A Single-Arm, Phase II Study of Retlirafusp Alfa in Combination With XELOX and Bevacizumab for the First-Line Treatment of Advanced RAS-Mutated Colorectal Cancer With Liver Metastases (CRLM)

A Single-Arm, Phase II Study of Retlirafusp Alfa in Combination With XELOX and Bevacizumab for the First-Line Treatment of Advanced RAS-Mutated Colorectal Cancer With Liver Metastases (CRLM)

This single-arm phase II trial enrolls patients with RAS-mutant, microsatellite-stable (MSS) unresectable colorectal cancer liver metastases receiving first-line treatment with Retlirafusp alfa combined with XELOX (capecitabine plus oxaliplatin) and bevacizumab. The primary endpoint is objective response rate (ORR). A total of 46 patients will be enrolled, and the study is expected to be completed between 2026 and 2029.

Inclusion Criteria:

1. Age: 18-75 years;

2. Unresectable colorectal adenocarcinoma confirmed by histopathology or cytology;

3. MSS/pMMR;

4. RAS-mutant;

5. ECOG PS score of 0-1;

6. No prior systemic treatment;

7. At least one measurable liver metastasis;

8. Expected survival of ≥3 months;

9. Normal function of major organs; no severe abnormalities in hematological, cardiac, pulmonary, hepatic, renal, or bone marrow function; and no immunodeficiency. Laboratory test results must meet the following requirements:

   ① Hemoglobin (Hb) ≥90 g/L;

   ② White blood cell (WBC) count ≥ 3.0 × 10⁹/L; neutrophil count (NEUT) ≥ 1.5 × 10⁹/L;

   ③ Platelet (PLT) count ≥ 100 × 10⁹/L

   ④ Renal function (serum creatinine, sCr) ≤ 1.5 times the upper limit of normal (ULN);

   ⑤ Total bilirubin (TBIL) ≤ 1.5 times the upper limit of normal (ULN);

10. Participants voluntarily enroll in this study, sign an informed consent form, demonstrate good compliance, and cooperate with follow-up;

11. The investigator believes the participant may benefit from treatment.

Exclusion Criteria:

1. History of or concurrent other malignant tumors, excluding cured basal cell carcinoma of the skin and cervical carcinoma in situ;
2. History of severe cardiovascular disease, such as congestive heart failure (New York Heart Association Class III-IV), myocardial infarction within the past 6 months, unstable angina, or severe arrhythmias;
3. Presence of active infections (e.g., sepsis, active tuberculosis) or uncontrolled autoimmune diseases;
4. History of severe gastrointestinal diseases, such as active peptic ulcers, intestinal obstruction, or gastrointestinal bleeding, which may affect drug absorption or increase treatment-related risks;
5. History of active cirrhosis, uncontrolled comorbidities, chronic myopathy, active hepatitis, or persistent unexplained elevation of serum transaminases;
6. Coagulation disorders with a tendency to bleed (must meet the following criterion 14 days prior to enrollment: INR within the normal range without the use of anticoagulants); Subjects receiving treatment with anticoagulants or vitamin K antagonists, such as warfarin, heparin, or their analogs; low-dose warfarin (1 mg orally once daily) or low-dose aspirin (daily dose not exceeding 100 mg) is permitted for prophylactic purposes, provided that the International Normalized Ratio (INR) of prothrombin time is ≤ 1.5;
7. Allergy to or contraindications for the study drug;
8. Pregnant or breastfeeding women, or patients planning to become pregnant during the study or within 6 months after the study ends and who are not using effective contraception;
9. Presence of other serious, uncontrolled medical conditions or psychiatric disorders that may affect the patient's ability to participate in the study or undergo evaluation;
10. History of thyroid dysfunction, where thyroid function cannot be maintained within the normal range even with medication;
11. Patients with severe, uncontrolled hypertension (systolic blood pressure ≥ 150 mmHg or diastolic blood pressure ≥ 90 mmHg despite antihypertensive medication), or a history of hypertensive crisis or hypertensive encephalopathy;
12. Patients with a history of severe bleeding or a high risk of bleeding, including but not limited to: clinically significant bleeding (e.g., ≥ Grade 2 gastrointestinal bleeding) occurring within 3 months prior to the first administration of the study drug; active hemoptysis (hemoptysis volume ≥ half a teaspoon, approximately 2.5 mL of fresh blood, within the past month); imaging evidence of tumor invasion of major blood vessels; or an untreated coagulation disorder (however, patients receiving a stable dose of anticoagulant therapy with an INR within the therapeutic range may be considered for enrollment following the investigator's assessment);
13. Patients who have experienced the following arterial or venous thromboembolic events within 6 months prior to the first administration of the study drug: cerebrovascular accident (including ischemic stroke and transient ischemic attack), myocardial infarction, acute coronary syndrome, uncontrolled deep vein thrombosis, or pulmonary embolism (superficial venous thrombosis, such as PICC-related upper extremity venous thrombosis, may be considered on a case-by-case basis if assessed by the investigator as low risk);
14. Patients deemed unsuitable for inclusion in this study by the investigator.