The purpose of this study is to see whether the study drug, amivantamab, is an effective treatment for people with EGFR- or MET-amplified esophagogastric cancer. The researchers will also look at whether amivantamab is a safe treatment that causes few or mild side effects in participants.

Inclusion Criteria:

• Subject or legally authorized representative is willing and able to provide written informed consent.
• Patients with previously treated metastatic or unresectable histologically-confirmed esophagogastric cancer who have received at least 1 line of therapy.
• EGFR or MET amplification by tissue-NGS with copy number >8 and/or ctDNA amplification by any FDA and CLIA-approved assay
• No prior receipt of an EGFR or MET inhibitor for esophagogastric cancer. (Note: if a patient previously received a EGFR inhibitor, but subsequently demonstrated a MET amplification, or previously received a MET inhibitor, but subsequently demonstrated an EGFR-amplification, inclusion is permitted).
• Patients with HER2+ (IHC 3+ or IHC 2+/FISH+) tumors must have progressed on trastuzumab.
• Measurable disease based on RECIST 1.1.
• ≥ 18 years of age on day of signing informed consent.
• Have an ECOG performance status of 0, 1, or 2.
• Adequate organ function, defined as:

A. Hemoglobin ≥9 g/dL

B. ANC ≥1.0 x 10^9 /L

C. Platelets ≥75 x 10^9 /L

D. AST and ALT ≤3 x ULN (≤5 x ULN for subjects with liver metastases)

E. Total bilirubin ≤1.5 x ULN; subjects with Gilbert's syndrome can enroll if conjugated bilirubin is within normal limits

F. Serum creatinine <1.5 x ULN or if available, calculated or measured creatinine clearance >50 mL/min/1.73 m^2

• Women of childbearing potential and male patients with women of childbearing potential partners must be willing to use an adequate method of contraception

Exclusion Criteria:

• Prior chemotherapy, targeted small molecule therapy, or biological therapy, within 2 weeks prior to study day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent (excluding alopecia).
• If subject received major surgery, they must have recovered adequately prior to starting therapy.
• Known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy.
• Known active hepatitis B (e.g., HBsAg reactive or polymerase chain reaction detectable).

Note: Subjects with a prior history of HBV demonstrated by positive hepatitis B core antibody are eligible if they have at Screening 1) a negative HBsAg and 2) a HBV DNA (viral load) below the lower limit of quantification, per local testing. Subjects with a positive HBsAg due to recent vaccination are eligible if HBV DNA (viral load) is below the lower limit of quantification, per local testing.

• Known active hepatitis C (e.g., HCV RNA [qualitative] is detected).

Note: Subjects with a prior history of HCV, who have completed antiviral treatment and have subsequently documented HCV RNA below the lower limit of quantification per local testing are eligible.

• Other clinically active or chronic liver disease.
• Subject has uncontrolled inter-current illness, including but not limited to poorly controlled diabetes, ongoing or active infection (i.e., has discontinued all antibiotics for at least one week prior to first dose of study drug), or psychiatric illness/social situation that would limit compliance with study requirements. Subjects with medical conditions requiring chronic continuous oxygen therapy are excluded.
• Pulmonary embolism (PE) and deep vein thrombosis (DVT), within 1 month of start of study drug.
• Myocardial infarction, unstable angina, stroke, transient ischemic attach (TIA), or coronary/peripheral artery bypass graft, or any acute coronary syndrome within 6 months of start of study drug.
• Congestive heart failure defined as New York Heart Association (NYHA) Class III-IV or hospitalization for congestive heart failure (any NYHA class) within 6 months of start of study drug.
• Interstitial lung disease (ILD), including drug-induced ILD or radiation pneumonitis requiring treatment with prolonged steroids or other immune suppressive agents that is unresolved or resolved within the last 3 months.
• Immune-mediated rash from checkpoint inhibitors that has not resolved prior to enrollment.
• Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial, in the opinion of the treating investigator.
• 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 6 months after the last dose of trial treatment.
• Prisoners, or subjects who are compulsory detained.

Memorial Sloan Kettering Cancer Center supports the international committee of medical journal editors (ICMJE) and the ethical obligation of responsible sharing of data from clinical trials. The protocol summary, a statistical summary, and informed consent form will be made available on clinicaltrials.gov when required as a condition of Federal awards, other agreements supporting the research and/or as otherwise required. Requests for deidentified individual participant data can be made beginning 12 months after publication and for up to 36 months post publication. Deidentified individual participant data reported in the manuscript will be shared under the terms of a Data Use Agreement and may only be used for approved proposals. Requests may be made to: crdatashare@mskcc.org.