For unresectable and metastatic advanced biliary tract cancers (BTCs), gemcitabine plus cisplatin (GP regimen) has been established as the standard first-line treatment based on the findings of the ABC-02 trial. As the first large-sample phase III randomized clinical trial enrolling patients with locally advanced or metastatic biliary tract cancers, the ABC-02 study demonstrated that the GP regimen improved the efficacy of chemotherapy for biliary tract malignancies and confirmed the synergistic effect between gemcitabine and cisplatin.

Phase III trials of immunotherapy combined with chemotherapy have also yielded encouraging outcomes in patients with advanced biliary tract cancers (BTCs).

The TOPAZ-1 trial was a global, randomized, double-blind, phase III randomized controlled study evaluating durvalumab or placebo combined with gemcitabine plus cisplatin for advanced biliary tract cancer. A total of 685 patients were randomly assigned to the durvalumab plus GC group (D+GC, n=341) or the placebo plus GC group (PBO+GC, n=344). The median follow-up duration was 23.4 months (20.6-25.2) and 22.4 months (21.4-23.8) for the two groups, respectively.

Median overall survival (mOS) was significantly prolonged in the D+GC group compared with the PBO+GC group (12.9 months vs 11.3 months; HR=0.76, 95% CI: 0.64-0.91). OS hazard ratios (HRs) with corresponding 95% CIs indicated consistent clinical benefits of the D+GC regimen across all pre-specified subgroups: initially unresectable disease (HR=0.79, 95% CI: 0.65-0.95), recurrent disease (HR=0.76, 95% CI: 0.49-1.20); and by primary tumor site: intrahepatic cholangiocarcinoma (HR=0.78, 95% CI: 0.62-0.99), extrahepatic cholangiocarcinoma (HR=0.61, 95% CI: 0.41-0.91), and gallbladder cancer (HR=0.90, 95% CI: 0.64-1.25).

The 12-month, 18-month and 24-month OS rates were 54.3% vs 47.1%, 34.8% vs 24.1%, and 23.6% vs 11.5% (D+GC vs PBO+GC), respectively. The incidence of grade 3/4 treatment-related adverse events (TRAEs) was 60.9% in the D+GC group versus 63.5% in the PBO+GC group. The rate of treatment discontinuation due to any TRAE was 8.9% and 11.4% in the two groups respectively.

KEYNOTE-966 is a randomized, double-blind, placebo-controlled phase III trial conducted across 175 medical centers worldwide. A total of 1069 patients were randomized to receive pembrolizumab plus gemcitabine and cisplatin (pembrolizumab group, n=533) or placebo plus gemcitabine and cisplatin (placebo group, n=536). At the final analysis, the median follow-up time was 25.6 months (IQR: 21.7-30.4).

The median OS was 12.7 months (95% CI: 11.5-13.6) in the pembrolizumab group and 10.9 months (95% CI: 9.9-11.6) in the placebo group (HR=0.83, 95% CI: 0.72-0.95; one-sided p=0.034, with a prespecified significance threshold of p=0.0200).

Among the treated population, grade 3-4 adverse events were reported in 420 of 529 patients (79%) in the pembrolizumab group and 400 of 534 patients (75%) in the placebo group. Grade 3-4 TRAEs occurred in 369 patients (70%) in the pembrolizumab group and 367 patients (69%) in the placebo group.

Deaths attributable to adverse events occurred in 31 patients (6%) in the pembrolizumab group and 49 patients (9%) in the placebo group. Among these, 8 patients (2%) in the pembrolizumab group and 3 patients (1%) in the placebo group died from TRAEs.

Although chemoimmunotherapy has become the standard first-line regimen for advanced biliary tract cancers (BTCs), substantial unmet medical needs remain in clinical practice. First, the survival benefit is modest. In the TOPAZ-1 and KEYNOTE-966 trials, the median overall survival (OS) was prolonged by merely 1.3 to 1.8 months with chemoimmunotherapy versus chemotherapy alone. The objective response rate (ORR) remains below 30%, and disease progression eventually occurs in most patients. Second, there is a lack of validated predictive biomarkers. To date, no reliable biomarkers are available to accurately identify patients most likely to benefit from chemoimmunotherapy. Consequently, some patients fail to achieve satisfactory clinical outcomes while suffering from unnecessary treatment-related toxicities. Third, a subset of patients show poor tolerance to current regimens. Cisplatin-induced adverse events such as nephrotoxicity and gastrointestinal reactions may compromise treatment adherence. Therefore, safer chemotherapy combinations and novel combination strategies are urgently required.

