Neoadjuvant Gemcitabine Plus Trastuzumab Rezetecan in HER2-positive UTUC

Prior treatment

• Received live attenuated vaccines within 4 weeks prior to enrollment or plan to receive such vaccines during the study.
• Received systemic chemotherapy, anti-PD-1/PD-L1 agents, or HER2-targeted therapy within the previous 6 months.
• Untreated acute or chronically active hepatitis B or hepatitis C infection. Patients receiving antiviral therapy may be considered eligible at the investigator's discretion with ongoing viral load monitoring.
• Uncontrolled concurrent illnesses, including but not limited to:
  • HIV infection (positive HIV antibody).
  • Severe active infection with inadequate clinical control.
  • Evidence of severe or uncontrolled systemic disease (e.g., severe psychiatric or neurological disorders, epilepsy or dementia; unstable or decompensated respiratory, cardiovascular, hepatic or renal disease; uncontrolled hypertension defined as CTCAE Grade ≥2 hypertension despite medical treatment).

Other illness

• Known hypersensitivity to gemcitabine, Trastuzumab Rezetecan, or any of their excipients.
• Active, known or suspected autoimmune disease.
• Known history of primary immunodeficiency.
• Known history of solid organ allotransplantation or allogeneic hematopoietic stem cell transplantation.
• Active bleeding, newly diagnosed thromboembolic disease requiring therapeutic anticoagulation, or bleeding diathesis.
• Diagnosis of another malignant tumor within the past 5 years.
• Active tuberculosis

Other

• Female patients who are pregnant or breastfeeding.

• The subject voluntarily participates in the study, provides written informed consent, and is able to comply with study procedures and follow-up visits.
• Aged between 18 and 75 years.
• Patients diagnosed with upper tract urothelial carcinoma (UTUC) who are candidates for radical nephroureterectomy with bladder cuff excision.
• Clinical stage T1N0M0 - T2-T4aN1M0 (evaluated by CT/MRI/PET-CT).
• Histopathology confirms urothelial carcinoma as the predominant component; IHC testing shows HER2 expression of 2+ to 3+.
• ECOG performance status ≤ 2.
• Laboratory parameters meet all of the following criteria:
  • Absolute neutrophil count ≥ 1.5 × 10⁹/L
  • Platelets ≥ 100 × 10⁹/L; hemoglobin ≥ 90 g/L
  • Total bilirubin ≤ 1.5 × ULN
  • Aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP) ≤ 2.5 × ULN; serum creatinine ≤ 3 × ULN
• Cardiac function: New York Heart Association (NYHA) classification \< Grade III.