Neratinib In Combination With Chemotherapy/Trastuzumab/Pembrolizumab In HER2 Gastroesophageal Cancer

Inclusion Criteria:

• Patients must have pathologically or cytologically confirmed esophageal, gastric orgastroesophageal junction (GEJ) adenocarcinoma by the enrolling institution.

• Patients must have esophageal, gastric or GEJ adenocarcinoma with HER2overexpression and/oramplification as determined by immunohistochemistry (IHC 3+) orfluorescent in situ hybridization (FISH+ as defined as HER2:CEP17 ratio ≥2.0 if IHC 2+). No central testing will be required. The testing can be performed on archivaltissue that is less than 6 months old. If archival tissue is more than 6 months old,a new biopsy must be obtained to confirm HER2 status prior to enrollment.

• Patients may have received no prior chemotherapy or be treatment naïve for stage IVdisease. Patients may have received prior adjuvant therapy (chemotherapy and/orchemoradiation) if more than 6 months have elapsed between the end of adjuvanttherapy and expected date of treatmentstart on this study. Patients who havereceived maintenance nivolumab after chemoradiation and surgery would be eligible aslong as the last dose of nivolumab was more than 3 months from thedate of expecteddate of treatment start on this study.

• Patients must have measurable disease per RECIST v1.1.

• Patients must not have active decompensated cardiomyopathy and must have a normalLVEF (≥ 53%). If a patient has a borderline LVEF (40-52%), they may be consideredafter consultation with cardiology and study PI.

• ECOG performance status 0 or 1.

• Demonstrate adequate organ function as outlined in protocol.

• Female patients of childbearing potential should have a negative urine or serumpregnancy within 72hours prior to receiving the first dose of study medication. Ifthe urine test is positive or cannot be confirmed as negative, a serum pregnancytest will be required.

• Female patients of childbearing potential should be willing to use 2 methods ofbirth control or be surgically sterile or abstain from heterosexual activity for thecourse of the study through 120 days after the last dose of study medication.Patients of childbearing potential are those who have not been surgically sterilizedor have not been free from menses for > 2 years.

• Male patients should agree to use an adequate method of contraception starting withthe first dose of study therapy through 120 days after the last dose of studytherapy.

• Participants with treated brain metastases are eligible if follow-up brain imagingafter central nervous system- (CNS-) directed therapy shows no evidence ofprogression at 4-6 weeks after treatment.

• Ability to understand and the willingness to sign a written informed consentdocument

Exclusion Criteria:

• Currently participating and receiving study therapy or has participated in a studyof an investigational agent and received study therapy or used an investigationaltreatment within 4 weeks of the first dose of treatment.

• Has had prior chemotherapy, targeted small molecule therapy, immunotherapy prior tostudy Day 1 for metastatic disease or who has not recovered (i.e., ≤ Grade 1 or atbaseline) from adverse events due to a previously administered agent with theexception of alopecia or immune mediated hypothyroidism.

Note: (a) If patient received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy. (b.) If patient received radiation treatment for brain metastases, then it should have completed more than 6 weeks prior to starting Day 1 of treatment.

• Has known active central nervous system (CNS) metastases and/or carcinomatousmeningitis.

• Has active autoimmune disease that has required systemic therapy in the past 2 years (i.e. disease modifying agents, immunosuppressants or corticosteroids). Replacementtherapy (i.e. thyroxine, insulin, physiologic doses of corticosteroids for adrenalor pituitary insufficiency etc.) is not considered a form of systemic therapy and isallowed.

• Has a diagnosis of immunodeficiency or receives chronic steroid therapy (in dosesexceeding prednisone 10 mg/day equivalent).

• Has history of non-infectious pneumonitis that required steroids or currentpneumonitis.

• Has an active infection requiring systemic therapy.

• Has baseline neuropathy > grade 1.

• Has a history or current evidence of any condition, therapy, or laboratoryabnormality that might confound the results of the trial, interfere with thesubject's participation for the full duration of the trial, or is not in the bestinterest of the subject to participate, in the opinion of the treating investigator.

• Has known psychiatric or substance abuse disorders that would interfere withcooperation with the requirements of the trial.

• Is pregnant or breastfeeding or expecting to conceive or father children within theprojected duration of the trial, starting with the pre-screening or screening visitthrough 120 days after the last dose of trial treatment.

• Has had COVID-19 infection within 90 days of confirming eligibility or has sequelaeof COVID-19 infection such as symptoms that cannot be explained by any other medicalevent or comorbidity.

• Vaccination for COVID-19 is allowed on the study unless patient had a grade 3 eventafter either dose of the vaccine and has not resolved to grade 1 beforeregistration.

• Is unwilling to give written informed consent, unwillingness to participate, orinability to comply with the protocol for the duration of the study.

• Has active or clinically significant cardiac disease including: (a.) Congestiveheart failure - New York Heart Association (NYHA) > Class II. (b) Active coronaryartery disease.(c) Cardiac arrhythmias requiring anti-arrhythmic therapy other thanbeta blockers or digoxin.(d) Unstable angina (anginal symptoms at rest), new-onsetangina within 3 months before initiation, or myocardial infarction within 6 monthsbefore initiation. (e) QTc interval >450 ms for men or >470 ms for women or knownhistory of QTc prolongationor Torsades de Pointes.

• Patient has significant chronic gastrointestinal disorder with diarrhea as a majorsymptom (e.g.,Crohn's disease, malabsorption, or Grade ≥2 (NCI CTCAE v.5.0) diarrheaof any etiology at screening).