Alternating HAIC and Systemic Chemotherapy With or Without Adebrelimab and Apatinib for Unresectable Biliary Tract Cancer

Biliary tract cancer (BTC), which includes intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, and gallbladder cancer, is an aggressive malignancy associated with a generally poor prognosis. For patients with unresectable, locally advanced, or metastatic disease, first-line systemic chemotherapy using gemcitabine and cisplatin remains the standard of care, although treatment outcomes are ofter suboptimal. HAIC has gained increasing attention in clinical practice, paticularly in China, for its ability to enhance local drug delivery and improve tumor control in cases of liver-dominant disease. Alternating HAIC with systemic chemotherapy may provide additive benefits by simultaneously targeting both intrahepatic and extrahepatic lesions.

Recent advances in immunotherapy and anti-angiogenic therapy have shown promise results in BTC. Adebrelimab, a PD-L1 inhibitor, and apatinib, a VEGFR2 inhibitor, have demonstrated antitumor activity in various solid tumors. Combining these agents with chemotherapy and HAIC may yield synergistic effects, potentially improving response rates and extending survival.

This prospective real-world study is designed to evaluate the effectiveness and safety of an alternating regimen of HAIC and systemic chemotherapy (gemcitabine plus cisplatin), with or without adebrelimab and apatinib, in patients with previously untreated, unresectable, locally advanced or metastatic BTC. Participants will be assigned to one of two cohorts based on patient preference and clinician judgment: Cohort A will receive HAIC and systemic chemotherapy combined with adebrelimab and apatinib, while Cohort B will receive HAIC and systemic chemotherapy alone. Dosing and administration will follow the standard treatment protocols.

The study will capture real-world data on objective tumor response, progression-free survival, overall survival, and safety profiles. Exploratory analyses may include patterns of disease progression, treatment adherence, and the influence of clinical and biological factors on outcomes. The results are anticipated to offer valuable evidence to guide clinical decision-making and help optimize first-line treatment strategies for patients with advanced BTC in routine practice.

• HAIC (Procedure): HAIC is administered using a gemcitabine plus cisplatin regimen, with dosing and administration according to each participating center's standard treatment protocols.
• Gemcitabine plus Cisplatin (Drug): Gemcitabine and cisplatin administered intravenously according to institutional standard first-line regimens for biliary tract cancer. Dosing and schedule follow each center's standard treatment protocols.
• Adebrelimab (Drug): Adebrelimab administered intravenously at a dose of 1200 mg every 3 weeks until disease progression or unacceptable toxicity.
• Apatinib (Drug): Apatinib administered orally at a dose of 250 mg once daily until disease progression or unacceptable toxicity.

Primary outcomes

• Overall Survival (OS) [The maximum time from receiving treatment to dying for any reason is 3 years.]: Overall survival (OS) was defined as the time from initiation of study treatment (first dose) to death from any cause.

Secondary outcomes

• Progression-free Survival (PFS) [Progression-free survival (PFS) analysis based on investigator assessment per RECIST 1.1, and will be assessed up to 2 years.]: Progression-free survival (PFS), assessed by investigators per RECIST version 1.1, was defined as the time from initiation of study treatment (first dose) to the first documentation of objective disease progression or death from any cause, which ever occurred first.
• Objective Response Rate (ORR) [Every 6 weeks for the first 24 weeks, then every 8 weeks until disease progression or study completion, up to 1 years.]: Disease assessments based on investigator assessments were determined by using RECIST version 1.1 guidelines. The ORR was defined as the percentage of patients with confirmed complete response (CR) or confirmed partial response (PR). The CR was defined as disappearance of all target and non-target lesions and no new lesions. The PR was defined as >= 30% decrease in the sum of diameters of target lesions (compared to baseline) and no new non-target lesion.
• Disease Control Rate (DCR) [Every 6 weeks for the first 24 weeks, then every 8 weeks until disease progression or study completion, up to 1 years.]: Disease control rate based on investigator assessments according to RECIST version 1.1 was defined as the rate of best objective response of complete response (CR), partial response (PR) or stable disease (SD).

Sex: All, ages: 18 Years to any

Inclusion Criteria:

1. Age ≥ 18 years at the time of enrollment.
2. Histologically or cytologically confirmed diagnosis unresectable, locally advanced, or metastatic BTC, including intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, and gallbladder cancer.
3. No prior systemic therapy for BTC, including chemotherapy, immunotherapy, or small-molecule targeted therapy.
4. Patients with disease recurrence ≥6 months after curative resection and completion of adjuvant therapy (chemotherapy or radiotherapy) are eligible.
5. Adequate liver function: defined as Child-Pugh Class A (score 5-6) or well-compensated Class B (score ≤7).
6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
7. At least one measurable lesion as defined by RECIST 1.1.
8. Assessed by the investigator as being able to tolerate and comply with the study treatment regimen.
9. Provision of written informed consent, voluntarily agreeing to participate after full explanation of the study protocol.

Exclusion Criteria:

1. Hepatic tumor burden occupying ≥50% of total liver volume.
2. History of liver transplantation.
3. Major surgery or invasive procedure (excluding intravenous catheter placement or percutaneous drainage) within 4 weeks prior to enrollment.
4. History or evidence of clinically significant bleeding, including: bleeding >30 mL within 3 months prior to enrollment (including hematemesis, melena, or hematochezia), hemoptysis (>5 mL of fresh blood) within 4 weeks prior to enrollment, or thromboembolic events (including stroke or transient ischemic attack) within the past 12 months.
5. Known active infection with human immunodeficiency virus (HIV).
6. Pregnant (a positive pregnancy test prior to study drug administration) or breastfeeding women.
7. Any condition, in the investigator's judgment, that could compromise patient satety, affect the assessment of study outcomes, or lead to premature discontinuation. this includes, but is not limited to: active alcohol or substance abuse, severe uncontrolled comorbidities, significant laboratory abnormalities, or social/family circumstances that could interfere with protocol compliance.