Adjuvant Trastuzumab Deruxtecan (Enhertu) & Nivolumab for Patients Who Are Disease Free After Completion of Trimodality Treatment for HER-2+ Cancers of Esophagus & Gastroesophageal Junction

Inclusion Criteria:

1. Pathologically confirmed primary adenocarcinoma of the esophagus, esophagogastricjunction or (Stomach involvement is allowed.).

2. HER2 overexpression defined by immunohistochemistry (IHC) 3+ or HER2 amplificationby fluorescence in situ hybridization (FISH). This may be defined by local orcommercial laboratories

3. Completed trimodality treatment with chemoradiation followed by esophagectomy andhad an R0 resection but did not achieve a complete pathologic response.

4. 4 - 12 weeks after esophagectomy.

5. Prior to trimodality treatment had stage T1N1-2 M0, T2-3N0-2 M0 disease.

6. Age ≥ 18

7. ECOG performance status 0-1

8. For women of childbearing potential, a negative serum pregnancy test within 7 daysprior to registration

9. Women of childbearing potential and male participants must practice highly effectiveform of non-hormonal contraception throughout the study, which is defined as fromstudy screening (ICF) through 2 months post last treatment; Non-sterilised malepartners of a woman of childbearing potential must use a male condom plus spermicide (condom alone in countries where spermicides are not approved) throughout thisperiod.

10. Ability to understand and the willingness to sign a written informed consentdocument.

11. LVEF ≥ 50% within 28 days before randomization/enrollment.

12. Adequate organ and bone marrow function within 14 days beforerandomization/enrolment. All parameters must meet the inclusion criteria on the sameday, and must be the most recent results available.

13. Evidence of post-menopausal status or negative serum pregnancy test for females ofchildbearing 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 thescreening visit and urine beta-human chorionic gonadotropin (β-HCG) pregnancy testprior to each administration of treatment. Women of childbearing potential aredefined as those who are not surgically sterile (i.e. underwent bilateralsalpingectomy, bilateral oophorectomy, or complete hysterectomy) or post-menopausal.Women will be considered post-menopausal if they have been amenorrheic for 12 monthswithout an alternative medical cause.

14. Female patients of childbearing potential who are sexually active with anon-sterilized male partner must use at least one highly effective method ofcontraception, from the time of screening and must agree to continue using suchprecautions for 7 months after the last dose of treatment. Not all methods ofcontraception are highly effective. Female patients must refrain from breastfeedingwhile on study and for 7 months after the last dose of treatment. Completeheterosexual abstinence for the duration of the study and drug washout period is anacceptable 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 arenot acceptable.

15. Non-sterilized male patients who are sexually active with a female partner ofchildbearing potential must use a condom with spermicide from screening to 4 monthsafter the final dose of treatment. Complete heterosexual abstinence for the durationof the study and drug washout period is an acceptable contraceptive method if it isin line with the patient's usual lifestyle (consideration must be made to theduration of the clinical trial); however, periodic or occasional abstinence, therhythm method, and the withdrawal method are not acceptable. It is stronglyrecommended for the female partners of a male patient to also use at least onehighly effective method of contraception throughout this period. In addition, malepatients should refrain from fathering a child, or freezing or donating sperm fromthe time of enrollment, throughout the study and for 4 months after the last dose oftreatment. Preservation of sperm should be considered prior to enrollment in thisstudy.

16. Female subjects must not donate, or retrieve for their own use, ova from the time ofenrollment and throughout the study treatment period, and for at least 7 monthsafter the final study drug administration. They should refrain from breastfeedingthroughout this time. Preservation of ova may be considered prior to enrollment inthis study.

Exclusion Criteria:

1. Has substance abuse or any other medical conditions such as clinically significantcardiac or psychological conditions, that may, in the opinion of the investigator,interfere with the subject's participation in the clinical study or evaluation ofthe clinical study results.

2. Patients with 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 myocardial related symptoms, should have acardiologic consultation before enrollment to rule out MI.

3. Corrected QT interval (QTcF) prolongation to > 470 msec (females) or >450 msec (males) based on average of the screening triplicate12-lead ECG.

4. History of arrhythmia (multifocal premature ventricular contractions, bigeminy,trigeminy, ventricular tachycardia), which is symptomatic or requires treatment (CTCAE Grade 3), symptomatic or uncontrolled atrial fibrillation despite treatment,or asymptomatic sustained ventricular tachycardia.

5. History of (non-infectious) ILD / pneumonitis that required steroids, has currentILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imagingat screening.

• Lung-specific intercurrent clinically significant illnesses including, but notlimited to, any underlying pulmonary disorder (e.g. pulmonary emboli withinthree months of the study enrollment, severe asthma, severe COPD, restrictivelung disease, pleural effusion etc.)

