Platform Trial Evaluating Treatment of Neoadjuvant Trastuzumab-deruxtecan Containing Combination Therapies for HER2+, Resectable Esophagogastric Adenocarcinoma

Inclusion Criteria:

1. Patient* has given written informed consent.

2. Patient is ≥ 18 years of age at time of signing the written informed consent.

3. Patient has histologically proven locally advanced (cT2-4, any cN, M0 OR any cT,cN+, M0 stage) gastric, esophagogastric junction or lower esophageal adenocarcinomathat:

4. Is considered technically resectable

5. Does not involve distant site of the peritoneal cavity

• confirmed by diagnostic laparoscopy for all patients with tumors locatedin the stomach and those with type 2 and 3 GEJ adenocarcinomas accordingto guideline recommendation [Lordick et al. 2022].
• Type 1 GEJ and lower esophageal tumors can be enrolled without diagnosticlaparoscopy (which is in line with guidelines and the current routinepractice in Germany)

4. Patient has a HER2 positive tumor (by local testing) defined by HER2 IHC 3+ or IHC 2+ plus ISH positive with a HER2:CEP17 ratio of ≥ 2 according to classically usedcriteria for defining HER2 positivity [Lordick et al. 2017] .

5. Patient has a ECOG performance status 0 or 1.

6. Patient has adequate blood count, liver-enzymes, and renal function:

7. ANC > 1,500 cells/μL without the use of hematopoietic growth factors

8. Platelet count ≥ 100 x 109/L (>100,000 per mm3)**

9. Hemoglobin ≥ 9 g/dL**

10. Serum total bilirubin ≤ 1.5x institutional upper normal limit (ULN)

11. AST (SGOT)/ALT (SGPT) ≤ 2.5 x institutional ULN

12. Patients not receiving therapeutic anticoagulation must have an INR ≤ 1.5 ULNand aPTT ≤ 1.5 ULN. The use of full dose anticoagulants is allowed as long asthe INR or PTT is within therapeutic limits (according to the medical standardin the institution) and the patient has been on a stable dose foranticoagulants for at least three weeks at the time of inclusion

13. Serum Creatinine ≤ 1.5 x ULN and a calculated creatinine clearance rate ≥ 50 mL /min

14. Female patients defined as women of childbearing potential (WOCBP) must agree toremain abstinent (refrain from heterosexual intercourse) or use contraceptivemethods that result in a failure rate of <1% per year during the treatment periodand for 6 months after last dose of chemotherapy or 7 months after the last dose ofT-DXd, whatever is later.

15. Male patients with WOCBP partners must agree to remain abstinent (refrain fromheterosexual intercourse) or use barrier contraceptive during the treatment periodas well as up to 4 months after last dose of T-DXd or up to 6 months after last doseof chemotherapy, whatever is later. Male patients must refrain from donating spermduring this same period.

Exclusion Criteria:

1. Patient received previous (radio)chemotherapy or HER2-targeted therapy for the samecondition or within the past five years for any other cancerous condition.

2. Patient received prior partial or complete esophagogastric tumor resection.

3. Patient has known hypersensitivity to any component of the T-DXd formulation as wellas a known history of severe allergic, anaphylactic, or other hypersensitivityreactions to chimeric or humanized antibodies or fusion protein and/or any knowncontraindication (including hypersensitivity) to one of the study drugs.

4. Patient has a history of (non-infectious) pneumonitis/interstitial lung disease thatrequired steroids or has current pneumonitis/interstitial lung disease.

5. Patient has lung-specific intercurrent clinically significant illnesses including,but not limited to, any underlying pulmonary disorder (e.g., pulmonary emboli withinthree months of the study enrolment, severe asthma, severe COPD, restrictive lungdisease, pleural effusion etc.).

6. Patient received a prior complete pneumonectomy

7. Patient has inadequate cardiac function (LVEF value < 50 %) as determined byechocardiography.

8. Patient has a known complete absence of dihydropyrimidine dehydrogenase (DPD)activity

9. Patient received treatment with brivudine, sorivudine or their chemically relatedanalogues within 28 days prior to stud enrollment

10. Patients has pernicious anemia or other megaloblastic anemia due to vitamin B12deficiency

11. Patient has peripheral sensitive neuropathy with functional deficits.

12. Patient has a medical history of myocardial infarction (MI) within 6 months beforeenrollment, symptomatic congestive heart failure (CHF) (New York Heart AssociationClass II to IV). Subjects with troponin levels above ULN at screening (as defined bythe manufacturer), and without any MI related symptoms should have a cardiologicconsultation during screening to rule out MI.

13. Patient has a corrected QT interval (QTc) prolongation to > 470 ms (females) or >450ms (males) based on average of the screening triplicate12-lead ECG.

14. Patient has a history of malignancy other than EGA except for:

15. Malignancy treated with curative intent and with no known active disease ≥ 5years before the first dose of study treatment and of low potential risk forrecurrence.

16. Adequately treated non-melanoma skin cancer or lentigo maligna without evidenceof disease.

17. Adequately treated carcinoma in situ without evidence of disease.

18. Patient has an uncontrolled infection requiring IV antibiotics, antivirals orantifungals

19. Patient has active primary immunodeficiency, known uncontrolled active HIV infectionor active hepatitis B or C (HBV/HCV) infection. Patients positive for HCV antibodyare eligible only if PCR is negative for HCV RNA. Subjects with past or resolved HBVinfection are eligible only if they meet all of the following criteria*:

• HBsAg(-) (for > 6 months off anti-viral treatment)

• Anti-HBc(+) (IgG or total Ig)

• HBV DNA undetectable

• Absence of cirrhosis or fibrosis on prior imaging or biopsy

• Absence of HCV co-infection or history of HCV co-infection

• Access to a local hepatitis B expert during and after the study

17. Patient has any autoimmune, connective tissue or inflammatory disorders (e.g.,Rheumatoid arthritis, Sjogren's, sarcoidosis etc.) with a documented or suspectedpulmonary involvement

18. Patient received live, attenuated vaccine within 30 days prior initiation of studydrug

19. Patient has any other serious concomitant or medical condition that, in the opinionof the investigator, presents a high risk of complications to the patient or reducesthe likelihood of clinical effect.

20. Patient participated in another interventional clinical study within 28 days priorto study enrollment or participation in a clinical study at the same time as thisstudy, unless it is an observational/ non-interventional study or during thefollow-up period of an interventional study.

21. Patient has taken an investigational drug within 28 days prior to initiation ofstudy drug.

22. Female patients, who are pregnant or breast feeding or planning to become pregnantwithin 7 months after the end of treatment. Female patients of childbearingpotential must have a negative serum pregnancy test result within 7 days prior toinitiation of study treatment