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:

• Sign written informed consent before initiating any trial-related procedures;
• ≥18 years and ≤79 years old, regardless of gender;
• Pathologically confirmed colorectal adenocarcinoma with liver metastases confirmed by pathology or imaging;
• No prior first-line systemic therapy (e.g., targeted therapy, immunotherapy, systemic chemotherapy) for liver metastases;
• At least one radiographically measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST version 1.1);
• 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;
• 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.
• ECOG performance status score 0-1;
• Life expectancy ≥12 weeks;
• No indications for emergency surgery due to primary tumor complications including significant bleeding or obstruction;
• 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;

• 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;
• Fertile female patients must have negative serum pregnancy test within 7 days before first dose;
• 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:

• Patients intolerant to systemic chemotherapy or surgery;
• Liver metastases occurring during or within 6 months after oxaliplatin-based adjuvant chemotherapy for the primary tumor;
• 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;
• History of myocardial infarction, severe/unstable angina, coronary artery bypass grafting, or heart failure (NYHA class III-IV) within 3 months before treatment initiation;
• Prior treatment with immune checkpoint inhibitors (e.g., anti-PD-1/L1, CTLA-4 inhibitors);
• Concurrent or prior malignancies;
• History of autoimmune diseases or allogeneic stem cell/solid organ transplant (excluding corneal transplant) rendering immunotherapy intolerance;
• Moderate-to-severe allergic reactions, hypersensitivity, or intolerance to antibody-based therapies;
• 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);
• Clinically symptomatic ascites/pleural/pericardial effusion requiring therapeutic intervention;
• Primary tumor obstruction, perforation or intra-abdominal infection within 3 months before treatment initiation, without appropriate management;
• Known hypersensitivity to active pharmaceutical ingredient or excipients of the investigational drug;
• Dysphagia, active peptic ulcer, intestinal obstruction, active gastrointestinal bleeding, gastrointestinal perforation, malabsorption syndrome, or uncontrolled inflammatory bowel disease;
• Pregnant or breastfeeding women;
• Concurrent participation in other clinical trials;
• Any other condition deemed inappropriate for study participation by the investigator.