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

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 (CCGLC-018)

This is a prospective, open-label, exploratory, phase II basket clinical trial designed to evaluate the efficacy and safety of sintilimab in combination with pyrotinib with or without chemotherapy in patients with advanced HER2-positive digestive system malignancies. Eligible patients include those with locally advanced unresectable or metastatic gastric, colorectal, hepatocellular, biliary tract, or pancreatic cancers. Patients will receive sintilimab and pyrotinib, with chemotherapy regimens selected at the investigator's discretion based on tumor type and clinical condition. The primary endpoint is objective response rate (ORR), with secondary endpoints including progression-free survival (PFS), disease control rate (DCR), overall survival (OS), and safety.

Immunotherapy, particularly immune checkpoint inhibitors (ICIs), has significantly advanced the treatment landscape for various solid tumors, but many patients still fail to respond or develop resistance. Combining ICIs with targeted agents may overcome these limitations. Pyrotinib is a pan-ErbB irreversible tyrosine kinase inhibitor (TKI) with potent activity against HER2, which is overexpressed in multiple digestive tract cancers including gastric, colorectal, biliary tract, and pancreatic cancers.

This basket trial investigates the efficacy and safety of sintilimab (a PD-1 inhibitor) combined with pyrotinib, with or without chemotherapy, in HER2-positive digestive system tumors. Patients must meet HER2 positivity criteria via IHC, FISH/CISH, or NGS. The study uses a Bayesian adaptive design to independently evaluate efficacy across cancer subtypes.

Patients will receive sintilimab (200 mg IV every 3 weeks) and pyrotinib (400 mg orally daily). Chemotherapy is optional and tailored by tumor type, including regimens such as FOLFOX, GC, XELOX, or AG, among others.

Primary endpoint: ORR per RECIST 1.1. Secondary endpoints: PFS, DCR, OS, and treatment-related adverse events (TRAEs).

The total planned enrollment is approximately 80 patients, with flexible sample size adjustments based on interim Bayesian analysis within each tumor cohort. Exploratory objectives include biomarker analysis (e.g., PD-L1, TMB, HER2 amplification/mutation) and tumor microenvironment changes.

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