Efficacy and Safety of HAIC Combined With Lenvatinib and PD-1 Inhibitors for Advanced Intrahepatic Cholangiocarcinoma

Efficacy and Safety of First-line Hepatic Arterial Infusion Chemotherapy With Liposomal Irinotecan Plus 5-FU/LV Combined With Lenvatinib and PD-1 Inhibitors for Advanced Intrahepatic Cholangiocarcinoma

Intrahepatic Cholangiocarcinoma (ICC), the second most prevalent primary malignant liver neoplasm, features highly aggressive biological behavior and dismal prognosis. Even following curative surgical resection, patients have a 5-year overall survival rate lower than 5%, while unresectable patients achieve a median overall survival of only around 6 months. Most patients are diagnosed with locally advanced disease; frequently, surgical resection is contraindicated owing to unfavorable tumor location, vascular invasion or multifocal tumor spread. Therefore, exploring effective therapeutic strategies to boost survival outcomes for such patients is extremely critical.

China carries a heavy disease burden of biliary tract malignancies, with approximately 140,000 newly diagnosed cases each year. The incidence of cholangiocarcinoma exceeds 6 per 100,000 persons (more than 84,000 annual new cases). Moreover, intrahepatic cholangiocarcinoma outnumbers extrahepatic cholangiocarcinoma in incidence, which underscores the urgent demand for optimized treatment strategies.

Hepatic Arterial Infusion Chemotherapy (HAIC) is a regional therapeutic approach. Its theoretical foundation lies in the biological trait that malignant liver tumors are predominantly supplied by the hepatic artery. This modality delivers high-dose chemotherapeutic agents straight to tumor lesions through arterial routes, raising local intratumoral drug concentration and simultaneously reducing systemic adverse toxic reactions.

In recent years, innovations in interventional techniques - especially the application of modified percutaneous hepatic arterial chemotherapy port implantation - have greatly elevated the safety, feasibility and patient adherence of HAIC. Hence, HAIC has attracted extensive attention in treating hepatobiliary malignancies including ICC. Current research focuses on the value of HAIC monotherapy, HAIC combined with systemic chemotherapy, targeted therapy or immunotherapy for unresectable ICC, as well as its potential role as neoadjuvant therapy.

Inclusion Criteria:

• Aged between 18 and 80 years old.

• Histologically or cytologically confirmed unresectable locally advanced or intrahepatic cholangiocarcinoma with metastasis.

• Liver function: Child-Pugh Class A (score 5-6) or favorable Class B (score ≤7).

• Have at least one measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.

• Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1.

• Estimated survival time > 12 months.

  • No prior systemic therapy for unresectable locally advanced or metastatic intrahepatic cholangiocarcinoma. Patients who received one line of adjuvant or neoadjuvant chemotherapy and experienced recurrence more than 6 months after chemotherapy completion are eligible.

• Adequate bone marrow function: Absolute Neutrophil Count (ANC) ≥ 1.5×10⁹/L, hemoglobin ≥ 90 g/dL, Platelet (PLT) ≥ 100×10⁹/L, White Blood Cell (WBC) ≥ 3.0×10⁹/L.

• Adequate renal function: Serum Creatinine (Cr) ≤ 1.5 × Upper Limit of Normal (ULN), or Creatinine Clearance (CCr) ≥ 60 mL/min (calculated by Cockcroft-Gault formula).

• Adequate coagulation function: Prothrombin Time (PT), Activated Partial Thromboplastin Time (APTT) and International Normalized Ratio (INR) ≤ 1.5 × ULN.

• No active or suspected infection.

• Female patients are not pregnant or breastfeeding. Fertile female and male patients must use effective contraception during the study and for 6 months after the end of study treatment.

• Patients shall have good compliance, be able to understand the study procedures, and provide written informed consent.

Exclusion Criteria:

• Patients with a history of other malignant tumors within the past 5 years, except for cured carcinoma in situ and basal cell carcinoma of the skin.
• Patients with obvious clinical bleeding symptoms or bleeding tendency within 3 months prior to treatment, including bleeding volume > 30 mL, hematemesis, melena, hematochezia, or hemoptysis with fresh blood > 5 mL within 4 weeks.

Patients with a history of venous or arterial thromboembolic events within the preceding 6 months, such as cerebrovascular accidents (transient ischemic attack, cerebral hemorrhage, cerebral infarction), deep vein thrombosis and pulmonary embolism.

• Patients requiring long-term anticoagulant therapy with warfarin or heparin, or long-term antiplatelet therapy (aspirin ≥ 300 mg/day or clopidogrel ≥ 75 mg/day).
• Patients with extensive distant metastases (e.g., peritoneal metastasis, multiple bone or brain metastases).
• Patients who have used strong CYP3A4 inducers within 3 weeks before the first dose, or strong CYP3A4 inhibitors / strong UGT1A1 inhibitors within 3 weeks before the first dose.
• Patients who have undergone major organ surgery within 4 weeks prior to treatment (excluding needle biopsy, central venous catheterization, port catheter placement, biliary stenting for biliary obstruction relief, percutaneous transhepatic biliary drainage and cholecystostomy), or those with planned elective surgery.
• Patients with active cardiac diseases within 6 months prior to treatment, including myocardial infarction and severe/unstable angina. Left ventricular ejection fraction < 50% on echocardiography, or uncontrolled arrhythmia.

Patients with congenital or acquired immunodeficiency, such as HIV infection, or active hepatitis (abnormal transaminases; HBV DNA ≥ 1000 IU/mL for hepatitis B, HCV RNA ≥ 1000 IU/mL for hepatitis C).

• Chronic HBV carriers with HBV DNA < 2000 IU/mL are eligible only if they receive concomitant antiviral therapy throughout the study.
• Patients with any other clinically significant metabolic, physical or laboratory abnormalities. At the investigator's discretion, patients with conditions unsuitable for the study drug (e.g., seizures requiring treatment), conditions that may interfere with interpretation of study results, or that place the patient at excessive risk are excluded.
• Patients with intestinal obstruction (excluding incomplete intestinal obstruction managed solely with enteral nutrition), or patients at risk of intestinal perforation (including but not limited to acute diverticulitis, abdominal abscess, and history of abdominal malignancy).
• Pregnant or breastfeeding female subjects.