A Prospective Study of Sacituzumab Tirumotecan Plus Pembrolizumab for Advanced Biliary Tract Cancer

Inclusion Criteria:

1. Subjects must voluntarily participate in the study, sign a written informed consent form (ICF), demonstrate good compliance, and cooperate with follow-up visits. Subjects must be $\\ge$ 18 and \< 75 years of age at the time of signing the ICF, with no gender restrictions.
2. Histologically and radiologically confirmed advanced biliary tract cancer (BTC) that is unresectable, recurrent, locally advanced, or metastatic, defined as Stage IIIA or higher according to the AJCC 8th edition staging system, including intrahepatic or extrahepatic cholangiocarcinoma and gallbladder cancer.
3. Disease progression after one or more prior lines of standard therapy.
4. Ineligible for radical surgery/local therapy for at least 4 weeks prior to baseline assessment, or experienced disease progression thereafter. The aforementioned treatments include lesion resection, ablation, transarterial chemoembolization (TACE), hepatic arterial infusion chemotherapy (HAIC), radiotherapy, etc. All acute toxicities from local therapy must have resolved to ≤ Grade 1 per CTCAE v5.0.
5. Presence of at least one measurable lesion (according to RECIST v1.1, the measurable lesion must have a longest diameter ≥ 10 mm by spiral CT scan, or a short axis ≥ 15 mm for enlarged lymph nodes).
6. ECOG performance status of 0 or 1 within 1 week prior to enrollment. Estimated life expectancy of ≥ 3 months as assessed by the investigator.
7. Adequate hematological and organ function, based on the following laboratory results obtained within 14 days prior to the initiation of study treatment (unless otherwise specified):

   Hematology: (No blood transfusion, no G-CSF administration, and no pharmacological correction within 14 days prior to screening) Hemoglobin (Hb) ≥ 90 g/L; Absolute Neutrophil Count (ANC) ≥ 1.5 \* 10\^9/L; Platelets (PLT) ≥100 \* 10\^9/L.

   Biochemistry: (No albumin transfusion within 14 days) Adequate liver function: ALT and AST ≤ 2.5 $\\times$ Upper Limit of Normal (ULN); for patients with liver metastases, ALT and AST ≤ 5 \* ULN.

   Serum bilirubin ≤ 2.0 \* ULN; these criteria do not apply to patients with confirmed Gilbert's syndrome. Any clinically significant biliary obstruction must be relieved prior to enrollment.
8. Adequate renal function: Serum creatinine ≤ 1.5 \* ULN, or creatinine clearance (CrCl) \> 50 mL/min (calculated using the standard Cockcroft-Gault formula):

   Female: CrCl = ((140 - Age) \* Weight (kg) \* 0.85) / (72 \* Serum Creatinine (mg/dL)); Male: CrCl = ((140 - Age) \* Weight (kg) \* 1.00) / (72 \* Serum Creatinine (mg/dL)).
9. Women of childbearing potential: Must agree to remain abstinent (refrain from heterosexual intercourse) or use a contraceptive method with an annual failure rate of \< 1% during the treatment period and for at least 6 months after the last dose of study medication.
10. Males: Must agree to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agree not to donate sperm.

Exclusion Criteria:

1. Prior treatment with TROP2-targeted therapy and/or topoisomerase I inhibitors.
2. Patients currently receiving approved or investigational systemic anti-cancer therapies, including chemotherapy, biological immunotherapy, targeted therapy, or traditional Chinese medicine with specific anti-cancer indications. (Such treatments are permitted if completed at least 4 weeks prior to enrollment).
3. Histopathological findings indicating mixed hepatocellular cholangiocarcinoma, the presence of squamous cell carcinoma or sarcomatoid components, or ampullary carcinoma.
4. Presence of other uncured malignancies within the past 5 years (excluding cured basal cell carcinoma of the skin and cervical carcinoma in situ).
5. Clinically significant gastrointestinal diseases.
6. Clinically significant cardiovascular or cerebrovascular diseases.
7. Hepatic or renal insufficiency:

   Hepatic insufficiency: e.g., presence of jaundice, ascites, and/or bilirubin \> 3 \* ULN.

   Renal insufficiency: Urine protein-to-creatinine ratio \> 3.5 g/24 hours, routine urinalysis showing proteinuria ≥ ++, confirmed 24-hour urine protein \> 1.0 g, or renal failure requiring hemodialysis or peritoneal dialysis.

   Received strong CYP3A4 inhibitors within 7 days prior to study entry, or strong CYP3A4 inducers within 12 days prior to study entry.
8. Active autoimmune disease, a history of autoimmune disease, or risk of immune-mediated diseases:

   Active Hepatitis B \[Hepatitis B surface antigen (HBsAg) positive, requiring HBV-DNA testing; HBV-DNA ≥ 500 IU/mL or above the lower limit of detection (LLOD), whichever is higher\] or Hepatitis C (HCV antibody positive, and HCV-RNA above the LLOD). Note: Subjects who are HBsAg positive are required to receive anti-HBV therapy during the study treatment period.
9. Neurological diseases:

   Patients with epilepsy requiring pharmacological treatment. Known active central nervous system metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases who have stable brain metastatic disease (no evidence of progression on imaging for at least 4 weeks prior to the first study treatment, and any neurological symptoms have returned to baseline) are eligible to participate, provided there is no evidence of new or enlarging brain metastases, and they have not used steroids for at least 7 days prior to study treatment. However, patients with carcinomatous meningitis are excluded regardless of clinical stability.
10. Presence of an ongoing or active infection.
11. Documented severe dry eye syndrome, severe meibomian gland disease and/or blepharitis, or a history of corneal diseases that may interfere with or delay corneal healing.
12. Pregnant or lactating women.
13. Any condition that, in the opinion of the investigator, would interfere with the evaluation of the study drug, subject safety, or the interpretation of study results, or any other condition rendering the subject unsuitable for participation in the study.