Phase 2 Study of Trastuzumab Deruxtecan in the Neoadjuvant Treatment, or Trastuzumab Deruxtecan Plus Capecitabine Plus Durvalumab(MEDI4736) in the Preoperative and Postoperative Adjuvant Treatment for Patients with HER2 Positive Gastric and Gastroesophageal Junction Adenocarcinoma

Inclusion Criteria:

1. Histologically confirmed adenocarcinoma of the gastric or gastroesophageal junction.

2. Has HER2 overexpression (IHC3+, or IHC2+ and ISH positive [FISH or DISH]). (HER2 Lowexpression: IHC1+, or IHC2+ and ISH-negative [FISH or DISH] with HER2-ECD > 11.6ng/mL in the exploratory cohort).

3. Have previously untreated gastric and gastroesophageal junction adenocarcinoma andcT2-4 and/or cN+M0.according to the UICC TNM classification (8th edition),

4. Age ≥ 20 years as the day of informed consent.

5. Has an ECOG performance status (PS) of 0 or 1.

6. Has a left ventricular ejection fraction (LVEF) ≥ 50% by either echocardiogram (ECHO) or multigated collecting acquisition (MUGA) scan within 28 days beforeenrollment (acceptable on the same day of the week).

7. Has a corrected QT interval (QTc) ≦ 470 ms in females, or QTc ≦ 450 ms in malesbased on a 12-lead ECG screening within 28 days before enrollment (allowed on thesame day of the week). [Fridericia's correction is recommended]

8. Satisfies all of the following requirements within 14 days before enrollment (allowed on the same day of the week).

• Absolute neutrophil count ≧1500 / mm3 [except for assessment ≦ 14 days afteradministration of Granules colony-stimulating factors (G-CSF)]

• Hemoglobin ≧ 8.0 g/dL (except for those measured within 7 days after wholeblood transfusion or packed red blood cells)

• Platelet count ≧100000 per mm3 (excluding measurements within 7 days afterplatelet transfusion).

• Total bilirubin ≦1.5 mg/dL (patients with gilbert's syndrome will be allowed ifthey have < 3.0 mg/dL).

• AST(GOT)≦100 IU/L

• ALT(GPT)≦100 IU/L

• Serum albumin ≧ 2.5 g/dL

• Calculated creatinine clearance (Cockcroft-Gault ＊) or the actual value ≧ 30mL/min ＊ Cockcroft-Gault equation: creatinine clearance= (140 - age) × body weight (kg) / (72 × Serum creatinine) (* 0.85 x the value obtained for females).

• PT(INR)< 1.8

• aPTT < 60 seconds

9. Has a treatment-free period from the end of pre-treatment to before enrollment (allowed on the same day of the week), defined as: i. Surgery with general anesthesia : ≧ 4 weeks ii. Radiotherapy: ≧ 4 weeks (including palliative stereotactic body radiation therapy to the chest; palliativestereotactic body radiation therapy to other than the chest ≧ 2 weeks; abdominalvertebral bodies should be included in the abdomen). iii. Chloroquine and hydroxychloroquine : ≧ 15 days

10. Has a prior radiotherapy or surgical AE recovered of ≦ Grade 1 or ≦ baseline onCTCAE v5.0. However, this shall not apply to events where the symptoms are stableeven if they are grade 2 or higher.

11. Female of childbearing potential have a negative pregnancy test within 7 days beforeenrollment (allowed on the same day of the week). Male and Female of childbearingpotential agree to contraception for a period (4 months for male and 7 months forFemale) from informed consent to the last dose of study drug (see 4.3 "Pregnancy andcontraception").

12. Written informed consent of participation in the study has been obtained from thepatient.

Exclusion Criteria:

1. Has a medical history of myocardial infarction or congestive heart failure (New YorkHeart Association Classes II-IV) within 6 months before enrollment, corresponding tothe value diagnosed as myocardial infarction as defined by the *validated testwithin 28 days before enrollment (allowed on the same day), unstable angina, or anyserious arrhythmia requiring treatment.

• tested in local institutions **: Enrollment is allowed with value exceeds ULNif myocardial infarction can be excluded.

2. Active other cancers [Synchronous other cancers and metachronous other cancerswithin 3 years prior to enrollment, but carcinoma in situ or other lesionscorresponding to mucosal carcinoma that are considered curable with local treatmentwill not be included in active other cancers.]

3. Has serious (hospitalized) complications (intestinal palsy, intestinal obstruction,pulmonary fibrosis, diabetes mellitus that is difficult to control, heart failure,myocardial infarction, unstable angina, renal failure, liver failure, psychiatricdisorders, cerebrovascular disorders, etc.).

4. Has history of gastrointestinal perforation and/or gastrointestinal fistula within 6months before enrollment.

5. Has any of the following infections:

• HBs antigen positive

• HBs antibody or HBc antibody and HBV-DNA positive

• Active hepatitis C (eg, if HCV RNA is detected qualitatively) Patients who areHBsAg positive but who have achieved HBV DNA level < 1.3 log IU/mL (2.1 logcopies/mL) after treatment with antiviral drugs such as NAs, are eligible forthe study.

6. HIV infection

7. Lung diseases defined as:

• Has a history of non-infectious interstitial lung disease or pneumonitis thatrequired treatment, has interstitial lung disease or pneumonitis, or these lungdiseases cannot be ruled out by radiographic examination before enrollment.

• Severe pulmonary disease (eg, pulmonary embolism within 3 months prior toenrollment, serious bronchial asthma, severe COPD, restrictive pulmonarydisease, or pleural effusion). Lung-related autoimmune or connective tissue or inflammatory diseases (eg,rheumatoid arthritis, Sjögren's syndrome, or sarcoidosis) with clinically severepulmonary risks.

• Has history of pneumonectomy.

8. Has history of concomitant autoimmune disease or chronic or recurrent autoimmunedisease.

9. Administration of systemic corticosteroids (except prophylactic administration fordiagnostic tests or allergic reactions, and temporary use for the purpose ofreducing edema associated with radiotherapy) or immunosuppressants is required, orhas received these treatments within 14 days before enrollment in the study.

10. Has unhealed wounds, ulcers, or fractures.

11. If patients are a pregnancy or breastfeeding patient.

12. Has documented severe hypersensitivity to study drug active ingredients oradditives.

13. Has history/complications of severe hypersensitivity reactions to other monoclonalantibodies.

14. has uncontrolled acute systemic infection that requires Infusion intravenousantibiotic, antiviral, or antifungal drug.

15. Unwilling or unable to follow study protocol or any of the instructions by thephysician.

16. The investigator or subinvestigator considered it ineligible for the study.