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

According to the study design, 90 patients aged 18 to 80 years, with an ECOG score of 0-1, histologically confirmed colorectal adenocarcinoma, pMMR, KRAS/NRAS/BRAF wild-type, and unresectable metastases, including at least one measurable lesion as per RECIST 1.1 criteria, will be randomly assigned to three groups. They will receive the following treatments:

Arm A: Cetuximab β + Fruquintinib Arm B: Cetuximab β + Fruquintinib + anti-PD1 antibody Arm C: Cetuximab β + Fruquintinib + anti-PD1/CTLA4 antibody The primary endpoint is progression-free survival (PFS), and secondary endpoints include safety, ORR, and DCR.

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:

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

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

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

• Prothrombin time (PT), activated partial thromboplastin time (APTT), international normalized ratio (INR) ≤ 1.5 × ULN (without anticoagulant therapy);
• 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.
• Echocardiogram assessment: Left ventricular ejection fraction (LVEF) ≥ 50%.
• 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.
• 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).
• Female patients must meet one of the following conditions:

• Postmenopausal (defined as no menses for at least 1 year, with no other confirmed causes besides menopause), or
• Surgically sterilized (removal of ovaries and/or uterus), or
• 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.
• 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

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

• 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)];

• Multiple factors affecting oral medication (e.g., inability to swallow, chronic diarrhea, intestinal obstruction, etc.);
• History or tendency of gastrointestinal bleeding or perforation within 4 weeks prior to enrollment;
• Patients with active inflammatory bowel disease within 4 weeks prior to enrollment;
• Uncontrolled pleural effusion, pericardial effusion, or ascites requiring repeated drainage;
• Unresolved toxicities from any prior antitumor therapy exceeding CTCAE Grade 1 (excluding alopecia and oxaliplatin-induced neurotoxicity ≤ Grade 2);
• Major surgical treatment, incisional biopsy, or significant traumatic injury within 28 days prior to the start of study treatment (excluding gastrointestinal endoscopic biopsy);
• Symptoms of active bleeding within 1 week prior to screening, without significant improvement or control;
• Patients with any bleeding event ≥ CTCAE Grade 3 within 4 weeks prior to study initiation, or presence of unhealed wounds, ulcers, or fractures;
• 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;
• History of psychoactive drug abuse with inability to abstain;
• 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.
• 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.
• 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.
• Tumor-related symptoms and treatment:

• 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);
• 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;

• 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.