These limitations indicate that current chemoimmunotherapy regimens require further optimization. Novel and more effective combination treatment strategies need to be explored to maximize clinical benefits and improve patient prognosis.

Inclusion Criteria:

• Provide written informed consent prior to any study-related procedures.
• Male or female subjects aged ≥ 18 years and ≤ 75 years.
• Histologically or cytologically confirmed locally advanced or metastatic biliary tract malignancies, including intrahepatic cholangiocarcinoma (iCCA), extrahepatic cholangiocarcinoma (eCCA) and gallbladder carcinoma (GBC).
• No prior systemic anti-tumor treatment. Subjects who have completed adjuvant therapy for more than 6 months are eligible for enrollment.
• Estimated overall survival > 6 months.
• Have at least one measurable lesion per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1).
• Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 0 or 1.
• Adequate organ function with all laboratory parameters meeting the following criteria:

Absolute neutrophil count (ANC) ≥ 1.5 × 10⁹/L without the use of granulocyte colony-stimulating factor within the preceding 14 days; Platelet count ≥ 100 × 10⁹/L without blood transfusion within the preceding 14 days; Hemoglobin > 9 g/dL without blood transfusion or erythropoietin administration within the preceding 14 days; Total bilirubin ≤ 1.5 × upper limit of normal (ULN); Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 2.5 × ULN. For subjects with liver metastases, AST or ALT ≤ 5 × ULN is acceptable; Serum creatinine ≤ 1.5 × ULN and creatinine clearance (calculated using the Cockcroft-Gault formula) ≥ 60 mL/min; Adequate coagulation function: International Normalized Ratio (INR) or prothrombin time (PT) ≤ 1.5 × ULN; Normal thyroid function: Thyroid-stimulating hormone (TSH) within the normal range. Subjects with abnormal baseline TSH are also eligible if total triiodothyronine (total T3) or free triiodothyronine (FT3) and free thyroxine (FT4) are within normal limits; Cardiac biomarkers within the normal range. Isolated laboratory abnormalities deemed clinically insignificant by the investigator are permitted.

• For females of childbearing potential: Urine or serum pregnancy test must be negative within 3 days prior to the first dose of study drug (Cycle 1 Day 1). A serum pregnancy test is required if the urine test result is inconclusive. Females are defined as non-childbearing potential if they have been postmenopausal for at least 1 year, or have undergone surgical sterilization or hysterectomy.
• All subjects with childbearing potential (male and female) must use contraceptive methods with an annual failure rate below 1% throughout the treatment period and for 120 days after the last dose of study drug.

Exclusion Criteria:

• Diagnosis of any other malignant disease within 5 years prior to the first dose, excluding radically cured basal cell carcinoma, squamous cell carcinoma of the skin, and/or radically resected carcinoma in situ.
• Currently participating in an interventional clinical study, or having received any other investigational product or device within 4 weeks before the first dose.

Prior treatment with anti-PD-1, anti-PD-L1 or anti-PD-L2 agents, or drugs targeting other T cell co-stimulatory or co-inhibitory receptors (e.g., CTLA-4, OX-40, CD137).

• Received systemic treatment with traditional Chinese medicines with anti-tumor indications or immunomodulatory drugs (including thymosin, interferon, interleukin; excluding local administration for controlling pleural effusion) within 2 weeks prior to the first dose.
• History of active autoimmune diseases requiring systemic therapy (e.g., disease-modifying drugs, glucocorticoids, immunosuppressants) within 2 years before the first dose. Replacement therapy (e.g., thyroxine, insulin, physiological glucocorticoids for adrenal or pituitary insufficiency) is not regarded as systemic therapy. History of primary immunodeficiency is also excluded. Subjects with only positive autoimmune antibodies will be assessed by the investigator for the presence of autoimmune diseases.
• Received systemic glucocorticoids (excluding intranasal, inhaled or other topical glucocorticoids) or any other immunosuppressive therapy within 4 weeks prior to the first dose.

Note: Physiological doses of glucocorticoids (≤ 10 mg prednisone per day or equivalent) are permitted.

