Fruquintinib Combined With Capecitabine as Adjuvant Extended Therapy After R0 Resection and Perioperative Chemotherapy in Patients With Liver-Only Metastatic Colorectal Cancer

Prior treatment

• Evidence of tumor recurrence on baseline imaging prior to randomization.
• PD or SD with tumor enlargement \> 10% after preoperative chemotherapy assessed by RECIST 1.1.
• More than 8 weeks between the last perioperative chemotherapy cycle and randomization.
• Within 5 years prior to randomization, a previous or concurrent malignancy of a different site or histology from colorectal cancer, except for curatively resected cervical carcinoma in situ, non-melanoma skin cancer, and superficial bladder tumors such as non-invasive tumors (Ta), carcinoma in situ (Tis), and tumors invading only the lamina propria (T1).
• Receipt of the following systemic therapies within 4 weeks before the start of treatment: cytotoxic therapy, signal transduction inhibitors, immunotherapy, or hormonal therapy.
• Major surgery, open biopsy, or significant traumatic injury within 28 days before the start of study treatment.
• Congestive heart failure of Grade 2 or higher; unstable angina (angina symptoms at rest) or new-onset angina within 3 months prior to study screening; myocardial infarction within 6 months before the start of study treatment; arrhythmias requiring anti-arrhythmic drug therapy, except β-blockers or digoxin.

Other illness

• Uncontrolled infection, diarrhea, or intestinal obstruction.
• A history of HIV infection.

Lab values

• Use of biological agents (e.g., antibodies targeting VEGF or EGFR) after hepatic surgery, unless such biologic therapy was administered before liver surgery and only the pre-specified number of cycles was given after resection.
• Adverse events from prior treatment not resolved to NCI-CTCAE Grade 1, except for alopecia and/or oxaliplatin-induced neuropathy of ≤ Grade 2, and hemoglobin (HGB) ≥ 90 g/L.

Other

• Presence of extrahepatic metastases. Suspicious lesions must be rigorously evaluated by imaging and/or pathological biopsy to exclude extrahepatic metastases.
• Pregnancy.
• Lactation.
• Inability to swallow oral tablets (crushing of tablets is not permitted).

• Male or female, aged 18 to 80 years (inclusive).
• Pathologically confirmed colorectal adenocarcinoma of the pMMR / MSI-L / MSS types.
• Diagnosis of stage IVa colon cancer with liver-only metastases confirmed by contrast-enhanced chest and abdominal CT or MRI, and meeting one of the following treatment conditions:
  • Synchronous liver metastases: has undergone radical surgery (R0 resection) of both the primary tumor and liver metastases and at least 3 but not more than 6 months of perioperative chemotherapy containing a fluoropyrimidine combined with oxaliplatin or irinotecan (i.e., 12 cycles on a 2-week schedule or 8 cycles on a 3-week schedule);
  • Metachronous liver metastases: previously received at least 3 months of adjuvant chemotherapy (single-agent fluoropyrimidine or fluoropyrimidine combined with oxaliplatin) after radical primary resection, developed liver-only metastases at least 12 months after completion of adjuvant therapy (including radiotherapy), then underwent repeat R0 resection of liver metastases and at least 3 but not more than 6 months of perioperative chemotherapy (fluoropyrimidine combined with oxaliplatin or irinotecan);
  • Metachronous liver metastases: previously received no adjuvant chemotherapy after radical primary resection, developed liver-only metastases and underwent R0 resection of liver metastases, followed by at least 3 but not more than 6 months of perioperative chemotherapy (single-agent fluoropyrimidine or a combination regimen);
  • Metachronous liver metastases: previously received no more than 6 months of adjuvant chemotherapy (single-agent fluoropyrimidine or oxaliplatin combined with a fluoropyrimidine) after radical primary resection, and developed liver metastases within 6 to 12 months after completion of adjuvant therapy, followed by R0 resection of liver metastases. For these patients, the previous adjuvant chemotherapy regimen cannot be reused as perioperative chemotherapy for liver metastases. If prior adjuvant chemotherapy was a single-agent fluoropyrimidine, perioperative chemotherapy for liver metastases must consist of a fluoropyrimidine combined with oxaliplatin or irinotecan.
  • Converted to resectable liver metastases with any regimen and completed no more than 6 months of perioperative chemotherapy.
• Both the primary colorectal tumor and liver metastases have been completely resected (R0), where hepatic R0 may be achieved by R0 resection or by radiofrequency ablation of lesions with a maximum diameter \< 2 cm and fewer than 5 lesions. Patients who underwent staged (two-stage) hepatectomy are also eligible. Subjects with positive surgical margins are not eligible.
• Clinical Risk Score (CRS) ≥ 2 according to the MSKCC clinical risk assessment system. (Scoring: one point is assigned for each of the following - \> 1 liver metastasis; maximum diameter ≥ 5 cm; synchronous liver metastases, or metachronous liver metastases with a disease-free interval (DFS) \< 1 year; positive primary-tumor lymph nodes; CEA ≥ 3× the upper limit of normal. The CRS is the cumulative score.)
• If preoperative chemotherapy was administered, the response assessed by RECIST 1.1 is CR, PR, or SD.
• No evidence of residual tumor on contrast-enhanced chest and abdominal CT or MRI within 4 weeks prior to randomization.
• ECOG performance status score of 0-2.
• Laboratory tests confirm adequate bone marrow, hepatic, renal, and cardiac function:
  • Total bilirubin (TBIL) ≤ 1.5 × ULN Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 × ULN Lipase ≤ 1.5 × ULN Serum creatinine ≤ 1.5 × ULN Glomerular filtration rate ≥ 30 mL/min/1.73 m² INR ≤ 1.5 × ULN; patients receiving warfarin or heparin may still be enrolled if they have no underlying coagulation abnormality Absolute neutrophil count (ANC) ≥ 1.5 × 10⁹/L; platelet count (PLT) ≥ 75 × 10⁹/L; hemoglobin (HGB) ≥ 90 g/L Essentially normal electrocardiogram (ECG)
• Willing and able to sign the informed consent form.
• Male and female subjects of childbearing potential must agree to use highly effective contraception throughout the study and for at least 3 months after the last dose of study treatment.