Perioperative Disitamab Vedotin/Tislelizumab Shows Promise in High-Risk UTUC

Combining the human epidermal growth factor receptor 2 (HER2)–targeted therapy disitamab vedotin (Aidixi; RC-48) plus the immune checkpoint inhibitor tislelizumab (Tevimbra) with kidney-sparing surgery demonstrated promising efficacy and safety in patients with high-risk upper tract urothelial carcinoma (UTUC), according to results from the phase 2 DISTINCT-1 trial (NCT05912816) presented at the 2025 European Society for Medical Oncology (ESMO) Congress.¹

At a median follow-up of 13 months (range, 12-26), the kidney-intact event-free survival (KI-EFS) rate at 1 year was 70% (n = 14/20), achieving a high rate of nephron preservation compared with radical nephroureterectomy (RNU).

Regarding secondary end points, the combination exhibited promising tumor downstaging with a 50% improvement in clinical complete response (cCR) within the 4 months between induction therapy completion and subsequent kidney-sparing surgery. Notably, treatment response was found to correlate with HER2 overexpression (2+/3+), suggesting the need for future biomarker validation studies. The agent also showed a favorable safety profile, with grade 3 or greater toxicities observed in 10% of patients.

“This organ-preservation paradigm challenges the historical dominance of radical nephroureterectomy and represents a promising therapeutic strategy for selected patients with high-risk UTUC,” concluded Jiwei Huang, Department of Urology, Ren Ji Hospital at Shanghai Jiao Tong University School of Medicine, China, in his mini oral session presentation.¹

Although RNU is the current standard of care for high-risk UTUC, emerging data suggest that this therapeutic approach has the potential to redefine the current treatment paradigm, thanks to its nephron preservation capabilities, which can optimize patient outcomes.

About Disitamab Vedotin

Disitamab vedotin is an antibody-drug conjugate targeting HER2 with a corresponding monoclonal antibody.² The agent was approved in China in June 2021 for the treatment of patients with HER2-overexpressing, locally advanced and metastatic gastric cancer and gastroesophageal junction adenocarcinoma who have received at least 2 lines of systemic chemotherapy.

The drug has also previously demonstrated promise in other genitourinary cancer studies in combination with other agents. These include toripalimab (Loqtorzi; NCT05302284) in HER2-positive advanced urothelial carcinoma and BCG in high-risk non–muscle invasive bladder cancer.

DISTINCT-1 Trial Design and Patient Characteristics

The ongoing phase 2 DISTINCT-1 trial is a prospective, single-arm study evaluating disitamab vedotin plus tislelizumab in patients with histologically confirmed high-risk UTUC.³

The study has enrolled 20 patients to receive a regimen of 2.0 mg/kg disitamab vedotin and 200 mg tislelizumab every 3 weeks for 4 cycles, with radiographic assessment at week 12. Depending on assessment results, eligible patients who met renal preservation criteria underwent kidney-sparing surgery such as ureteroscopic tumor ablation (n = 9) or segmental ureteral resection (n = 6), while all others underwent standard-of-care RNU (n = 5).

To be included, patients must have a HER2 expression immunohistochemistry (IHC) score of 0 to 3+. In terms of distribution, the majority of patients had a HER2 IHC score of 1+ (n = 7), followed by 3+ (n = 6), 0 (n = 4), and 2+ (n = 3).

The study’s primary end point is 1-year KI-EFS; secondary end points include cCR, pathological complete response, renal function preservation, time to RNU, overall survival, and safety.

DISCLOSURES: All authors declared no conflicts of interest.

REFERENCES

1. Huang J. Disitamab vedotin plus tislelizumab as nephron-sparing therapy for high-risk upper tract urothelial carcinoma: the phase II DISTINCT-I trial. Presented at: ESMO 2025 Congress; October 17-21, 2025; Berlin, Germany. Abstract 3071MO.

2. Deeks ED. Disitamab vedotin: first approval. Drugs. 2021;81(16):1929-1935. doi:10.1007/s40265-021-01614-x

3. Combination of RC48 and tislelizumab for renal preservation in high-risk UTUC patients. ClinicalTrials.gov. Updated May 14, 2025. Accessed November 4, 2025. https://clinicaltrials.gov/study/NCT05912816