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