Biomarker-Enriched Kidney-Preserving Strategy With Disitamab Vedotin Plus Tislelizumab in HER2-Positive High-Risk Upper Tract Urothelial Carcinoma

A Prospective, Multicentre, Single-Arm Phase II Study Evaluating a Response-Adapted Kidney-Preserving Strategy Using Neoadjuvant Disitamab Vedotin Plus Tislelizumab in Patients With HER2-Positive High-Risk Upper Tract Urothelial Carcinoma (DISTINCT-II)

This is a prospective, multicentre, single-arm phase II study evaluating a response-adapted kidney-preserving strategy in patients with HER2-positive high-risk upper tract urothelial carcinoma (UTUC). Patients will receive neoadjuvant disitamab vedotin plus tislelizumab, followed by response-adapted local treatment, including kidney-sparing surgery or radical nephroureterectomy based on predefined criteria.

The primary objective is to assess whether this multimodal strategy can achieve clinically meaningful oncologic control while preserving renal function, as measured by 1-year kidney-intact event-free survival (KI-EFS). Secondary and exploratory objectives include evaluation of clinical response, survival outcomes, safety, renal function preservation, and longitudinal dynamics of circulating and urinary tumor DNA.

This is a prospective, multicentre, single-arm, phase II clinical trial designed to evaluate the efficacy and safety of a response-adapted kidney-preserving treatment strategy in patients with HER2-positive high-risk upper tract urothelial carcinoma (UTUC).

Eligible patients will receive neoadjuvant systemic therapy consisting of disitamab vedotin in combination with tislelizumab administered every 3 weeks for 2-4 cycles. Tumour response will be assessed after two cycles using radiographic evaluation and clinical assessment. Patients demonstrating clinical benefit will proceed to complete induction therapy, followed by comprehensive restaging including imaging, ureteroscopy with biopsy, and urine cytology.

Subsequent local treatment will be determined according to a predefined response-adapted algorithm. Patients meeting protocol-specified criteria will undergo kidney-sparing surgery (KSS), including segmental ureterectomy or endoscopic ablation depending on tumour location and anatomical feasibility. Patients not meeting criteria for KSS will undergo radical nephroureterectomy (RNU).

The primary objective of the study is to determine whether this multimodal strategy can achieve clinically meaningful oncologic control while preserving renal function in a biomarker-selected population.

In addition, longitudinal biospecimen collection will be conducted to evaluate the dynamics of urinary tumor DNA (utDNA) and circulating tumor DNA (ctDNA) as exploratory biomarkers of treatment response and minimal residual disease.

Inclusion Criteria:

• Age ≥18 years at the time of informed consent.
• Histologically confirmed upper tract urothelial carcinoma (UTUC) arising from the renal pelvis or ureter, based on ureteroscopic biopsy.
• High-risk UTUC, defined by at least one of the following features: Tumour size ≥2 cm; High-grade cytology or biopsy; Radiographic evidence of local invasion (≥cT2); Hydronephrosis; Multifocal disease
• Clinical stage cT1-T3, N0-N1, M0, based on radiographic assessment.
• N1 disease is permitted only if lymph nodes are considered resectable.
• HER2-positive disease, defined as immunohistochemistry (IHC) score of 1+，2+ or 3+ on tumour tissue, assessed according to predefined criteria.
• At least one measurable lesion according to RECIST version 1.1.
• ECOG performance status of 0-1
• Adequate organ function, including: Hematologic function; Hepatic function; Renal function (no strict upper/lower limit required);
• Patients must be considered potential candidates for a kidney-preserving treatment strategy, including: Absolute or relative indication for renal preservation (e.g., solitary kidney, baseline renal insufficiency), or Strong preference for kidney preservation after multidisciplinary discussion
• Ability to understand and willingness to sign written informed consent.

Exclusion Criteria:

• Evidence of distant metastatic disease (M1).
• Unresectable or bulky nodal disease (≥N2) not amenable to curative-intent surgery.
• Prior systemic therapy for urothelial carcinoma, including:Chemotherapy; Immunotherapy; HER2-targeted therapy.
• Prior radical nephroureterectomy for current disease.
• Active autoimmune disease requiring systemic treatment within the past 2 years.
• Current use of immunosuppressive medication, excluding physiologic doses of corticosteroids.
• Uncontrolled intercurrent illness, including but not limited to: Active infection requiring systemic therapy; Uncontrolled cardiovascular disease; Significant pulmonary disease
• Known active hepatitis B, hepatitis C, or HIV infection with uncontrolled viral replication.
• History of another malignancy within the past 5 years, except: Adequately treated basal cell carcinoma; Squamous cell skin cancer; In situ carcinoma.
• Pregnant or breastfeeding women.
• Any condition that, in the opinion of the investigator, would interfere with study participation or interpretation of results.