The Safety and Efficacy of Cetuximab Beta Plus Fruquintinib With or Without Immune Checkpoint Inhibitorrs in First-line Treatment of RAS/BRAF Wild Type Unresectable Metastatic Colorectal Cancer

Inclusion Criteria:

1）Subjects voluntarily join this study, sign the informed consent form, and demonstrate good compliance; 2) Age: 10-80 years old, ECOG PS score of 0-1. For patients aged 80-85, comprehensive functional assessments must be completed, and they may be enrolled if the investigator deems them tolerable, with an expected survival of over 3 months; 3) Histopathologically and/or cytologically confirmed, unresectable metastatic colorectal adenocarcinoma confirmed by MDT discussion (UICC/AJCC TNM staging system for colorectal cancer, 8th Edition, 2017); 4) At least one measurable lesion confirmed according to RECIST 1.1 criteria; 5) Adequate function of major organs, meeting the following criteria:

1. Hematological examination standards (no blood transfusion or use of hematopoietic growth factors for correction within 7 days prior to screening):

   1. Hemoglobin (HGB) ≥ 90 g/L;
   2. Absolute neutrophil count (NEUT) ≥ 1.5 × 10⁹/L;
   3. Platelet count (PLT) ≥ 75 × 10⁹/L;
2. Biochemical tests must meet the following criteria:

   1. Total bilirubin (TBIL) ≤ 1.5 × ULN (≤ 3 × ULN for subjects with Gilbert's syndrome);
   2. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN. If with liver metastases, ALT and AST ≤ 5 × ULN;
   3. Serum creatinine (CR) ≤ 1.5 × ULN or creatinine clearance rate (CCR) ≥ 50 ml/min.
3. Coagulation function or thyroid function tests must meet the following criteria:

   1. Prothrombin time (PT), activated partial thromboplastin time (APTT), international normalized ratio (INR) ≤ 1.5 × ULN (without anticoagulant therapy);
   2. Thyroid-stimulating hormone (TSH) ≤ ULN; if abnormal, T3 and T4 levels should be assessed (FT3 and FT4 may be substituted if T3/T4 are unavailable at the center). Subjects may be enrolled if T3 and T4 levels are normal.
4. Echocardiogram assessment: Left ventricular ejection fraction (LVEF) ≥ 50%.
5. Hepatitis B surface antigen (HBsAg) negative. If HBsAg positive, hepatitis B virus deoxyribonucleic acid (HBV-DNA) must be \< 2500 copies/mL or 500 IU/mL for enrollment.
6. HCV antibody negative or HCV-RNA negative subjects may enroll; if HCV-RNA positive, subjects must have alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 × ULN to enroll. Subjects with co-infection of hepatitis B and hepatitis C are excluded (positive for HBsAg or HBcAb, and positive for HCV antibody).
7. Female patients must meet one of the following conditions:

   1. Postmenopausal (defined as no menses for at least 1 year, with no other confirmed causes besides menopause), or
   2. Surgically sterilized (removal of ovaries and/or uterus), or
   3. Of childbearing potential but must meet the following:

      * Serum/urine pregnancy test within 7 days prior to enrollment must be negative;
      * Agree to use contraception with a failure rate of \< 1% per year or maintain abstinence (avoiding heterosexual intercourse) (from signing the ICF until at least 6 months after the last dose of the study drug) (contraceptive methods with a failure rate of \< 1% per year include bilateral tubal ligation, male sterilization, correct use of hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, copper intrauterine devices, or condoms);
      * Must not be breastfeeding.
8. Male patients must meet the following: Agree to abstinence (avoiding heterosexual intercourse) or use contraception, as specified: When the partner is a woman of childbearing potential or is pregnant, the male patient must remain abstinent or use a condom during the treatment period and for at least 6 months after the last dose to prevent fetal drug exposure. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or post-ovulation methods) and withdrawal are not acceptable methods of contraception.

