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.

Study Overview

• Status: Not yet recruiting
• Conditions: Upper Tract Urothelial Carcinoma
• Intervention / Treatment: Drug: RC48 Combined With Tislelizumab

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 50
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: jiwei huang; Phone Number: 8613651682825; Email: huangjiwei@renji.com

Study Locations

• China
  • Shanghai Municipality
    • Shanghai, Shanghai Municipality, China
      • Ethics Committee of Shanghai Renji Hospital
      • Contact: Qi Lu; Phone Number: +86021-68383364; Email: rjllb3364@163.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Neoadjuvant disitamab vedotin + tislelizumab followed by response-adapted surgery; Drug: Disitamab Vedotin Administered intravenously at 2.0 mg/kg every 3 weeks Drug: Tislelizumab Administered intravenously at 200 mg every 3 weeks Procedure: Surgery Kidney-sparing surgery (segmental ureterectomy or endoscopic ablation) or radical nephroureterectomy based on predefined criteria	Drug: RC48 Combined With Tislelizumab; In this trial, RC48 was scheduled to be administered at a dose of 2.0 mg/kg every 3 weeks, with the first dose on day 1 of the first cycle. Tislelizumab was administered at a dose of 200 mg every 3 weeks, with the first dose on day 1 of the first 21-day cycle. The drug is diluted with normal saline and administered by intravenous drip for one hour.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Kidney-Intact Event-Free Survival (KI-EFS) at 1 year	KI-EFS is defined as the time from study enrollment to the first occurrence of any of the following events: High-risk recurrence of upper tract urothelial carcinoma (local, regional, or distant), defined according to prespecified clinical or radiographic criteria Death from any cause Conversion to radical nephroureterectomy (RNU) for any reason Patients without an event will be censored at the date of last disease assessment.	From enrollment to 12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Kidney-Intact Event-Free Survival at 2 years	KI-EFS is defined as the time from study enrollment to the first occurrence of any of the following events: High-risk recurrence of upper tract urothelial carcinoma (local, regional, or distant), defined according to prespecified clinical or radiographic criteria Death from any cause Conversion to radical nephroureterectomy (RNU) for any reason Patients without an event will be censored at the date of last disease assessment.	Up to 24 months
Disease-Free Survival (DFS) Renal Function Preservation	Time from definitive local treatment (KSS or RNU) to upper tract recurrence or death from any cause. Isolated bladder recurrence will not be counted as an event.	Up to 24 months
Clinical Complete Response (cCR) Rate After Induction Therapy	Clinical complete response (cCR) was defined as concordant negative findings on cross-sectional imaging, ureteroscopy, urine cytology, and targeted biopsy according to predefined criteria	Immediately after Induction Therapy
Clinical Complete Response (cCR) Rate After Kidney-Sparing Surgery	Clinical complete response (cCR) was defined as concordant negative findings on cross-sectional imaging, ureteroscopy, urine cytology, and targeted biopsy according to predefined criteria	1 month after surgery
Renal Function Preservation	Change in estimated glomerular filtration rate (eGFR)	Up to 12 months
Safety and Tolerability	Incidence of treatment-related adverse events graded by CTCAE v5.0	Up to 90 days post-treatment

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
ctDNA/utDNA Dynamics	Detection tumor DNA (ctDNA/utDNA) using a fixed deep-sequencing panel.	Up to 12 months
HER2 expression level Exploratory Molecular Analyses	HER2 expression level pre-Induction Therapy	baseline, pre-Induction Therapy

Collaborators and Investigators

• Sponsor: RenJi Hospital
• Collaborators: Peking University First Hospital; West China Hospital; Tianjin Medical University Second Hospital

Study record dates

Study Major Dates

• Study Start (Estimated): May 31, 2026
• Primary Completion (Estimated): December 31, 2027
• Study Completion (Estimated): December 31, 2028

Study Registration Dates

• First Submitted: May 4, 2026
• First Submitted That Met QC Criteria: May 7, 2026
• First Posted (Actual): May 13, 2026

Study Record Updates

• Last Update Posted (Actual): May 13, 2026
• Last Update Submitted That Met QC Criteria: May 7, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Tislelizumab; upper tract urothelial carcinoma; Disitamab Vedotin; Kidney-Preserving
• Additional Relevant MeSH Terms: tislelizumab
• Other Study ID Numbers: DISTINCT II

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No