• Any autoimmune, connective tissue or inflammatory disorders (e.g. Rheumatoidarthritis, Sjogren's, sarcoidosis etc.) where there is documented, or asuspicion of pulmonary involvement at the time of screening. Full details ofthe disorder should be recorded in the eCRF for patients who are included inthe study.

• Prior pneumonectomy (complete)

6. Uncontrolled infection requiring IV antibiotics, antivirals, or antifungals

7. Active primary immunodeficiency, known uncontrolled active HIV infection or activehepatitis B or C infection, such as those with serologic evidence of viral infectionwithin 28 days of Cycle 1 Day 1. Subjects with past or resolved hepatitis B virus (HBV) infection who are anti-HBc positive (+) are eligible only if they are HBsAgnegative (-).

8. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerasechain reaction is negative for HCV RNA.

9. Receipt of live, attenuated vaccine (mRNA and replication deficient adenoviralvaccines are not considered attenuated live vaccines) within 30 days prior to thefirst dose of trastuzumab deruxtecan. Note: Patients, if enrolled, should notreceive live vaccine during the study and up to 30 days after the last dose oftreatment.

10. Has unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to Grade ≤ 1 or baseline. Note: Subjects maybe 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] andmanaged with standard of care treatment) that the investigator deems related toprevious anticancer therapy, such as:

• Chemotherapy-induced neuropathy

• Fatigue

11. Known allergy or hypersensitivity to study treatment or any of the study drugexcipients.

12. History of severe hypersensitivity reactions to other monoclonal antibodies.

13. Pregnant or breastfeeding female patients, or patients who are planning to becomepregnant.

14. Multiple primary malignancies within 3 years, with the exception of

• adequately resected non-melanoma skin cancer

• curatively treated in-situ disease

• other solid tumors curatively treated

• contralateral breast cancer.

15. A pleural effusion, ascites or pericardial effusion that requires drainage,peritoneal shunt, or pleurx catheter

16. No prior treatment with nivolumab, other immunotherapy agents for esophageal cancer,or trastuzumab deruxtecan or other HER2 directed agent or other investigationalanti-cancer agent.

17. Pregnant women, or patients planning to become pregnant, are excluded from thisstudy because both nivolumab and trastuzumab deruxtecan have the potential forteratogenic or abortifacient effects.

18. In order for patients with known history of testing positive for humanimmunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS) tobe eligible, they must be on a stable highly active antiretroviral therapy (HAART)regimen, have CD4 counts > 350, with no detectable viral load on quantitative PCRwithin 4 weeks of registration.

19. Patients with active autoimmune disease or history of autoimmune disease that mightrecur, which may affect vital organ function or require immune suppressive treatmentincluding systemic corticosteroids, should be excluded. These include but are notlimited to patients with a history of immune related neurologic disease, multiplesclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome,myasthenia gravis; systemic autoimmune disease such as SLE, connective tissuediseases, scleroderma, inflammatory bowel disease, Crohn's, ulcerative colitis, andpatients with a history of toxic epidermal necrolysis (TEN), Stevens-Johnsonsyndrome, or phospholipid syndrome should be excluded because of the risk ofrecurrence or exacerbation of disease. Patient with vitiligo, endocrine deficienciesincluding thyroiditis managed with replacement hormones including physiologiccorticosteroids are eligible. Patients with rheumatoid arthritis and otherarthropathies, Sjogren's syndrome and psoriasis controlled with topical medicationand patients with positive serology, such as antinuclear antibodies (ANA),anti-thyroid antibodies should be evaluated for the presence of target organinvolvement and potential need for systemic treatment (which would preclude them)but should otherwise be eligible. All information to be documented by treatingphysician.

20. Patients are permitted to enroll if they have vitiligo, type I diabetes mellitus,residual hypothyroidism due to autoimmune condition only requiring hormonereplacement (such as Hashimoto's thyroiditis), psoriasis not requiring systemictreatment, or conditions not expected to recur in the absence of an external trigger (precipitating event), as confirmed by treating physician.

21. Patients should be excluded if they have a condition requiring systemic treatmentwith either corticosteroids (>10 mg daily prednisone equivalents) or otherimmunosuppressive medications within 14 days of day 1 study drug administration.Inhaled or topical steroids and adrenal replacement doses <10 mg daily prednisoneequivalents are permitted in the absence of active autoimmune disease. Patients arepermitted to use topical, ocular, intra-articular, intranasal, and inhalationalcorticosteroids (with minimal systemic absorption). A brief course ofcorticosteroids for prophylaxis (e.g., contrast dye allergy) or for treatment ofnon-autoimmune conditions (e.g., delayed-type hypersensitivity reaction caused bycontact allergen) is permitted.

22. Any other medical condition that will prevent the safe administration of study drugsin the opinion of the treating physician.

23. Planned concomitant, non-protocol directed anti-cancer therapy during the trial.