Inclusion Criteria:
1. Patients must have been diagnosed with histologically or cytologically confirmed gastrointestinal cancer (esophagus, stomach, colon, biliary, pancreas or unknown primary likely GI), and been deemed unresectable or have at least one site of metastatic disease
2. Patients must have evaluable or measurable disease by RECIST 1.1 criteria
3. 4.1.3 Patients' tumors must have HER2-overexpressing:
1. (IHC 3+ or IHC2+/ISH+) advanced gastroesophageal cancer (including gastroesophageal junction adenocarcinoma).
2. IHC 3+ for other GI cancers
4. Patients must have received at least one prior line of HER2 directed therapy for metastatic/unresectable disease and completed treatment at least 2 weeks prior to C1D1 (only for Gastroesohageal cancers, not for other GI cancers)
5. Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
6. Age \> 18 years.
7. ECOG performance status 0-2
8. Patients must have normal organ and marrow function as defined below
* Leukocytes \> 3,000/mcL
* Absolute neutrophil count \> 1,500/mcL
* Platelets \> 90,000/mcL
* Hemoglobin \> 9 gm/dl
* Total bilirubin \< 2 times institutional normal limits
* AST/ALT (SGOT/SGPT) \< 5 times institutional normal limits if liver metastases and \</+ 2 times institutional normal limits otherwise
* Creatinine \< 2.0mg/dL OR
* Creatinine clearance \> 50 Ml/min/1.73 m2 for patients with creatinine levels above institutional normal
9. Left Ventricular Ejection Fraction ≥ 45% or lower limit of normal.
10. Chemotherapy is harmful to the human fetus. For this reason, females of childbearing potential must be willing to use an effective method of contraception, as outlined in Section 4.4, for the course of the study through at least 6 months after the last dose of study medication. Males who have women of childbearing (WOCB) partners must agree to use an effective method of contraception as outlined in Section 4.4 for the course of the study through 8 months after the last dose of study medication.
11. Patients should be willing and able to swallow oral tablet medications
12. Ability to understand and willingness to sign a written informed consent and HIPAA consent document
Exclusion Criteria:
1. Patients who have had chemotherapy, or radiotherapy within 2 weeks prior to C1D1 or those who have not recovered from adverse events due to agents administered more than 2 weeks earlier (secondary hypothyroidism from prior immunotherapy is permissible if controlled on thyroid hormone replacement). Recovery is defined as any treatment onset adverse events returning to baseline or otherwise deemed not clinically significant.
2. Patients may not be receiving any other investigational agents for advanced cancer and must not have received prior treatment with TDxD
3. Immunotherapy and treatments involving any investigational agents must be discontinued for \>21 days before Cycle 1 Day 1 (C1D1)
4. Patients with known untreated brain metastases are excluded from this study because of their poor prognosis and frequent development of neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. Treated brain metastases are allowed (requires stability on MRI at least 4 weeks after initial treatment). Patients with treated brain metastases are allowed to be treated with steroid and/or anti-convulsants if the dose remains stable or decreases over the last 4 weeks prior to C1D1
5. Patients with ongoing diarrhea (\> 4 bowel movements/day) unresolved despite medical and best supportive care in the two weeks preceding therapy
6. Patients will be excluded if they have had interstitial lung disease or pneumonitis or were suspected to have interstitial lung disease or pneumonitis that could not be ruled out on imaging at screening or if they had a history of noninfectious interstitial lung disease or pneumonitis that had been treated with glucocorticoids. Similarly, patients with clinically significant lung disease requiring O2 support or impaired lung function per investigator should be excluded
7. History of allergic reactions attributed to compound of similar chemical or biologic composition to the agent(s) used in this study
8. Patients receiving any medications or substances that are strong inhibitors or inducers of Neratinib and/or TDxD are ineligible.
9. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
10. Has a QT interval corrected by Fridericia's formula (QTcF) prolongation to \>470 msec (female subjects) or \>450 msec (male subjects) based on average of the Screening triplicate12-lead ECG.
11. Any patients with immune deficiency are at increased risk of lethal infections when treated with marrow-suppressive therapy, including uncontrolled HIV with CD4 count \<200, untreated Hepatitis B are excluded from the study. Patients who have been treated for hepatitis C definitively with evidence of sustained virologic response, as well as HIV and hepatitis B patients on treatment with undetectable viral load will be eligible for inclusion.
12. Pregnant or breast feeding.
