Fruquintinib Plus Anti-EGFR Antibody for Third-Line Treatment of RAS Wild-Type mCRC

Inclusion criteria

• Age 18-75 years, inclusive.
• Fully informed about the study and willing to sign written informed consent.
• Histologically confirmed metastatic or advanced colorectal adenocarcinoma.
• Tumor confirmed as NRAS, KRAS, and BRAF wild-type.
• At least one measurable lesion according to RECIST 1.1 criteria.
• ECOG performance status of 0-1.
• Estimated life expectancy ≥ 12 weeks.
• Prior treatment with oxaliplatin- and irinotecan-based therapy, or failure of at least two prior standard regimens.
• Prior treatments must have included fluoropyrimidine, oxaliplatin, and irinotecan (with or without bevacizumab or cetuximab).
• Treatment failure defined as disease progression during therapy or within 3 months after last treatment, or intolerance to toxicity.
• Recurrence within 6 months after adjuvant/neoadjuvant therapy is considered as first-line failure.
• Adequate organ function within 7 days prior to enrollment:

• ANC ≥ 1.5 × 10⁹/L
• Platelets ≥ 80 × 10⁹/L
• Hemoglobin ≥ 8 g/dL
• Total bilirubin ≤ 1.5 × ULN
• AST/ALT ≤ 2.5 × ULN (≤ 5 × ULN in liver metastasis)
• Serum creatinine ≤ 1.5 × ULN and creatinine clearance ≥ 50 mL/min
• INR ≤ 1.5 or APTT ≤ 1.5 × ULN
• No receipt of blood products or growth factors within 14 days prior to enrollment.
• Able and willing to comply with study procedures and follow-up.

Exclusion criteria

• Unable or unwilling to comply with the study protocol.
• Prior treatment with VEGFR tyrosine kinase inhibitors (e.g., regorafenib).
• Participation in another clinical trial within 4 weeks.
• Systemic anticancer therapy within 4 weeks before enrollment.
• Uncontrolled hypertension (SBP > 140 mmHg or DBP > 90 mmHg).
• Any condition that affects drug absorption or inability to take oral medication.
• Active gastric or duodenal ulcer, ulcerative colitis, or tumor-related active bleeding.
• Positive fecal occult blood (≥ ++) without endoscopic exclusion of bleeding.
• Arterial or deep venous thrombosis within 6 months.
• Significant bleeding within 2 months (melena, hematemesis, hemoptysis).
• Stroke or transient ischemic attack within 12 months.
• Significant cardiovascular disease:

• Acute myocardial infarction within 6 months
• Severe or unstable angina
• Heart failure NYHA class > II
• Clinically significant arrhythmia requiring treatment
• LVEF < 50%
• History of other malignancies within 5 years (except adequately treated in-situ cancers or early non-invasive cancers).
• Uncontrolled active infection, including HBV or HCV (HBV DNA ≥ 1×10⁴ copies/mL or >2000 IU/mL).
• Pregnant or breastfeeding women.
• Urine protein ≥ 2+ or 24-hour urine protein > 1.0 g.
• HIV-positive individuals.
• Any condition that, in the investigator's judgment, makes the patient unsuitable for the study.