• Active hemoptysis (expectoration of at least 2.5 mL / half a teaspoon of fresh blood) or active gastrointestinal bleeding within 3 months before the first dose of study drug.
• Imaging evidence of tumor invasion or infiltration into major blood vessels, or bleeding tendency assessed by the investigator or radiologist.
• Underwent major surgery within 4 weeks prior to the first dose of study drug (biopsy procedures are excluded).
• Presence of severe unhealed wounds, ulcers or fractures.
• Continuous use of aspirin (> 325 mg/day) or other nonsteroidal anti-inflammatory drugs known to inhibit platelet function for 10 consecutive days currently or within 10 days prior to the first dose of study drug.
• Continuous treatment with full-dose oral or parenteral anticoagulants or thrombolytic agents for 10 consecutive days currently or within 10 days prior to the first dose of study drug.

Note: Prophylactic use of low-dose anticoagulants is allowed. Low-dose warfarin (≤ 1 mg/day), low-dose heparin (≤ 12,000 U/day) or low-dose aspirin (≤ 100 mg/day) for prophylaxis is permitted provided that INR ≤ 1.5.

• History of hereditary bleeding diathesis, coagulation disorders or thrombosis. Clinically uncontrolled pleural effusion or ascites. Subjects with no need for drainage or no obvious re-accumulation of effusion within 3 days after drainage cessation are eligible.
• History of allogeneic organ transplantation (corneal transplantation excluded) or allogeneic hematopoietic stem cell transplantation.

Known hypersensitivity to the active ingredients or excipients of sintilimab, ipilimumab N01 used in this study.

• Failure to fully recover from toxicities and/or complications caused by prior interventions before treatment initiation (i.e., residual toxicity > Grade 1 or not returning to baseline; fatigue and alopecia are excluded).
• Positive for human immunodeficiency virus (HIV) 1/2 antibodies.
• Untreated active hepatitis B, defined as HBsAg positive with HBV-DNA level exceeding the upper limit of normal range of the local laboratory.

Note: Subjects with hepatitis B meeting the following criteria are eligible:

1. HBV viral load < 2.5 × 10³ copies/mL (500 IU/mL) prior to the first dose, and receive anti-HBV therapy throughout the study treatment period.

2. Subjects with anti-HBc positive, HBsAg negative, anti-HBs negative and undetectable HBV viral load do not require prophylactic anti-HBV treatment, but shall be closely monitored for viral reactivation.

   • Active HCV infection (HCV antibody positive with HCV-RNA level above the lower limit of detection).

Received live attenuated vaccine within 4 weeks prior to the first dose.

• Pregnant or breastfeeding women.

• Presence of any severe or uncontrolled systemic diseases, including but not limited to the following:

  1. Significant, symptomatic and refractory abnormalities in cardiac rhythm, conduction or morphology on resting electrocardiogram, such as complete left bundle branch block, second-degree or higher atrioventricular block, ventricular arrhythmia or atrial fibrillation.
  2. Unstable angina, congestive heart failure, or chronic heart failure with New York Heart Association (NYHA) functional class ≥ 2.
  3. Any arterial thrombosis, embolism or ischemic events within 6 months before enrollment, such as myocardial infarction, unstable angina, cerebrovascular accident or transient ischemic attack.
  4. Underwent major surgery including craniotomy, thoracotomy or laparotomy within 4 weeks prior to the first dose; or unhealed wounds, ulcers or fractures. Tissue puncture biopsy or other minor surgeries within 7 days before the first dose are excluded, except for venous catheterization for infusion.
  5. Poorly controlled blood pressure (systolic blood pressure > 140 mmHg, diastolic blood pressure > 90 mmHg).
  6. Active pulmonary tuberculosis.
  7. Active or uncontrolled infections requiring systemic treatment.
  8. Clinically active diverticulitis, intra-abdominal abscess or gastrointestinal obstruction.
  9. Hepatic diseases such as liver cirrhosis, decompensated liver disease, acute or chronic active hepatitis.
  10. Poorly controlled diabetes (fasting blood glucose > 10 mmol/L).
  11. Urinalysis showing urine protein ≥ ++, confirmed by 24-hour urine protein quantification > 1.0 g.
  12. Psychiatric disorders leading to inability to cooperate with treatment.

• Any medical history, concomitant diseases, treatments or abnormal laboratory findings that may interfere with study results or prevent subjects from completing the study, or any other conditions deemed inappropriate for enrollment by the investigator due to potential risks.