Fruquintinib Versus Bevacizumab Plus Chemotherapy in Second-Line RAS-Mutant Metastatic Colorectal Cancer (FRU-RAS)

Prior treatment

• Enrolled in another clinical study within the 4 weeks prior to enrollment in this study;
• Previously received anti-angiogenic small molecule targeted drug treatment, such as fruquintinib, etc.;
• Experienced severe infection within 4 weeks prior to enrollment (e.g., requiring intravenous infusion of antibiotics, antifungal drugs, or antiviral drugs);
• Had active bleeding or coagulation disorders within 2 months prior to enrollment, had a bleeding tendency or was receiving thrombolytic therapy, and was assessed by the investigator as unsuitable for enrollment;
• Had other malignant tumors within 5 years prior to enrollment or at the same time (except for cured basal cell carcinoma of the skin and cervical carcinoma in situ);
• Pregnant (positive pregnancy test before medication) or breastfeeding women;

Other illness

• Symptomatic brain or leptomeningeal metastases (except for those who have undergone local radiotherapy or surgery for brain metastases for more than 6 months and have stable disease control);
• Hypertension that cannot be well controlled with antihypertensive drugs (systolic blood pressure ≥ 140 mmHg or diastolic blood pressure ≥ 90 mmHg);
• Known to be allergic to the study drug or any of its excipients;
• Unable to take oral medication or the investigator judged that the subject had a condition that affected drug absorption;

Lab values

• Had active heart disease within 6 months prior to treatment, including myocardial infarction, severe/unstable angina pectoris. Echocardiography showed left ventricular ejection fraction \< 50%, or had poorly controlled arrhythmia;
• Had active or uncontrolled severe infections 1) Known human immunodeficiency virus (HIV) infection; 2) Known history of clinically significant liver disease, including viral hepatitis \[known hepatitis B virus (HBV) carriers must be excluded from active HBV infection, i.e., HBV DNA positive (\>1×10\^4 copies/mL or \>2000 IU/mL); 3) Known hepatitis C virus (HCV) infection and HCV RNA positive (\>1×10\^3 copies/mL), or other hepatitis, liver cirrhosis;

Other

• Urinalysis indicated proteinuria ≥ 2+, and 24-hour urine protein quantification \> 1.0g;
• Other situations judged by the investigator as unsuitable for inclusion in this study.

• Patients voluntarily participate in the study, sign the informed consent form, and have good compliance.
• 18 years ≤ age ≤ 75 years.
• Histologically and/or cytologically confirmed unresectable metastatic colorectal cancer.
• RAS mutant type.
• Previously received chemotherapy based on fluoropyrimidines (5-fluorouracil or capecitabine, etc.), oxaliplatin or irinotecan; previous adjuvant/neoadjuvant therapy is allowed. If recurrence or metastasis occurs during or within 6 months after adjuvant/neoadjuvant therapy, it is considered as the failure of first-line systemic chemotherapy for advanced disease.
• Patients must have at least one measurable lesion (RECIST 1.1).
• ECOG performance status 0-1.
• Expected survival ≥ 12 weeks.
• Blood tests (without blood transfusion within 14 days) 1) Absolute neutrophil count ≥ 1.5×10\^9/L, platelet count ≥ 100×10\^9/L, hemoglobin concentration ≥ 9g/dL; 2) Liver function tests (AST and ALT ≤ 2.5×ULN, bilirubin ≤ 1.5×ULN; if there is liver metastasis, AST and ALT ≤ 5×ULN); 3) Renal function (serum creatinine (Cr) ≤ 1.5×ULN, or creatinine clearance rate (CCr) ≥ 60ml/min); 4) Coagulation, international normalized ratio (INR) ≤ 1.5×ULN, prothrombin time (PT) and activated partial thromboplastin time (APTT) ≤ 1.5×ULN; 5) Thyroid function, thyroid stimulating hormone (TSH) ≤ upper limit of normal (ULN); if abnormal, FT3 and FT4 levels should be examined, and patients with normal FT3 and FT4 levels can be included.
• Women of childbearing age are willing to use medically approved effective contraceptive measures (such as intrauterine devices, contraceptives or condoms) during the study and for 3 months after the last administration of the study drug; for male subjects whose partners are of childbearing age, it is recommended to take effective contraceptive measures during the study and for 3 months after the last administration of the study drug.