A Prospective, Open-label, Exploratory Basket Trial to Evaluate the Efficacy and Safety of Sintilimab Combined With Pyrotinib ± Chemotherapy in Patients With Advanced Digestive System Tumors

Inclusion Criteria:

* Age ≥18 years
* Patients with unresectable locally advanced T3-4 stage or M1 stage metastatic digestive system tumors confirmed by histology or cytology, including gastric cancer, colorectal cancer, hepatocellular carcinoma, biliary tract cancer and pancreatic cancer
* Patients who have not received systematic treatment in the past or whose disease has progressed or is intolerant after standard first-line treatment, and whose disease has progressed for more than 6 months after neoadjuvant therapy/whose last adjuvant therapy failed/who have completed (new) adjuvant therapy for less than 6 months from disease recurrence can be enrolled
* Histologically or cytologically confirmed HER2-positive (IHC 3+ or IHC 2+/FISH-amplified/NGS-confirmed) locally advanced or metastatic digestive system tumors (including gastric, colorectal, hepatocellular, biliary tract cancers)
* ECOG performance status 0-2
* At least one measurable lesion per RECIST 1.1 criteria
* Adequate organ function:
* Hematologic: ANC ≥1.5×10⁹/L, platelets ≥75×10⁹/L, hemoglobin ≥9 g/dL
* Hepatic: Total bilirubin ≤1.5×ULN; ALT/AST ≤2.5×ULN (≤5×ULN for liver metastases/HCC); albumin ≥28 g/L
* Renal: Serum creatinine ≤1.5×ULN or CrCl ≥50 mL/min; urine protein \<2+ (if ≥2+, 24-hour urine protein \<1 g)
* Coagulation: INR ≤2.3 or PT prolongation ≤6 seconds
* Life expectancy ≥12 weeks
* Fertile patients must use effective contraception during treatment and for 6 months after last dose
* Willing and able to provide written informed consent

Exclusion Criteria:

* Previous treatment with any HER2-targeted therapy (e.g., trastuzumab)
* History of hematologic malignancies
* Pregnancy, lactation, or plans to become pregnant during study
* Last anticancer therapy ≤28 days prior to enrollment or unresolved toxicities from prior therapy
* Contraindications to immunotherapy including:
* History of organ transplantation
* Severe autoimmune diseases
* Grade ≥4 immune-related adverse events from prior immunotherapy
* Uncontrolled active infections
* Use of systemic immunosuppressants (\>10 mg/day prednisone equivalent) within 14 days
* Known hypersensitivity to PD-1 inhibitors, pyrotinib, or monoclonal antibodies
* Participation in other clinical trials within 3 months
* Symptomatic ascites, pleural or pericardial effusion requiring drainage
* Life-threatening bleeding events within 3 months or arterial/venous thrombosis within 6 months (except stable catheter-related thrombosis)
* History of pulmonary fibrosis, interstitial lung disease, or drug-related pneumonitis
* Active tuberculosis requiring treatment or treated within past year
* Major surgery within 4 weeks or unhealed surgical wounds
* Severe dysfunction of major organs (heart, lungs, liver, kidneys, CNS)
* Any other condition that may increase risk or interfere with study results as judged by investigator