Lvosidenib (AK112) Combined With CapeOX and Radiotherapy in Patients With Unresectable Metastatic MSS-type Colorectal Cancer

Inclusion Criteria:

* Aged 18-75.
* ECOG performance status of 0-1.
* Initial diagnosis confirmed by colonoscopy and pathology as colorectal adenocarcinoma.
* Imaging confirmation of multiple measurable metastases, deemed unresectable initially after MDT discussion.
* No prior treatment or more than 1 year since completion of initial untreated/post-operative adjuvant chemotherapy, and no previous anti-tumor therapy thereafter.
* With good organ function, without contraindications for surgery or chemotherapy.
* Prothrombin time (PT) and activated partial thromboplastin time (APTT) ≤ 1.5 × ULN, and international normalized ratio (INR) ≤ 1.5 × ULN (if not receiving anticoagulant therapy).
* Urine protein \< 2+; if urine protein ≥ 2+, 24-hour urine protein quantitative test must show ≤ 1g protein.
* Left ventricular ejection fraction (LVEF) ≥ 55%. 12-lead electrocardiogram: Fridericia-corrected QT interval (QTcF) \< 470 msec.
* Expected survival \> 6 months.
* Clear status of KRAS, NRAS, BRAF, and HER2 genes.
* Microsatellite stable or mismatch repair protein proficient patients.

Exclusion Criteria:

* Age \<18 years or \>75 years.
* History of any other malignancy within 5 years, except adequately treated cervical carcinoma in situ, squamous cell carcinoma of the skin, or basal cell carcinoma that has been effectively controlled.
* Malignant pleural or peritoneal effusion.
* Severe internal medical complications preventing chemotherapy or surgery.
* Clinical or radiological evidence of spinal cord compression, or tumor within 3 mm of the spinal cord on MRI.
* Imaging-confirmed brain, ovarian, or peritoneal metastases.
* Patients deemed suitable for aggressive systemic treatment to achieve conversion after MDT discussion.
* Pathologically diagnosed signet ring cell carcinoma.
* Patients with microsatellite instability or mismatch repair protein deficiencies.
* Patients with intestinal obstruction, perforation, bleeding requiring emergency surgical resection.
* Immunodeficiency diseases, including primary immunodeficiency diseases (genetically determined) or secondary immunodeficiency diseases.
* Known or suspected interstitial pneumonia.
* Severe cardiovascular diseases, including but not limited to conditions meeting NYHA class (III or higher), myocardial infarction or cerebrovascular accident (ischemic stroke, symptomatic cerebral infarction) within the past 3 months prior to first dosing, unstable angina or unstable arrhythmias within the past 1 month prior to first dosing, congestive heart failure beyond the above criteria, symptomatic superior vena cava syndrome, etc.
* Venous thromboembolic events within the past 3 months, such as deep vein thrombosis and pulmonary embolism.
* History of receiving live attenuated vaccines within 28 days prior to first study drug administration or anticipated need for live attenuated vaccines during the study period.
* Active hepatitis B (defined as positive hepatitis B surface antigen \[HBsAg\] with HBV-DNA ≥500 IU/ml).
* Hepatitis C (defined as positive hepatitis C virus antibody \[HCV-Ab\]).
* History of tuberculosis infection or treatment within the past 1 year prior to signing informed consent.
* History of or planned allogeneic bone marrow or solid organ transplantation.
* Abnormal coagulation function (INR \> 1.5 or APTT \> 1.5 × ULN), with bleeding tendency or undergoing thrombolysis or requiring long-term anticoagulant therapy with warfarin or heparin, or requiring long-term antiplatelet therapy (aspirin ≥ 300 mg/day or clopidogrel ≥ 75 mg/day).
* Peripheral neuropathy of Grade ≥2 according to NCI-CTCAE v5.0.
* Concurrent other infectious diseases unsuitable for participation in this study.