AACR Adaptive Biomarker-Driven Organ Preservation Trial in Gastroesophageal Adenocarcinomas

Inclusion Criteria: * Histologically confirmed, resectable adenocarcinoma of the stomach, esophagus, or gastroesophageal junction (Stage II or higher, T2N0 with high-risk features). * Complete surgical resection deemed achievable by multidisciplinary evaluation. * Willingness to undergo tumor biopsies for biomarker analysis (HER2, FGFR2b, PD-L1, MSI) at screening, progression, or pre/post- surgery. * Life expectancy ≥ 24 weeks. Eastern Cooperative Oncology Group (ECOG) performance status ≤1. * Adequate organ function: * Hematologic: absolute neutrophil count (ANC) ≥1.5 ×10⁹/L, platelets ≥100 ×10⁹/L, hemoglobin ≥ 8 g/dL * Hepatic: aspartate aminotransferase (AST)/ alanine aminotransferase (ALT) ≤2.5 × ULN, total bilirubin ≤1.5 × upper limit of normal (ULN) (≤2.5 × ULN for Gilbert's) * Renal: creatinine ≤1.5 × ULN or creatinine clearance ≥50 mL/min/1.73 m² * Willingness for blood samples to be drawn for research purposes. * Baseline dihydropyrimidine dehydrogenase (DPD) testing per local guidelines; dosing of 5-FU adjusted for deficiency. * Use of two effective contraception methods for women of childbearing potential and men during and 4 months after study; pregnant or breastfeeding women excluded. * Must have the ability to understand and the willingness to sign a written informed consent document. * Willingness and able to comply with the protocol for the duration of the study, including attending scheduled visits, examinations, the screening procedure, and having their tumor and blood molecularly characterized. * Understands they must meet all Inclusion and Exclusion criteria in the sub-protocol for the treatment for which they will be later assigned Additional inclusion criteria for all sub-studies: • FFPE tumor sample tested at a central laboratory confirming PD-L1 Tumor Area Positivity (TAP) score ≥1%. Additional inclusion criteria specific to HER2 sub-study: * Histologically confirmed diagnosis of resectable (i.e., radical surgery eligible), HER2-positive (defined as 3+ HER2 expression by IHC or 2+ HER2 expression by immunohistochemistry (IHC) with in situ hybridization (ISH)-positivity per central assessment) adenocarcinoma of the stomach or esophagus, including the gastroesophageal junction. * Formalin-fixed, paraffin-embedded (FFPE) tumor sample tested at a central laboratory confirming HER2-positive status. * Left ventricular ejection fraction (LVEF) ≥50% as determined by either echocardiogram or multiple gated acquisition scan (MUGA). Exclusion criteria: * Unresectable disease, peritoneal dissemination, and/or positive cytology on laparoscopy. * Peripheral neuropathy ≥ Grade 2. * Active infection. * Chronic growth factor support for white blood cells or granulocytes. * Concurrent anti-cancer therapy (exceptions: supportive care medications ≥1 month prior, low molecular weight heparin, prior adjuvant hormonal therapy \>3 years, palliative radiation ≤14 days prior). * Local/systemic therapy for current gastroesophageal diagnosis (except one FLOX/ mFOLFOX6 dose during screening). * Significant medical conditions compromising safety or protocol compliance. * Preexisting cardiac conditions. * Stroke, transient ischemic attack (TIA), or myocardial infarction within 6 months. * Prior FGFR-targeted therapy. * Prior HER2-targeted therapy (except \>5 years prior for breast cancer). * Prior checkpoint inhibitor therapy (anti-PD-1/PD- L1/PD-L2). * Conditions preventing safe surgery/biopsy. * Malabsorption syndrome or inability to swallow oral medication. * Pregnant or nursing women * History of stem cell or organ transplant. * Major surgery within 14 days. * Other malignancy within 3 years (exceptions: basal/squamous cell carcinoma, in situ malignancy, low-risk prostate cancer). * Systemic corticosteroids \>10 mg prednisone/ day or immunosuppressive therapy ≤14 days prior (exceptions: adrenal replacement, topical/ inhaled, short prophylactic courses). * HIV with CD4 \<350, active hepatitis B or C. * Active or relapsing autoimmune disease (exceptions: controlled type I diabetes, hypothyroidism on replacement, controlled celiac disease, mild skin disease, other non- recurrent diseases). Additional exclusion criteria for all sub-studies: * History of hypersensitivity or contraindications to any active substance/active ingredient of any study medication, including chemotherapy components monoclonal antibodies, recombinant proteins, and/or any of the excipients listed in the ingredients of any drug formulation * Poorly controlled seizures * Clinically significant bleeding (CTCAE ≥ Grade 3) from the gastrointestinal (GI) tract within 4 weeks prior to enrollment. * Administered a live vaccine ≤ 4 weeks prior to enrollment * History of interstitial lung disease or non-infectious pneumonitis, or with severe dyspnea at rest or requiring supplementary oxygen therapy. * Treated with another investigational product within 28 days of enrolment. Exclusion criteria specific to HER2 sub-study: * Total lifetime anthracycline load exceeding 360 mg/m² of doxorubicin or equivalent * QTc Fridericia (QTcF) \>470 ms. Note: For subjects with longer QTcF on initial electrocardiogram (ECG), follow-up ECG may be performed in triplicate to determine eligibility (e.g., after correction of electrolyte abnormalities, or discontinuation of QT-prolonging drugs). * Ongoing Grade 2 or greater diarrhea