Editor’s Note: Upper tract urothelial carcinoma (UTUC) is an aggressive malignancy of the urinary system, with high-risk subtypes associated with substantial risks of recurrence, metastasis, and poor prognosis. For decades, radical nephroureterectomy has been the standard treatment for high-risk UTUC. However, this approach inevitably leads to irreversible renal function impairment and may even result in renal failure, significantly compromising long-term quality of life. At the 2026 European Association of Urology Congress (EAU26), Professor Wei Xue and Professor Ji-Wei Huang from Renji Hospital, Shanghai Jiao Tong University School of Medicine, presented the DISTINCT-I study. This groundbreaking research explores a novel kidney-sparing strategy that integrates perioperative antibody–drug conjugate (ADC) therapy with immunotherapy and nephron-sparing surgery, providing original evidence from China for personalized management of high-risk UTUC.
Following the conference, Oncology Frontier – UroStream invited Professor Ji-Wei Huang to provide an in-depth interpretation of the study findings and their clinical significance.
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Question: The DISTINCT-I study challenges the conventional surgical paradigm for high-risk UTUC by proposing perioperative systemic therapy combined with nephron-sparing surgery. What clinical challenges does this study aim to address?
Professor Ji-Wei Huang: The DISTINCT-I study is a prospective, multicenter, open-label phase II clinical trial designed to evaluate the kidney-sparing efficacy of disitamab vedotin combined with tislelizumab in patients with high-risk UTUC.
The primary goal of this study is to address a longstanding clinical dilemma in the management of high-risk UTUC. Current treatment strategies are largely based on risk stratification. For low-risk UTUC, kidney-sparing approaches are recommended by both EAU and CSCO guidelines. However, for high-risk UTUC, radical nephroureterectomy remains the standard recommendation, with kidney-sparing options considered only in exceptional cases, such as patients with a solitary kidney, severe renal insufficiency, or those requiring dialysis after nephrectomy.
Radical surgery inevitably leads to irreversible renal function decline, which is a major clinical concern. The rationale behind the DISTINCT-I study is not merely to achieve tumor downstaging, but to maximize renal preservation while maintaining effective tumor control. By integrating systemic therapy with surgery, we aim to break the conventional paradigm that “high-risk disease mandates nephrectomy,” enabling a dual benefit of oncologic control and renal function preservation.
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Question: Based on current data, how effective is the combination of disitamab vedotin and tislelizumab as neoadjuvant therapy? What clinical potential does it demonstrate?
Professor Ji-Wei Huang: The combination of disitamab vedotin and tislelizumab has demonstrated excellent tumor shrinkage and antitumor activity in the neoadjuvant setting.
The key efficacy endpoint—objective response rate (ORR), defined as the proportion of patients achieving complete response (CR) or partial response (PR)—reached 70%–75%. This indicates that the majority of patients experienced significant tumor reduction, creating favorable conditions for subsequent precise kidney-sparing surgery.
The results following combined modality treatment are even more encouraging. After neoadjuvant therapy, 25% of patients achieved clinical complete response (cCR) at the first ureteroscopic evaluation, with no detectable tumor on imaging or endoscopy. Following surgical intervention, the overall cCR rate approached 75%.
Another key endpoint, 1-year kidney-intact event-free survival (KIEFS), reached 70%. This means that at one year, 70% of patients successfully preserved their kidney without recurrence, progression, or metastasis—demonstrating both strong oncologic control and effective organ preservation.
Approximately 30% of patients ultimately underwent radical surgery due to insufficient response, but the overall trend clearly indicates substantial clinical benefit for the majority.
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Question: Does perioperative ADC–immunotherapy impact surgical difficulty, complication risk, or postoperative recovery?
Professor Ji-Wei Huang: Based on the DISTINCT-I data, neoadjuvant therapy had minimal impact on subsequent surgery.
Two main types of nephron-sparing procedures were performed: endoscopic laser ablation and segmental ureterectomy. In both cases, neoadjuvant treatment did not increase surgical difficulty or negatively affect postoperative recovery.
In terms of safety, the combination regimen was well tolerated. The incidence of grade ≥3 treatment-related adverse events was approximately 10%, and severe adverse events were manageable. Importantly, the treatment did not compromise surgical feasibility or patient recovery, and it did not impose additional technical challenges for surgeons. Overall, the approach is clinically feasible and safe.
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Question: If validated, how might this strategy reshape the treatment pathway for high-risk UTUC?
Professor Ji-Wei Huang: The DISTINCT-I study is currently in the phase II exploratory stage, with 20 patients enrolled so far. Nevertheless, it has already opened a new therapeutic pathway for selected high-risk UTUC patients.
Most patients treated with this kidney-sparing approach maintained normal postoperative renal function, achieving a dual breakthrough in tumor control and renal preservation.
Moving forward, we plan to expand the sample size and conduct multicenter validation to generate higher-level evidence. If long-term safety and efficacy are confirmed, this strategy has the potential to reshape clinical guidelines and fundamentally challenge the traditional paradigm of radical nephrectomy for high-risk UTUC.
This shift could transform kidney-sparing treatment from an exceptional option into a viable standard approach. More importantly, it would significantly reduce the risk of postoperative renal failure, improve long-term quality of life, and minimize complications related to renal dysfunction.
Ultimately, this represents a transition in UTUC management—from “removing the kidney to control cancer” to “preserving the kidney while effectively treating cancer”—offering a more precise and patient-centered therapeutic strategy for UTUC worldwide.
Professor Ji-Wei Huang
