Inclusion Criteria:
* Pathologically documented adenocarcinoma of the stomach (clinical stage before surgery of AJCC I-III), gastroesophageal junction, or lower oesophagus (to include Type I Siewert only), with HER2 overexpression (IHC 3+ or IHC 2+/ISH+) based on local tissue testing results.
* ctDNA positive after surgery as per Signatera assay
* Capable of giving signed informed consent prior to any mandatory study specific procedures, sampling, or analyses and which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.
* Male and female participants must be at least 18 years of age at the time of signing the ICF.
* Treated with neoadjuvant chemotherapy before surgery for at least six weeks.
* Surgical resection with clear margins (R0).
* Recovered from surgery in the opinion of the investigator.
* No previous treatment with trastuzumab or other HER2 directed therapy.
* No evidence of metastatic disease on post-surgical CT.
* Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
* Has LVEF ≥ 50% by either echocardiogram (ECHO) or multigated acquisition (MUGA) scan within 28 days before treatment.
* Has adequate organ and bone marrow function within 14 days before treatment allocation as below:
* Platelet count ≥ 100x109/L (Platelet transfusion is not allowed within 1 week prior to screening assessment, use of thrombopoietin receptor agonists is not allowed within 2 weeks prior to screening assessment)
* Haemoglobin ≥ 80 g/L. Participants requiring transfusions or growth factor support to maintain haemoglobin ≥ 80 g/L are not eligible. (Red blood cell transfusions is not allowed within 1 week prior to screening assessment)
* Absolute neutrophil count ≥ 1.5 x 109/L (granulocyte-colony stimulating factor \[G-CSF\] administration is not allowed within 1 week prior to screening assessment
* ALT/AST ≤ 3 x ULN
* Total bilirubin ≤ 1.5 x ULN or \< 3 x ULN in the presence of documented Gilbert's Syndrome (unconjugated hyperbilirubinemia)
* Serum albumin ≥ 3.0 g/dl
* Creatinine clearance ≥ 50 mL/min as calculated using the Cockcroft-Gault equation
* Adequate clotting function International Normalized Ratio (INR) or prothrombin time and either partial thromboplastin or activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN.
* Reproduction:
* Evidence of post-menopausal status or negative serum pregnancy test for females of childbearing potential who are sexually active with a non-sterilised 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.
I. Women aged \<50 years will be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels in the post-menopausal range for the site.
II. Women aged ≥ 50 years will be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses \> 1 year ago, had chemotherapy-induced menopause with last menses \>1 year ago.
* Female participants of childbearing potential who are sexually active with a non-sterilised 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 participants must refrain from breastfeeding and must not donate (or retrieve their own for use) ova, from the time of screening, throughout the study treatment period, and for at least 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 in line with the patient's usual lifestyle (consideration must be made to the duration of the clinical trial); however, periodic or occasion abstinence, the rhythm method, and the withdrawal method are not acceptable methods of contraception.
* Non-sterilised male participants 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.
* It is strongly recommended for the female partners of a male participant to also use at least one highly effective method of contraception throughout this period. In addition, male participants should refrain from fathering a child or freezing or donating sperm from screening, throughout the study treatment period, and for at least 4 months after the last dose of IMP.
* Investigators should advise male participants on the conservation of sperm prior to starting treatment because of the possibility of irreversible infertility/testicular damage due to IMP administered in this study.
* Female subjects must not donate, or retrieve for their own use, ova from the time of enrolment and 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 prior to enrolment in this study, can be discussed with the patient if clinically appropriate to do so.
Exclusion Criteria:
* Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AE's, or compromise the ability of the participant to give written informed consent.
* Participants with a medical history of myocardial infarction within 6 months before treatment or symptomatic CHF (New York Heart Association Class II to IV), unstable angina pectoris, clinically important cardiac arrhythmias, or a recent (\<6 months) cardiovascular event, including myocardial infarction, unstable angina pectoris, and stroke. Participants with troponin levels above ULN at screening (as defined by the manufacturer)m and without myocardial related symptoms, should have a cardiologic consultation before enrolment to rule out myocardial infarction.
* Corrected QT interval (QTcF) prolongation to \> 470 msec (females) or \> 450 msec (males) based on average of the screening triplicate 12-lead ECG
* History of (non-infectious) ILD/pneumonitis, current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening.
* Any of the following:
1. Lung-specific intercurrent clinically significant illnesses including, but not limited to, any underlying pulmonary disorder (e.g., clinically significant pulmonary emboli within 3 months of treatment, severe asthma, severe chronic obstructive pulmonary disease, restrictive lung disease, clinically significant pleural effusion etc.)
2. Any autoimmune, connective tissue, or inflammatory disorders with pulmonary involvement (e.g., rheumatoid arthritis, Sjogren's, sarcoidosis etc.), where there is documented, or a suspicion of, pulmonary involvement at the time of screening
3. Prior pneumonectomy (complete)
* Uncontrolled infection requiring intravenous (IV) antibiotics, antivirals, or antifungals
* Multiple primary malignancies within the prior 3 years, except adequately resected non-melanoma skin cancer, curatively treated in situ disease, or other solid tumours curatively treated.
* A pleural effusion, ascites or pericardial effusion that requires drainage, peritoneal shunt.
* Unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to Grade ≤1 or baseline. The following exemption will apply; stable chronic G2 toxicity which in the opinion of the investigator is not reasonably expected to be exacerbated by treatment with study drugs.
* Known allergy or hypersensitivity to T-DXd or any of the study drug components
* History of severe hypersensitivity reactions or other monoclonal antibodies
* Pregnant or breastfeeding female participants, or participants who are planning to become pregnant
* Involvement in the planning and/or conduct of the study
* Has substance abuse or any other medical conditions, that may, in the opinion of the investigator, interfere with the subjects participation in the clinical study or evaluation of the clinical study results
* Receipt of live, attenuated vaccine within 30 days prior to the first dose of trastuzumab deruxtecan. Note: Patients, if enrolled, should not receive live vaccine during the study and up to 30 days after the last dose of IMP
* Active primary immunodeficiency, known human immunodeficiency virus (HIV) infection, or active hepatitis B or C infection. Patients positive for hepatitis (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
* Judgement by the Investigator that the participant should not participate in the study, if the participant is unlikely to comply with study procedures, restrictions, and requirements.
