mRNA and replication deficient adenoviral vaccines are not considered attenuated live vaccines) within 30 days prior to the first dose of trial intervention.
• Has unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to ≤Grade 1 or baseline.
• Applicable for main cohort only: Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior the first dose of trial intervention.

Other illness

• Has known additional malignancy that is progressing or has required active treatment within the past 3 years. Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ, excluding carcinoma in situ of the bladder, who have undergone potentially curative therapy are not excluded.
• Has a history of severe hypersensitivity reactions (≥Grade 3) to either the drug substances or inactive ingredients in the drug product.
• Has an uncontrolled infection requiring systemic antibiotics, antivirals, or antifungals.
• Has substance abuse, other medical conditions such as clinically significant cardiac or psychological conditions, or any other circumstance such that it is not in the best interest of the participant to participate, that may, in the opinion of the investigator, interfere with the participant’s participation in the clinical trial or evaluation of the clinical trial results.
• 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.
• Applicable for main cohort only: Has an active autoimmune disease that has required systemic treatment in past 2 years(ie, with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc) is not considered a form of systemic treatment and is allowed.
• Applicable for main cohort only: Has active tuberculosis (Mycobacterium tuberculosis), defined as clinical symptoms suggestive of tuberculosis, radiological findings, microbiological confirmation and exclusion of latent tuberculosis. Participants with past infection but treated and recovered at the time of screening are eligible. No testing for tuberculosis is required unless mandated by local health authority.
• Applicable for main cohort only: History of allogenic tissue/solid organ transplant.
• 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).
• Any autoimmune, connective tissue, or inflammatory disorders (eg, rheumatoid arthritis,Sjogren’s, sarcoidosis etc) where there is documented, or a suspicion of, pulmonary involvement at the time of screening. Full details of the disorder should be recorded in the eCRF for participants who are included in the trial.

Lab values

• Has active or uncontrolled hepatitis B virus infection. Participants are eligible if they meet the criteria below: a. HBsAg positive with chronic HBV infection (lasting 6 months or longer) and meet the additional conditions below: • HBV DNA viral load <2000 IU/mL • Start or maintain antiviral treatment if clinically indicated as per the investigator b. Normal transaminase values, or if liver metastases are present, has abnormal transaminase values with AST/ALT <3 × ULN that are not attributable to HBV infection.
• Has active or uncontrolled hepatitis C virus infection. Participants are eligible if they meet the conditions below: a. History of hepatitis C infection with an HCV viral load that is below the level of detection in the absence of antiviral therapy during the previous 4 weeks. b. Normal transaminase values or, if liver metastases are present, has abnormal transaminase values with AST/ALT <3 × ULN that are not attributable to HCV infection.
• 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.

Other

• Is pregnant or breastfeeding or planning to become pregnant.
• 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.

• 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.
• Adequate organ and bone marrow function within 14 days before randomization. Transfusion (red blood cell or platelet) or G-CSF administration is not allowed within 14 days prior to the day on which bone marrow function is assessed or at any time after this day and prior to Cycle 1 Day 1. Please refer to the protocol for further details..
• Adequate treatment washout period before randomization. Please refer to the protocol for further details.
• Male and female participants of reproductive/childbearing potential must agree to use a highly effective form of contraception, as detailed in Section 10.3.4, or avoid intercourse during trial intervention and for at least 7 months for females and 4 months for males after the last dose of trial intervention. Please refer to the protocol for further details.
• Male participants must not freeze or donate sperm starting at randomization and throughout the trial period, and at least 4 months after the last dose of T-DXd. For participants receiving pembrolizumab, trastuzumab, 5-FU, capecitabine, cisplatin, or oxaliplatin, sites should follow local label or institutional guidelines. Preservation of sperm should be considered prior to randomization in this trial.
• Female participants must not donate, or retrieve for their own use, ova from the time of randomization and throughout the trial intervention period, and for at least 7 months after the last dose of T-DXd. For participants receiving pembrolizumab, trastuzumab, 5-FU, capecitabine, cisplatin, or oxaliplatin, sites should follow local label or institutional guidelines. They should refrain from breastfeeding throughout this time. Preservation of ova may be considered prior to randomization in this trial.
• Is willing and able to comply with scheduled visits, trial intervention plan, laboratory tests, other trial procedures, and trial restrictions.
• Is willing and able to participate in the collection of PRO data. Note: If a participant is unable to read the questionnaire (ie, blind or illiterate) or if the linguistic version is not available for the participant’s native or preferred language, that participant will be exempted from completing PRO questionnaires but may still participate in the trial.
• 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 22C3 PharmDx 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 measurif progression has been shown in such lesions.
• LVEF ≥50% within 28 days before randomization.
• ECOG performance status of 0 or 1 assessed within 7 days before randomization.