Adjuvant TRastuzumab Deruxtecan for HER2-positive Gastroesophageal Cancer With Persistence of miNImal Residual Disease

Inclusion Criteria of the Interventional TRINITY study: 1. Written informed consent and any locally required authorization (such as the European Union \[EU\] Data Privacy Directive) obtained from the patient/legal representative prior to performing any protocol-related procedures, including screening evaluations. 2. Compliance with all the study procedures and treatments. Patients must be accessible for treatment and follow-up. Patients registered on this trial must be treated and followed at the participating Centre. 3. Age ≥ 18 years old. 4. Eastern Cooperative Oncology group (ECOG) Performance Status 0-1. 5. Life expectancy of at least 12 weeks. 6. Resected gastric or gastroesophageal junction (Siewert I-II-III) cancer/esophageal adenocarcinoma, after the completion of pre-operative chemotherapy with FLOT, as per standard clinical practice. 7. Absence of distant metastases as defined by post-operative radiological assessments (contrast-enhanced CT scan of the thorax and abdomen or, in case of contraindications, non-contrast-enhanced chest CT scan and abdomen Magnetic Resonance Imaging) 8. Presence of locally determined HER2 overexpression/amplification on the post-treatment surgical tissue specimen defined as IHC 3+ or 2+/ISH amplified. 9. Positivity of the post-operative liquid biopsy, performed 2-6 weeks after the radical surgery. 10. LVEF ≥ 50% within 28 days before randomization/enrolment. 11. Adequate bone marrow and organ function within 14 days before randomization/enrolment as described below: 1. Neutrophil count ≥ 1.5 x 10\^3/μL 2. Platelet count ≥ 100 x 10\^6/μL 3. Haemoglobin ≥ 9 g/dL 4. Total bilirubin lower than 1.5 time the upper-normal limits (ULN) of the Institutional normal values 5. AST (SGOT) and/or ALT (SGPT) \<3 x ULN 6. serum albumin ≥ 2.5 g/dL 7. Creatinine clearance (calculated according to Cockroft and Gault) \> 60 mL/min 8. International normalised ratio or Prothrombin time and either partial thromboplastin or activated partial thromboplastin time ≤ 1.5 × ULN 12. Evidence of post-menopausal status or negative serum pregnancy test for females of childbearing potential who are sexually active with a non-sterilized male partner. For women of childbearing potential, a negative result for serum pregnancy test (test must have a sensitivity of at least 25 mIU/mL) must be available at the screening visit and urine beta-human chorionic gonadotropin (β-HCG) pregnancy test prior to each administration of IMP. Women of childbearing potential are defined as those who are not surgically sterile (i.e. underwent bilateral salpingectomy, bilateral oophorectomy, or complete hysterectomy) or post-menopausal. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause. 13. Female patients of childbearing potential who are sexually active with a non-sterilized male partner must use at least one highly effective method of contraception, from the time of screening and must agree to continue using such precautions for 7 months after the last dose of IMP. Not all methods of contraception are highly effective. Female patients must refrain from breastfeeding while on study and for 7 months after the last dose of IMP. Complete heterosexual abstinence for the duration of the study and drug washout period is an acceptable contraceptive method if it is line with the patient's usual lifestyle (consideration must be made to the duration of the clinical trial); however, periodic or occasional abstinence, the rhythm method, and the withdrawal method are not acceptable. 14. Non-sterilized male patients who are sexually active with a female partner of childbearing potential must use a condom with spermicide from screening to 4 months after the final dose of IMP for T-DXd while 6 months for docetaxel and oxaliplatin. Complete heterosexual abstinence for the duration of the study and drug washout period is an acceptable contraceptive method if it is in line with the patient's usual lifestyle (consideration must be made to the duration of the clinical trial); however, periodic or occasional abstinence, the rhythm method, and the withdrawal method are not acceptable. It is strongly recommended for the female partners of a male patient to also use at least one highly effective method of contraception throughout this period. In addition, male patients should refrain from fathering a child, or freezing or donating sperm from the time of randomisation/enrolment, throughout the study and for 4 months after the last dose of IMP for T-DXd while 6 months for docetaxel and oxaliplatin. Preservation of sperm should be considered prior to enrollment in this study. 15. Female subjects must not donate, or retrieve for their own use, ova from the time of randomization/enrolmentand throughout the study treatment period, and for at least 7 months after the final study drug administration. They should refrain from breastfeeding throughout this time. Preservation of ova may be considered prior to enrollment in this study. Exclusion Criteria of the Interventional TRINITY study: 1. Involvement in the planning and/or conduct of the study (applies to both Investigator staff and/or staff at the study site) 2. Participation in another clinical study with an investigational product during the last 12 months 3. Signs of distant metastases at any site. 4. Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, renal disease, neurological disease or peripheral neuropathy, serious chronic gastrointestinal conditions associated with diarrhea, or substance abuse or any other medical or psychiatric illness/social situations that in the opinion of the investigator would limit compliance with study requirement, interfere with the subject's participation in the clinical study, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent or interfere with the evaluation of the clinical study results. 5. Patients with a medical history of myocardial infarction (MI) within 6 months before randomization/enrolment, symptomatic congestive heart failure (CHF) (New York Heart Association Class II to IV), Subjects with troponin levels above ULN at screening (as defined by the manufacturer), and without any myocardial related symptoms, should have a cardiologic consultation before enrollment to rule out MI. 6. Corrected QT interval (QTcF) prolongation to \> 470 msec (females) or \>450 msec (males) based on average of the screening triplicate12-lead ECG. 7. 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 criteria: * Lung-specific intercurrent clinically significant illnesses including, but not limited to, any underlying pulmonary disorder (e.g. pulmonary emboli within three months of the study enrollment, severe asthma, severe COPD, restrictive lung disease, pleural effusion etc.) * Any autoimmune, connective tissue or inflammatory disorders (e.g. 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 patients who are included in the study. * Prior pneumonectomy (complete) 9. Uncontrolled infection requiring IV antibiotics, antivirals, or antifungals 10. Active primary immunodeficiency, known human immunodeficiency virus (HIV) infection not under adequate disease control (that is defined as the presence of all the following conditions: receiving stable regimen of highly active anti-retroviral therapy for at least 4 weeks prior to study enrollment, CD4+ count above 250 cells/μL, undetectable viral load on standard polymerase chain reaction-based tests, absence of any HIV-related opportunistic infections for at least 4 weeks prior to study enrollment and no requirement for concurrent antibiotics or antifungal agents for the prevention of opportunistic infections), or active hepatitis B or C infection (HBsAg, anti-HBs, anti-HBc, anti-HCV). Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA. Patients who are anti-HBc positive and HBsAg negative or patients with HBsAg positive have to dose HBV-DNA. If HBV DNA is undetectable (\<10UL/ml or under the limit of detection per local lab standard) are considered as HBV negative. Subjects should be tested for HIV prior to randomization/enrollment if required by local regulations or institutional review board (IRB)/ethics committee (EC). 11. Receipt of live, attenuated vaccine (mRNA and replication deficient adenoviral vaccines are not considered attenuated live vaccines) within 30 days prior to the first dose of T-DXd. Note: Patients, if enrolled, should not receive live vaccine during the study and up to 30 days after the last dose of IMP. 12. Has unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to Grade ≤ 1 or baseline. Subjects may be enrolled with chronic, stable Grade 2 toxicities (defined as no worsening to \>Grade 2 for at least 3 months prior to \[randomization/enrollment/Cycle 1 Day 1\] and managed with standard of care treatment) that the investigator deems related to previous anticancer therapy, such as: chemotherapy-induced neuropathy and fatigue. 13. Known allergy or hypersensitivity to study treatment or any of the study drug excipients. 14. History of severe hypersensitivity reactions to other monoclonal antibodies. 15. Pregnant or breastfeeding female patients, or patients who are planning to become pregnant. 16. Multiple primary malignancies within 3 years, except for * adequately resected non-melanoma skin cancer * curatively treated in-situ disease * other solid tumors curatively treated 17. A pleural effusion, ascites or pericardial effusion that requires drainage, peritoneal shunt, or Cell-free and Concentrated Ascites Reinfusion Therapy (CART). 18. LVEF\< 50% within 28 days before enrolment. 19. Prior treatment with an anti-HER2 agent. 20. Absence of locally determined HER2 overexpression/amplification on the surgical specimen defined as IHC 0 or 1+ or 2+/ISH not amplified. 21. Negativity of ctDNA at the post-operative liquid biopsy. 21\. Known dihydropyrimidine dehydrogenase (DPD) enzyme deficiency based on local laboratory testing before the start of pre-operative FLOT regimen. Confirmation of the assessment of DPD status before the start of pre-operative FLOT in the patient's records should be provided before the enrollment in the interventional study.