Iparomlimab/Tuvonralimab Combined With Bevacizumab and CAPEOX as Conversion Therapy for Colorectal Cancer Liver Metastasis

Inclusion Criteria:

Patients who meet all the following criteria will be included in this study:

1. Sign written informed consent before initiating any trial-related procedures;
2. ≥18 years and ≤79 years old, regardless of gender;
3. Pathologically confirmed colorectal adenocarcinoma with liver metastases confirmed by pathology or imaging;
4. No prior first-line systemic therapy (e.g., targeted therapy, immunotherapy, systemic chemotherapy) for liver metastases;
5. At least one radiographically measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST version 1.1);
6. Multidisciplinary team (MDT)-confirmed initially unresectable liver metastases (criteria for unresectability: inability to achieve R0/R1 resection via surgery, or anticipated residual liver volume \<30% post-resection, or inability to preserve adequate hepatic inflow/outflow for residual liver). Patients with extrahepatic metastases (excluding brain/bone metastases) amenable to local treatment are eligible;
7. Genetic testing results confirming either RAS mutation or right-sided colon location with RAS wild-type status, absence of BRAF V600E mutation, and microsatellite stability (MSS)/proficient mismatch repair (pMMR) confirmed through immunohistochemistry (IHC) or PCR testing.
8. ECOG performance status score 0-1;
9. Life expectancy ≥12 weeks;
10. No indications for emergency surgery due to primary tumor complications including significant bleeding or obstruction;
11. Adequate organ function meeting the following laboratory parameters:

    i. Absolute neutrophil count (ANC) ≥1.5×10\^9/L without granulocyte colony-stimulating factor support within 14 days; ii. Platelet count (PLT) ≥75×10\^9/L without transfusion within 14 days; iii. Hemoglobin (HGB) \>70 g/L without transfusion or erythropoietin use within 14 days; iv. Total bilirubin (TBIL) ≤1.5×upper limit of normal (ULN); serum albumin (Alb) ≥28.0 g/L; v. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤5×ULN; vi. Serum creatinine ≤1.5×ULN and creatinine clearance (calculated by Cockcroft-Gault formula) ≥60 mL/min; vii. Normal coagulation function: International Normalized Ratio (INR) or prothrombin time (PT) ≤1.5×ULN;
12. Fertile female patients or male patients with fertile partners must agree to use highly effective contraception (failure rate \<1% per year) from 7 days before first dose until 24 weeks post-treatment;
13. Fertile female patients must have negative serum pregnancy test within 7 days before first dose;
14. Patients must be capable of and willing to comply with study protocol requirements, including scheduled visits, treatment plans, laboratory tests, and other trial-related procedures.

Exclusion Criteria:

Patients who meet any of the following exclusion criteria will be excluded from this study:

1. Patients intolerant to systemic chemotherapy or surgery;
2. Liver metastases occurring during or within 6 months after oxaliplatin-based adjuvant chemotherapy for the primary tumor;
3. Major surgery within 6 weeks before treatment initiation, anticipated requirement for major surgery during the study, or presence of severe traumatic injury, fractures, ulcers, or non-healing wounds;
4. History of myocardial infarction, severe/unstable angina, coronary artery bypass grafting, or heart failure (NYHA class III-IV) within 3 months before treatment initiation;
5. Prior treatment with immune checkpoint inhibitors (e.g., anti-PD-1/L1, CTLA-4 inhibitors);
6. Concurrent or prior malignancies;
7. History of autoimmune diseases or allogeneic stem cell/solid organ transplant (excluding corneal transplant) rendering immunotherapy intolerance;
8. Moderate-to-severe allergic reactions, hypersensitivity, or intolerance to antibody-based therapies;
9. Clinically significant bleeding symptoms or high bleeding risk within 3 months before treatment initiation (e.g., gastrointestinal bleeding, gastroesophageal varices, hemorrhagic gastric ulcer, or history of hematochezia, hematemesis, or hemoptysis);
10. Clinically symptomatic ascites/pleural/pericardial effusion requiring therapeutic intervention;
11. Primary tumor obstruction, perforation or intra-abdominal infection within 3 months before treatment initiation, without appropriate management;
12. Known hypersensitivity to active pharmaceutical ingredient or excipients of the investigational drug;
13. Dysphagia, active peptic ulcer, intestinal obstruction, active gastrointestinal bleeding, gastrointestinal perforation, malabsorption syndrome, or uncontrolled inflammatory bowel disease;
14. Pregnant or breastfeeding women;
15. Concurrent participation in other clinical trials;
16. Any other condition deemed inappropriate for study participation by the investigator.