Exclusion Criteria:

1. Presence of MSI-H/dMMR patients.
2. Concurrent diseases and medical history:

   1. Diagnosis of or concurrent other malignancies within the past 3 years. The following conditions are eligible for enrollment:

      Cured cervical carcinoma in situ, non-melanoma skin cancer, and superficial bladder tumors \[Ta (non-invasive tumor), Tis (carcinoma in situ), and T1 (tumor invading the basement membrane)\];
   2. Multiple factors affecting oral medication (e.g., inability to swallow, chronic diarrhea, intestinal obstruction, etc.);
   3. History or tendency of gastrointestinal bleeding or perforation within 4 weeks prior to enrollment;
   4. Patients with active inflammatory bowel disease within 4 weeks prior to enrollment;
   5. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring repeated drainage;
   6. Unresolved toxicities from any prior antitumor therapy exceeding CTCAE Grade 1 (excluding alopecia and oxaliplatin-induced neurotoxicity ≤ Grade 2);
   7. Major surgical treatment, incisional biopsy, or significant traumatic injury within 28 days prior to the start of study treatment (excluding gastrointestinal endoscopic biopsy);
   8. Symptoms of active bleeding within 1 week prior to screening, without significant improvement or control;
   9. Patients with any bleeding event ≥ CTCAE Grade 3 within 4 weeks prior to study initiation, or presence of unhealed wounds, ulcers, or fractures;
   10. Arterial/venous thrombotic events within 6 months, such as cerebrovascular accidents (including transient ischemic attack, cerebral hemorrhage, cerebral infarction), deep vein thrombosis, and pulmonary embolism;
   11. History of psychoactive drug abuse with inability to abstain;
   12. Patients with any severe and/or uncontrolled diseases, including:

       * Uncontrolled hypertension (systolic blood pressure ≥150 mmHg or diastolic blood pressure ≥100 mmHg after standard antihypertensive therapy);
       * Myocardial ischemia ≥ Grade 2, myocardial infarction, arrhythmias (including QTc ≥450 ms for males, QTc ≥470 ms for females), and congestive heart failure ≥ Grade 2 (New York Heart Association (NYHA) classification);
       * Active or uncontrolled severe infections (≥ CTCAE Grade 2 infection);
       * Liver cirrhosis, active hepatitis\*; (\*Active hepatitis \[Hepatitis B reference: HBsAg positive and HBV DNA positive (\>2500 copies/mL or \>500 IU/mL); Hepatitis C reference: HCV antibody positive and HCV viral titer above the upper limit of normal\]. Note: Eligible HBsAg-positive or HBcAb-positive subjects and hepatitis C patients require continuous antiviral therapy to prevent viral reactivation.)
       * Renal failure requiring hemodialysis or peritoneal dialysis;
       * History of immunodeficiency, including HIV positivity or other acquired or congenital immunodeficiency diseases, or history of organ transplantation;
       * Poorly controlled diabetes (fasting blood glucose \>10 mmol/L);
       * Urinalysis showing urine protein ≥++ and confirmed 24-hour urine protein quantification \>1.0 g;
       * History of clear neurological or psychiatric disorders, including epilepsy or dementia requiring treatment.
   13. Patients with known active or suspected autoimmune diseases. Patients with immune-related hypothyroidism requiring thyroid hormone replacement therapy and well-controlled type I diabetes are allowed. Patients with vitiligo requiring no intervention or resolved childhood asthma/allergies requiring no intervention in adulthood are allowed.

       * Receipt of live vaccines within 28 days prior to enrollment. However, inactivated viral vaccines for seasonal influenza are permitted, while live attenuated influenza vaccines administered intranasally are not allowed.
       * Patients requiring systemic glucocorticoids (\>10 mg/day prednisone equivalent) or other immunosuppressive drugs within 14 days prior to enrollment or during the study. The following conditions are allowed for enrollment:
       * Use of topical or inhaled glucocorticoids in the absence of active autoimmune diseases;
       * Adrenal glucocorticoid replacement therapy at doses ≤10 mg/day prednisone equivalent.
   14. Participation in other clinical studies or initiation of study treatment within 14 days after the end of prior clinical study treatment. History of severe allergy to any monoclonal antibody.
3. Tumor-related symptoms and treatment:

   1. Surgery (excluding prior diagnostic biopsies), radiotherapy, chemotherapy, or other anticancer therapies within 4 weeks prior to the start of study treatment (calculated from the end date of the last treatment as the washout period);
   2. Prior postoperative adjuvant therapy containing anti-angiogenic targeted drugs (including bevacizumab, cetuximab, panitumumab, aflibercept, regorafenib, etc.);

   d) Patients with symptomatic brain metastases or those whose symptoms have been controlled for less than 2 months;
4. Patients deemed by the investigator to have concomitant diseases that seriously endanger subject safety or affect study completion, or who are otherwise considered unsuitable for enrollment.