Neratinib in Combination with Chemotherapy, Trastuzumab, Pembrolizumab in Patients with Stage HER2 Overexpressing Stage IV Gastroesophageal Cancers

Inclusion Criteria

• Patients must have pathologically or cytologically confirmed esophageal, gastric or gastroesophageal junction (GEJ) adenocarcinoma by the enrolling institution
• Patients must have esophageal, gastric or GEJ adenocarcinoma with HER2 overexpression and/or amplification as determined by immunohistochemistry (IHC 3+) or fluorescent in situ hybridization (FISH+ as defined as HER2:CEP17 ratio >= 2.0 if IHC 2+). In addition, patients must be tested for PD-L1 and the result must be positive (CPS of 1 or more). No central testing will be required and local confirmation will be sufficient to determine eligibility. Antibody clones for HER2 and PD-L1 immunohistochemical testing will be per local testing guidelines. The testing can be performed on archival tissue 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 IV disease. Patients may have received prior adjuvant therapy (chemotherapy and/or chemoradiation) if more than 6 months have elapsed between the end of adjuvant therapy and expected date of treatment start on this study. Patients who have received maintenance nivolumab after chemoradiation and surgery would be eligible as long as the last dose of nivolumab was more than 3 months from the date of expected date of treatment start on this study
• Patients must have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1
• Patients must not have active decompensated cardiomyopathy and must have a normal left ventricular ejection fraction (LVEF) ( >= 53%). If a patient has a borderline LVEF (40-52%), they may be considered after consultation with cardiology and study principal investigator (PI)
• Age 18 years or older
• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
• Absolute neutrophil count (ANC) >= 1500/mcL
• Platelets >= 100,000/mcL
• Hemoglobin >= 9 g/dl
• Serum creatinine =< 1.5 x upper limit of normal (ULN) OR measured creatinine clearance >= 60 mL/min
• Serum total bilirubin =< 1.5 x ULN OR direct bilirubin =< ULN for subjects with total bilirubin levels > 1.5 ULN (except patients with Gilbert's disease ( =< 3 x ULN)
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN OR ≤ 5 x ULN for subjects with liver metastases
• Albumin >= 3 mg/dL
• Female subject of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication. A serum pregnancy test will be required if the urine test is positive or cannot be confirmed as negative.
• Female subjects of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication. Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 2 years
• Male subjects should agree to use an adequate method of contraception (except for those that are surgically sterile) starting with the first dose of study therapy through 120 days after the last dose of study therapy
• Any participant with treated brain metastases are eligible if follow-up brain imaging after central nervous system– (CNS-) directed therapy shows no evidence of progression at 4-6 weeks after treatment
• Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria

• Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational treatment within 4 weeks of the first dose of treatment
• Has had prior chemotherapy, targeted small molecule therapy, immunotherapy prior to study day 1 for metastatic disease or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events due to a previously administered agent with the exception of alopecia or immune mediated hypothyroidism. * Note: If the patient received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy * 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 carcinomatous meningitis
• Has active autoimmune disease that has required systemic therapy in the past 2 years (i.e. disease modifying agents, immunosuppressants or corticosteroids). Replacement therapy (i.e. thyroxine, insulin, physiologic doses of corticosteroids for adrenal or pituitary insufficiency etc.) is not considered a form of systemic therapy and is allowed
• Has a diagnosis of immunodeficiency or receives chronic steroid therapy (in doses exceeding prednisone 10 mg/day equivalent)
• Has history of non-infectious pneumonitis that required steroids or current pneumonitis
• Has an active infection requiring systemic therapy
• Has baseline neuropathy > grade 1
• Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject’s participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator
• Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
• Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment
• Has had COVID-19 infection within 90 days of confirming eligibility or has sequelae of COVID-19 infection such as symptoms that cannot be explained by any other medical event or comorbidity
• Vaccination for COVID-19 is allowed on the study unless patient had a grade 3 event after either dose of the vaccine and has not resolved to grade 1 before registration
• Is unwilling to give written informed consent, unwillingness to participate, or inability to comply with the protocol for the duration of the study
• Has active or clinically significant cardiac disease including: * Congestive heart failure – New York Heart Association (NYHA) > class II * Active coronary artery disease * Cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers or digoxin * Unstable angina (anginal symptoms at rest), new-onset angina within 3 months before initiation, or myocardial infarction within 6 months before initiation * QTc interval > 450 ms for men or > 470 ms for women or known history of QTc prolongation or Torsades de Pointes
• Patient has significant chronic gastrointestinal disorder with diarrhea as a major symptom (e.g., Crohn's disease, malabsorption, or grade >= 2 (National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] v.5.0) diarrhea of any etiology at screening)