Efficacy and Safety of Tislelizumab in Combination With Disitamab-vedotin as Neoadjuvant Therapy for HER2-positive High-risk Upper Tract Urothelial Carcinoma (UTUC)

Inclusion Criteria:

1. Radiographically(CT, MRI or PET-CT, etc.) and histologically confirmed diagnosis of localized HER-2 expressing upper urothelial carcinoma( (cT1-4N0-2M0, HER-2 immunohistochemistry (IHC) ≥ 1+); high risk disease (according to EAU Guidelines for UTUC); planning to receive radical nephroureterectomy (RNU), distal ureterectomy (DU) or ureteroscopic ablation (UA).
2. Male or female aged 18 years and above;
3. Expected survival time greater than 12 weeks;
4. An ECOG status score of 0-2;
5. Agree to provide specimens of blood, urine, and tissue examination (for detection of MRD, PD-L1 expression, HER2 expression, tumor mutation load, immunohistochemistry, DNA and RNA detection, etc.);

6. The level of organ function must meet the following requirements:

   • hematological indicators: absolute neutrophil count ≥ 1.5 × 10^9/L, platelet count ≥ 80 × 10^9/L, hemoglobin ≥ 6.0 g/dL (can be maintained by symptomatic treatment)
   • hepatic function: total bilirubin ≤ 1.5 times the upper limit of normal, and glutathione and glutamic oxalacetic transaminase ≤ 2.5 times the upper limit of normal;
   • renal function: GFR ≥ 15 ml/min;
   • Subjects voluntarily joined the study, signed an informed consent form, were compliant, and cooperated with the follow-up.

Exclusion Criteria:

1. Live attenuated vaccines, other than COVID-19 vaccine, received within 4 weeks prior to treatment or scheduled to be received during the study period
2. Active, known or suspected autoimmune disease;
3. Known history of primary immunodeficiency;
4. Known history of allogeneic organ transplantation and allogeneic hematopoietic stem cell transplantation
5. Female patients who are pregnant or breastfeeding
6. Untreated acute or chronic active hepatitis B or C infection. Patients who are receiving antiviral therapy with monitoring of viral copy number and are eligible for enrollment as determined by the physician on an individual patient basis;
7. Previous use of immunosuppressive drugs, excluding nasal spray and inhaled corticosteroids or physiologic doses of systemic steroids (i.e., no more than 10 mg/day prednisolone or equivalent pharmacologic physiologic doses of other corticosteroids), within 4 weeks prior to initiation of therapy
8. Known or suspected allergy history to tislelizumab and disitamab vedotin.
9. With a clear history of active tuberculosis.
10. Prior PD-1/PD-L1/CTLA-4 antibody or other immunotherapy;
11. Those who are participating in other clinical studies
12. Men of reproductive potential or women with the potential to become pregnant who are not using reliable contraception

13. Uncontrolled co-morbidities, including but not limited to

    • HIV-infected individuals (HIV-positive);
    • Severe infections that are active or poorly controlled clinically (including patients in the period of neocoronavirus infection)
    • Evidence of the presence of severe or uncontrolled systemic disease (e.g., severe psychiatric, neurological disease, epilepsy or dementia, unstable or uncompensated respiratory, cardiovascular, hepatic or renal disease, uncontrolled hypertension [i.e., defined as greater than or equal to CTCAE grade 2 hypertension despite medication]).