Retlirafusp Alfa Plus Targeted Therapy and Chemotherapy for Unresectable Colorectal Liver-Limited Metastases

Inclusion criteria

• Signed written informed consent before any trial-related procedure.
• Age ≥18 and ≤79 years, male or female.
• Histopathologically confirmed colorectal adenocarcinoma; liver metastasis confirmed by pathology or imaging.
• No prior first-line systemic therapy (targeted, immunotherapy, systemic chemotherapy) specifically for liver metastases.
• At least 1 measurable lesion per RECIST 1.1.
• Multidisciplinary-team-confirmed initially unresectable colorectal liver metastases (cannot achieve R0/R1 resection; or predicted future remnant liver volume < 30 %; or insufficient hepatic inflow/outflow). Patients with extra-hepatic metastases (excluding brain / bone metastases) amenable to local therapy are eligible.
• Microsatellite-stable (MSS) / mismatch-repair-proficient (pMMR) confirmed by IHC or PCR.
• ECOG Performance Status 0-1.
• Expected survival ≥12 weeks.
• No urgent-surgery indications (e.g., primary-tumor bleeding, obstruction).
• Adequate organ function within 14 days prior to first study-drug:

• ANC ≥1.5 × 10⁹/L; Platelets ≥75 × 10⁹/L; Hb > 70 g/L
• Total bilirubin ≤1.5 × ULN; Albumin ≥28.0 g/L
• AST / ALT ≤5 × ULN
• Creatinine ≤1.5 × ULN; Cockcroft-Gault creatinine clearance ≥60 mL/min
• INR / PT ≤1.5 × ULN
• Females of reproductive potential / males with reproductive-potential partners agree to highly-effective contraception starting 7 days prior first dose until 24 weeks after last dose.
• Serum pregnancy test negative within 7 days before first dose (women of child-bearing potential).
• Willing and able to comply with all trial visits, treatment and assessments.-

Exclusion criteria

• 1. Inability to tolerate systemic chemotherapy or subsequent surgery. 2. Liver metastases occurring during or within 6 months after completion of oxaliplatin-based adjuvant chemotherapy for primary colorectal tumor.

• Major surgery within 6 weeks before study entry; severe trauma / non-healing wounds / fractures.

• Myocardial infarction, unstable angina, coronary-artery-bypass-graft within prior 3 months; NYHA class III-IV heart failure.

• Prior treatment with immune-checkpoint-inhibitors (anti-PD-1/PD-L1, anti-CTLA-4 etc.).

• Concurrent or prior other malignancy whose expected survival is shorter than colorectal-liver-metastasis prognosis.

• History of allogeneic hematopoietic-stem-cell or solid-organ transplant (except corneal transplant).

• History of moderate-severe hypersensitivity / anaphylaxis to antibody-based therapeutics.

• Clinically-significant bleeding diathesis or major bleeding episode within prior 3 months (e.g., gastrointestinal bleeding, esophageal varices, hematemesis, hemoptysis).

• Symptomatic large-volume ascites / pleural effusion / pericardial effusion requiring intervention.

• Primary-tumor perforation, abdominal infection occurring within prior 3 months without adequate management.

• Known hypersensitivity to active ingredients or excipients of study drugs. 13. Active peptic ulcer, gastrointestinal obstruction, active GI bleeding, perforation, malabsorption, uncontrolled inflammatory bowel disease.

• Pregnant or lactating women. 15. Concurrent participation in another interventional clinical trial. 16. Any other condition judged by investigator to make subject unsuitable for trial participation.